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How many of the authors who publish in Cell Stem Cell dream that their work will eventually wind up in the clinic? Probably quite a few. In the 10 years since its launch, Cell Stem Cell has featured many innovative discoveries, and several of them have gone on to become the seeds of burgeoning biotechnology companies with therapeutic aspirations. Two scientists who have seen that happen are Benjamin Reubinoff (Figure 1) and Derrick Rossi (Figure 2), both of whom led the clinical translation of technologies that made their public debut in Cell Stem Cell.

This i3 is a data visualization based on the Cell Stem Cell tenth anniversary theme of lineage tracing. Using Scopus citations of Cell Stem Cell research papers, it illustrates both the evolution of the stem cell field and the way new research builds on work that came before. Users can navigate the graphic and the represented papers by stem cell type, organism, and author online at cell.com/i3/cell-stem-cell/lineage. To view this SnapShot, open or download the PDF.

The nature of compensation for women who donate eggs (oocytes) for research remains a contentious issue internationally. This position paper lays out the arguments for, and discusses the arrangements in which, a modest payment might be ethically justifiable.

The recent Court of Justice of the European Union (2011)xSee all ReferencesCourt of Justice of the European Union (2011) opinion in Brustle v. Greenpeace caught the attention of the California Institute for Regenerative Medicine (CIRM) and many others as a result of its severe restriction on the patentability of inventions arising from embryonic-stem-cell-related research. Strong criticism of the decision immediately arose in some quarters, including dire predictions that the ruling marked the end of human embryonic stem cell (hESC) research in Europe and, ultimately, that Europe would not have access to resulting therapies (Naik, 2011xSee all ReferencesNaik, 2011). At CIRM we fund academic and commercial scientists conducting stem cell research ranging from basic science through to early clinical work, and a significant proportion of our funded projects involve hESCs. We appreciate that patent protection can be an important incentive for investment, and that it also often promotes innovation as it allows innovators time and a mechanism to recoup their outlay (Rai et al., 2010xSee all ReferencesRai et al., 2010). Our view is that the impact of the recent Court ruling on stem cell research and regenerative medicine will be significant but varied. In some instances, the ruling may deter European hESC research, in others such research may nonetheless continue or even increase; in still others, no impact may occur.In the area of basic or foundational hESC research, for example, we would not expect a significant impact from the Court ruling provided scientists expect that there will be continued funding of such research by government and not-for-profit entities. We would not expect that a diminished ability to obtain patent protection for basic research inventions would materially decrease research funding from these sources. Government funders tend to be less profit-driven than commercial funders. Moreover, hESCs presently remain the “gold standard” for regenerative medicine research (Smith et al., 2009xSmith, K.P., Luong, M.X., and Stein, G.S. J. Cell. Physiol. 2009; 220: 21–29Crossref | PubMed | Scopus (70)See all References, Fung and Kerridge, 2011xFung, R.K. and Kerridge, I.H. Bioethics. 2011; 2011: 4See all References). We believe scientists conducting basic research will be reluctant to focus exclusively on adult stem cells or even induced pluripotent stem cells (iPSCs) given the unique advantages offered by hESCs.With respect to translational hESC research, the situation is more complicated. At this stage of research and development, profit-driven biotechnology and pharmaceutical companies are more actively involved. To the extent that the lack of patent protection following the Court ruling decreases the profit available (e.g., because patented inventions cannot be licensed and injunctions cannot be obtained to protect hESC patented inventions), biotechnology and pharmaceutical companies may be less motivated to invest in European hESC research. That effect may be even more dramatic for startup companies. A strong patent portfolio traditionally has been a prerequisite for attracting venture capital in the life sciences field. As reported by a U.S Department of Commerce white paper, “In a large-scale survey conducted in 2008, 76% of startup managers reported that VC investors consider patents important to funding decisions.” (Rai et al., 2010xSee all ReferencesRai et al., 2010.)On the other hand, we would not predict a complete dearth of European commercial investment in the hESC sector in the EU for several reasons. First, companies can still protect some of their work as traditional trade secrets. Second, as is often said of biologics, “The product is the process.” EU regulators will likely require that any company wishing to compete would have to incur the large expense of preclinical and clinical trials using their particular stem-cell-based therapy (Tam, 2010xTam, J.W.Y. Georgetown Law J. 2010; 98: 535–536See all ReferencesTam, 2010). Third, to varying degrees throughout Europe, the “Bolar Exemption” (European Union, 2004xSee all ReferencesEuropean Union, 2004) limited patent protection for certain types of research at this phase even before the Court ruling. Finally, the effect of the Court ruling on EU companies will vary depending on their specific circumstances. Companies that would have faced a freedom to operate problem because of hESC patents held by others may now be more likely to start, or continue, hESC research programs because the Court's ruling renders such patents unenforceable. Companies working on the “improvement” of hESC related-technologies, for instance, which would have faced patent infringement litigation or would have had to pay royalties, may find themselves more incentivized to perform hESC research in the EU following the Court's ruling. By contrast, companies holding foundational hESC inventions might be incentivized to work in jurisdictions that offer patent protection for hESC inventions (e.g., the USA).Despite the Court ruling we believe that sponsors of hESC-based therapies will locate trials in Europe for a number of reasons. Companies developing hESC therapies will ultimately desire to sell their products on the European market. The EMA may require data from European clinical trials before it approves of any future hESC-derived therapy. Moreover, recent studies suggest that over 50% of products headed for FDA approval are in clinical trials that involve foreign study sites (Levinson, 2010xSee all ReferencesLevinson, 2010).Finally the possibility that some companies could be attracted to Europe because of this decision cannot be discounted. Although the Court ruling does not directly impact the patentability of hESC inventions in the U.S., it will have a ripple effect there. American companies facing a freedom to operate problem because of U.S. patents held by others may now reconsider their business plans. Moving their research operations to Europe becomes a more attractive option because the EU counterparts of those patents are no longer enforceable. These companies will balance the benefit afforded by the new EU patent landscape against the protection that the Hatch Waxman Act provides for certain research activities in the U.S. and the significant costs of moving an already established and ongoing research operation. A cost differential that disfavors the U.S. as an alternative to the EU may incentivize companies to consider moving their trials and preclinical efforts to places such as India or China.As Yogi Berra once said, “It's tough to make predictions, especially about the future.” Everyone will need to wait and see how various stakeholders in the research community actually respond to the Court's ruling. Nevertheless, we are confident that the reaction will be dependent on many individual variables. As a result, we expect that some of the currently critical hESC research and development in the EU will continue to flourish.

Augenlicht and colleagues raise concerns about the impact of diet on stem cell regulation and call for more careful reporting on dietary conditions used in mouse studies on this topic. We agree that specific conditions for animal housing and care should be reported, and we encourage this in our STAR Methods guidelines for all papers. However, moving forward we will require more detailed reporting on dietary information for mouse studies where the main scientific focus concerns stem cell functions, and especially metabolism. This will include vendor information, stock number, and feeding schedules within the STAR Methods section and Experimental Models section of the Key Resource Table. We hope this will provide further reproducibility, robustness, and clarity in the papers we publish.

The response of adipose progenitors to metabolic states is a crucial, but poorly understood, determinant of metabolic health. The back-to-back papers by Joffin et al. (2021) and Shao et al. (2021) in this issue of Cell Stem Cell reveal how adipose-tissue-resident PDGFRβ+precursor cell fate is regulated by mitochondrial bioenergetic state and how such processes go wrong in obesity.

Disease modeling with human iPSCs has come a long way since it first began almost 10 years ago. Many of us can probably remember the time when just making an iPSC line from a patient with a recognized disease was a notable achievement. It didn’t take long, however, before expectations rose and we moved quickly past recapitulating relevant phenotypes to the situation today in which most studies aim to either teach us something substantial that we didn’t know before about a given disease or show a path to potential therapies (or, hopefully, both). Our understanding of line-to-line variation and controls improved, too, and as it became clear that simple comparison to a control line is not adequate, standards of either multiple lines or, when feasible, genetic correction became the norm.Many of the papers that make clear-cut progress toward understanding a disease using human iPSCs do so on the basis of a single characterized genetic mutation. There are understandable reasons why this is the case—it’s considerably easier to focus in on a relevant cell type and to make sure the controls are appropriate with a clear idea of the mutation that underlies the disease. However, some of the most prevalent and devastating diseases that our society faces don’t have that kind of readily identifiable underlying genetic basis, and instead are multifaceted and complex. Although there have, of course, been valuable studies, in general these diseases have proven markedly more difficult to model in a meaningful way with iPSCs.GWAS came at this problem from a different angle—using genomic technology to understand the genetic variation associated with different disease phenotypes to give us information about their association and basis. And we found that there is a lot of variation! The next challenge, however, is parsing which of the identified variants are functionally meaningful. We do have some tools to do that—genome editing technology has helped significantly—but at least with current approaches this analysis is time consuming and expensive, and not really feasible to apply at scale.This was the overall challenge that the NextGen consortium aimed to address—to use iPSC technology at a sufficiently large scale to allow robust analysis of the genetic basis of physiological variation. As Curtis Warren, Cashell Jacquish, and Chad Cowan outline in their overview piece, this consortium represents a joining together of nine hub groups across the United States, plus their collaborators, with the overall goal of generating a large collection of iPSC lines that would form a resource for investigation of physiology and disease. The different groups focus on distinct areas of investigation within the overall remit of the NHLBI (National Heart, Lung, and Blood Institute) and relevant diseases. We are very happy to now present the first coordinated wave of output of this consortium’s efforts, with seven papers in Cell Stem Cell, three in Stem Cell Reports, and one in EBioMedicine. We hope you will enjoy reading these papers and exploring them using our dedicated interactive web portal (http://www.cell.com/consortium/NextGen).The papers in this feature illustrate a broad range of the types of analyses that researchers can perform after putting together collections of iPSC lines. A number of the studies look at analysis of the iPSCs themselves, and give us an indication of how we can learn about the underlying genetic (or epigenetic) basis of variation through mining of information that comes from this type of large-scale resource. Some move further into disease modeling and use cells differentiated along specific lineages to understand the basis of variation in a range of disease contexts, based on existing knowledge and using that as a springboard to investigate the basis of phenotypic disease. Others take a more targeted approach to show how cells from this type of resource can be used for screening and drug discovery, with a particular focus on cardiovascular disease. Some studies also describe technological advances that were important for this project and have broader applicability. Taken together, these papers show how this consortium-based approach can be applied going forward to develop the initial analyses and move further toward the overall scientific and, ultimately, medical goals.NextGen is by no means the only project underway to gather a substantial resource of iPSC lines as an investigational tool. For example, there are two such efforts in Europe, the HipSci initiative in the UK and the EU project StemBANCC. We can presumably anticipate seeing further publications and analyses come from those and other efforts as the characterization unfolds. Although all of these projects have different remits, their underlying premise is similar—that by putting together large banks of iPSCs, we will be able to use them more effectively to help understand phenotypic disease. Projects like these also face similar challenges related to covering the costs of characterization, storage, and distribution of the lines to the research community. The NextGen investigators have addressed this latter issue by arranging to deposit their lines with WiCell and therefore make them available to the community via standard WiCell distribution policies.Beyond the emerging insights into the genetic basics of physiology and disease, what have we learned more broadly from this consortium so far? One not entirely surprising lesson is that this type of study is time consuming and expensive. The NHLBI NextGen consortium members are over 5 years into their project and yet still at an early stage of mining the resource that they have generated. With science funding increasingly under threat, especially in the United States, this project is a timely reminder that pioneering approaches to move our understanding of human disease forward often require considerable time and resources to both be effective and realize their full potential. A second lesson, I think, is that while iPSCs show considerable promise as a complement to GWAS in understanding the functional basis of variation, there is still quite a lot of work to do in terms of standardization of protocols and understanding of best practices to make this type of approach a reliable discovery tool. The potential is there, though, and it’s an exciting prospect to consider. Third, there are a variety of ways we can think about using this type of resource to further our underlying goal of using iPSC technology to develop better understanding of disease and more targeted therapeutic approaches. Some of them are illustrated here by this collection of papers; some are still to come.I hope that reading through these papers, and the associated commentary, will inspire some of you in our broader readership to apply these lessons as well, either to your existing projects or to new ones, and perhaps even to take advantage of the cellular and genomic resources that the project already provides. Moving forward, I also hope that these studies and others like them, when combined with current and future advances in technology and analysis tools, will indeed make a powerful contribution to helping us understand the ways in which we differ and how those differences contribute to disease.

The molecular basis dictating specificity of Zika virus infection in neural stem cells (NSCs) remains elusive. Two recent papers in Cell Stem Cell (Zhu et al., 2020) and Cell Reports (Wang et al., 2020) identify integrin αvβ5 as an internalization factor that increases susceptibility in NSCs and glioblastoma stem cells.

Summary Two recent papers in Cell Stem Cell and Nature Medicine ( Yao et al. [2019] and Ganesh et al. [2019] ) demonstrate the successful use of rectal cancer patient-derived organoids to predict patient responses to neoadjuvant chemoradiation therapy, paving the way toward a new paradigm for precision medicine.

In mammals, both parents make unique contributions to the offspring and maternal and paternal genomes are required for development. Two recent papers in Cell Stem Cell (Leng et al., 2019; Sagi et al., 2019) study uniparental embryos and uniparental embryonic stem cells to interrogate parent-of-origin effects in human embryogenesis.

Previous work demonstrating the existence of intermediate pluripotency states in post-implantation embryos had ignited a debate on whether "formative" pluripotency can be stabilized in pluripotent stem cell (PSC) lines. In this issue of Cell Stem Cell, two papers show that polarized epithelial and germ cell-competent formative PSCs can be maintained in modified activin-dependent conditions.

Think back to where you were and what you were doing 10 years ago. Maybe you were in graduate school, maybe even high school, or perhaps you had just started your first lab and were working out how to transition from being a postdoc to being a leader of a scientific team. It’s likely that a lot has changed for you in the intervening time. For us at Cell Stem Cell the same is also true. Ten years ago during May (the time of writing both this editorial and the very first one), we were working frantically to finalize the content for our launch issue. For editors, especially, but also for the entire team, launching a new journal is an exciting but very stressful experience. We are a little frantic again this year, too, putting together all of the materials and plans for this tenth anniversary issue, but this time against the backdrop of a wealth of material to look back on and digest.When we started talking within the editorial team about a theme to use for our tenth anniversary, we focused on thinking how we could best showcase the great science we’ve had the pleasure to publish, and the ways in which all of these important contributions have helped to build and advance the field. Working from an idea that came from a colleague (credit where credit’s due!), we were inspired by the concept of “Lineage Tracing,” based on both the obvious connection to the stem cell field and the way new scientific discoveries build on those that came before. We took this theme and ran with it, and we have put together a variety of articles from a range of different contributors that we hope will showcase how the work that we’ve published has fit into and helped advance the field overall.We have four overall article types in our special journal feature, each of which highlights the “lineage” associated with some of our most widely appreciated papers in a distinct way. We based our selection of papers on a combination of citation information, download data, and, particularly for the more recent examples, collaboration with PLUM Analytics to look at readership and sharing. We then organized the papers into topical themes that we felt represent some of the key overall interest areas that have developed over the past 10 years, and we selected an approach for highlighting how the Cell Stem Cell studies fit in. For a series of Voices articles, we chose three papers from each of five topical areas—cancer stem cells, disease modeling, aging, epigenetics, and single-cell technology—and asked a scientist who cited each paper to write about how the work contributed to the development of their thinking. For three topics—organoid technology, reprogramming, and genome editing—we asked one author each from three of our most prominent papers to contribute to a Q&A discussing the current questions and future directions in these rapidly moving areas. Because we understand that many stem cell researchers are motivated by the potential for their work to ultimately help patients, we have also included a Profile that illustrates this type of trajectory by focusing on two Cell Stem Cell papers that formed the underlying basis of biotech startup journeys leading to clinical trials using modified RNA technology and cell transplantation. Lastly, to go behind the scenes for one of our most exciting recent papers and show just how much dedication and coordination went into it on all sides, we asked Hongjun Song, Guo-Li Ming, and Hengli Teng to put together a Backstory article about the work that led up to their 2016 paper on Zika infection of neural progenitors. This paper formed one of the major underpinnings of the subsequent CDC declaration about the link between Zika and microcephaly. We have two different forms of this Backstory article, one in the standard journal format that is relatively conventional, and then an enhanced, more immersive version online with additional images and embedded videos. This approach is a new experiment for us, so we’d love to hear from you if you enjoy it and would like to see more. You can pick up a print copy of this special issue at our booth, #719, at the ISSCR 2017 Annual Meeting, along with a copy of our latest “Best Of” edition in your delegate bag. There will also be a digital edition of the entire issue on our dedicated anniversary website, which will go live before the ISSCR meeting.Returning to online presentation, we would also like to highlight the interactive data visualization, or i3, that will form the cornerstone of our anniversary website, our cover image, and the theme for our “Pin to Win” badges at ISSCR 2017. The i3 is also part of the lineage tracing theme, and the underlying inspiration for the approach that we took in fact comes from representations of clonal analysis of hematopoiesis. The data being represented are Scopus citations of Cell Stem Cell papers year by year since launch. We chose to focus on research papers, and we then categorized them by stem cell type and organism. Using those parameters, you will be able to navigate around our online tool to look at the citation contribution of specific areas and stem cell types over time as the journal and field has developed, and even at specific authors or papers. Cell Stem Cell is of course just one journal of the many that publish stem cell papers, and citations are also only one measure of field size and interest. However, we often hear feedback that Cell Stem Cell is a “must read” journal for the stem cell community and that it mirrors the way the field is changing and evolving. So, we’d like to think that in addition to chronicling the evolution of Cell Stem Cell itself, this visualization also gives a window into the ways that the stem cell field has developed over time. We’re already seeing some surprising things from navigating around the tool as we set it up and we hope that you will be able to help us figure them out!Many, many people deserve thanks for their contributions to the success of Cell Stem Cell and the role the journal plays in the stem cell community. Within Cell Press we’ve had a wonderful team of scientific editors, assistants, production editors, marketing managers, and designers. Beyond that we of course owe a tremendous debt of gratitude to all of the authors who chose to send their work to us or to write review articles, and to the reviewers who gave us invaluable feedback that helped us both select which articles we choose to publish and improve the quality of the ones that do appear. Our advisory editorial board members have been a fantastic source of support and input as well, and they have helped us shape the journal and its contribution to the field. We have also very much appreciated our ongoing partnership with the ISSCR and their support of Cell Stem Cell as an affiliated journal. More proximally, we’d like to thank Thermo Fisher for their support of our anniversary website and overall feature.The stem cell field has changed a lot in the past decade, and although 10 years ago the reprogramming field was already starting to take off, many other areas that are important now, such as organoid technology, CRISPR/Cas9 genome editing, and single-cell sequencing analytics, weren’t on the radar or even in existence. If history is anything to go by, we can expect many more new developments and exciting changes in the future as stem cell research continues to grow and evolve. Here at Cell Stem Cell we all very much look forward to seeing what the next 10 years will bring.

Two recent papers in Cell Stem Cell by Soliman et al. (2020) and Scott et al. (2019) explore the contributions of mesenchymal progenitor cells to fibrosis in heart and skeletal muscle. They find tissue-dependent roles for a subpopulation of mesenchymal progenitors expressing Hic1 with varied differentiation capacities and pathophysiologic contributions.

Hair follicle stem cells may themselves regulate the niche environment for hair follicle regrowth. A recent Science paper from Elaine Fuchs and colleagues (Gur-Cohen et al., 2019) suggests that this involves regulation of the lymphatic system and may have implications in understanding tissue regeneration.

Two recent papers (one by Román-Rodríguez et al., 2019 in this issue of Cell Stem Cell) highlight how the power of biological selection on hematopoietic stem cell fitness can facilitate gene therapies for Fanconi Anemia. A clinical trial using lentiviral gene replacement and a proof-of-concept targeted genome editing study show robust engraftment and expansion of gene-corrected cells at levels reaching therapeutic relevance.

This SnapShot highlights the breadth of organs that have been modeled by organoid technology across Cell Press and its partner journals. Editorially curated publications selected for this SnapShot, and listed in a related interactive data visualization, have made significant advancements in organoid technology. For each organ, you can view the cumulative number of relevant organoid papers through the end of 2018. To view this SnapShot, open or download the PDF.

Summary Previous analysis of RNA sequencing (RNA-seq) data from human naive pluripotent stem cells reported multiple point “mutations” in cancer-related genes and implicated selective culture conditions. We observed, however, that those mutations were only present in co-cultures with mouse feeder cells. Inspection of reads containing the polymorphisms revealed complete identity to the mouse reference genome. After we filtered reads to remove sequences of mouse origin, the actual incidence of oncogenic polymorphisms arising in naive pluripotent stem cells is close to zero., Highlights • Culture conditions for naive stem cells do not select for cancer-related mutations • Contaminating sequences in RNA-seq data can be misidentified as point mutations • Filtering to remove mouse sequences eliminates most mutations • Remaining mutations in naive stem cells are carried over from primed stem cells, Acquisition of pathogenic mutations during in vitro propagation is a concern for applications of pluripotent stem cells. In this paper, Stirparo and colleagues show that detection of multiple mutations in naïve stem cells by RNA-seq analysis is due to contamination with mouse sequences. The actual cancer mutation incidence is low.

Gupta and colleagues highlight recent work, including their own, that suggested based on lineage tracing that mural cells are adipogenic, contrasting with the conclusions of a recent Cell Stem Cell paper.

This year, we are delighted to welcome the stem cell community to the annual ISSCR meeting in our “home town” of Boston. The ISSCR last chose Boston as a venue for its meeting 9 years ago, when the society and the meeting were considerably smaller, so we are very excited to see the meeting back here now that it has grown into such an impressive and multifaceted event. In the registration bag this year, instead of a copy of our June issue, meeting attendees will find a variation on the popular “Best Of” reprint collection series focusing on Cell Stem Cell articles published in 2012. This collection will also be available in an extended version as an online digital edition, so even if you are not coming to Boston for the meeting this year, you will be able to browse and enjoy the full collection at your leisure.For the review feature in our June issue, we have chosen to focus on the application of stem cells to therapeutic discovery through a series of Perspectives from leaders in the field in the areas of disease modeling and application. In one of these articles, Florian Merkle and Kevin Eggan discuss disease modeling using human iPSCs, and in a second, Dinesh Puppala and Sandra Engle cover the integration of human pluripotent stem cells into drug discovery programs. The third article, from Fred Gage and colleagues, covers the application of iPSCs to devising treatments for neurological disease, while the fourth, from Jessica Garbern and Richard Lee, looks at cardiac regeneration. Together, these articles give a timely update on some of the key areas of development for the stem cell field. They also form a prelude for other events scheduled for later this year, particularly a Cell Symposium on “Using Stem Cells to Model and Treat Human Disease,” being held in Los Angeles in November. Between now and the Symposium, there will be two focused webinars on related topics, so look out for news about these soon as well. To complement this review feature, for our cover we have chosen a painting entitled “Popred” by the artist Sarah Ezekiel, who is connected to the theme of the issue through MND/ALS, one of the diseases that forms a focus of discovery efforts.This year also sees some important developments for Cell Stem Cell and the ISSCR. One of the most significant is that we are excited to welcome a new journal into the stem cell fold: Stem Cell Reports, which launches in June and at the ISSCR meeting. You will find a copy of the inaugural issue of this journal in your registration bag along with the Cell Stem Cell “Best Of” collection. Stem Cell Reports is a new journal owned and run by the ISSCR and published by Cell Press, and it has a distinguished editorial team led by Christine Mummery. With its open-access model and focus on concise papers, Stem Cell Reports will be a valuable complement to Cell Stem Cell for the publication of important studies in the stem cell field. The scope, focus, and emphasis of Cell Stem Cell will not change: it will continue to be owned and run by Cell Press and affiliated with the ISSCR. However, the ISSCR pages and articles that previously appeared in Cell Stem Cell have now instead moved to Stem Cell Reports, along with oversight by the ISSCR Scientific Director, Heather Rooke.At Cell Stem Cell, earlier this year we were very happy to add a new member to our in-house editorial team, Jonathan Saxe, who joined us from a postdoctoral position in Haifan Lin’s group at Yale University. This month, we have also made some changes to the organization and membership of our advisory editorial board. In keeping with our updated relationship with the ISSCR, the Cell Stem Cell ISSCR advisory board members (Arnold Kriegstein, Haifan Lin, Toshio Suda, and Leonard Zon) have transferred over to become part of the main Cell Stem Cell editorial board. They are joined on the board by 16 additional new members, all of whom we are delighted to welcome to our team: Iannis Aifantis, Caroline Alexander, Hans Clevers, Hongkui Deng, Elaine Dzierzak, Richard Gilbertson, Konrad Hochedlinger, Craig Jordan, Hanna Mikkola, Huck Hui Ng, Stuart Orkin, Emmanuelle Passegue, Kathrin Plath, Yoshiki Sasai, Deepak Srivastava, and Mervin Yoder. At the same time, we are bidding a fond farewell to Thomas Laux, Angela McNab, and Shinichi Nishikawa, and we thank them for all of their efforts and contributions over the past 6 years. Several of our new editorial board members have contributed to a Voices article in this issue, in which they prepared a short piece about a 2012 Cell Stem Cell paper that they particularly enjoyed. I hope you in turn will enjoy reading these diverse perspectives on a broad range of studies, and that doing so will perhaps encourage you to go back and revisit some of the papers with a fresh eye. The topics covered in these highlights range from chromatin regulation in ESCs (Brookes et al., 2012xBrookes, E., de Santiago, I., Hebenstreit, D., Morris, K.J., Carroll, T., Xie, S.Q., Stock, J.K., Heidemann, M., Eick, D., Nozaki, N. et al. Cell Stem Cell. 2012; 10: 157–170Abstract | Full Text | Full Text PDF | PubMed | Scopus (82)See all ReferencesBrookes et al., 2012) through morphogenesis (Nakano et al., 2012xNakano, T., Ando, S., Takata, N., Kawada, M., Muguruma, K., Sekiguchi, K., Saito, K., Yonemura, S., Eiraku, M., and Sasai, Y. Cell Stem Cell. 2012; 10: 771–785Abstract | Full Text | Full Text PDF | PubMed | Scopus (210)See all ReferencesNakano et al., 2012) and lineage contribution (van Amerongen et al., 2012xvan Amerongen, R., Bowman, A.N., and Nusse, R. Cell Stem Cell. 2012; 11: 387–400Abstract | Full Text | Full Text PDF | PubMed | Scopus (118)See all Referencesvan Amerongen et al., 2012) to the ways in which stem cell regulation contributes to hematopoietic disease and cancer (Ceccaldi et al., 2012xCeccaldi, R., Parmar, K., Mouly, E., Delord, M., Kim, J.M., Regairaz, M., Pla, M., Vasquez, N., Zhang, Q.S., Pondarre, C. et al. Cell Stem Cell. 2012; 11: 36–49Abstract | Full Text | Full Text PDF | PubMed | Scopus (73)See all ReferencesCeccaldi et al., 2012; Magee et al., 2012xMagee, J.A., Ikenoue, T., Nakada, D., Lee, J.Y., Guan, K.L., and Morrison, S.J. Cell Stem Cell. 2012; 11: 415–428Abstract | Full Text | Full Text PDF | PubMed | Scopus (58)See all ReferencesMagee et al., 2012; Kalaitzidis et al., 2012xKalaitzidis, D., Sykes, S.M., Wang, Z., Punt, N., Tang, Y., Ragu, C., Sinha, A.U., Lane, S.W., Souza, A.L., Clish, C.B. et al. Cell Stem Cell. 2012; 11: 429–439Abstract | Full Text | Full Text PDF | PubMed | Scopus (59)See all ReferencesKalaitzidis et al., 2012). This Voices article is also included in the “Best Of” collection as a complement to the selection of articles based on downloads, and all of the papers featured in the selections are included in the extended online edition.If you are coming to Boston for the 2013 ISSCR meeting, we hope you will have time to visit our booth in the exhibit hall (#627). You will be able to pick up a free copy of this June issue, an extra “Best Of” if you’d like one, plus many of the other journals in the Cell Press family, including Cell Reports, our broad scope open-access journal launched last year. You could also learn about our other planned activities, including the conference and webinars mentioned above, and meet editors from Cell Stem Cell and other Cell Press journals to get an inside look at the publishing process. We will have information about the new Cell Press full text and Snapshot iPad apps, and you will have a chance to try them out at the booth. At Cell Stem Cell, we have continued to expand our social media presence, and before and during the meeting we will post news and information via Twitter (@CellStemCell or https://twitter.com/cellstemcell) and Facebook (https://www.facebook.com/cellstemcell). Don’t forget to enter the Cell Press “Boston Experience” competition by sending us a photo of yourself at a Boston landmark (and yes, the convention center does count!) via social media or email for your chance to win an iPad Mini or a scarf featuring “Popred,” the painting that graces the cover of this issue and, if you are fortunate enough to win, could soon be gracing you.In closing, and unfortunately on a more somber note, I would like to take this opportunity to pay tribute to Dr. Christa Muller-Sieburg, who sadly passed away earlier this year. Dr. Muller-Sieburg made many pioneering contributions to studies of HSCs, and particularly, as Connie Eaves and colleagues outlined in their Perspective article last year (Copley et al., 2012xCopley, M.R., Beer, P.A., and Eaves, C.J. Cell Stem Cell. 2012; 10: 690–697Abstract | Full Text | Full Text PDF | PubMed | Scopus (69)See all ReferencesCopley et al., 2012), to initial investigations of HSC heterogeneity that formed a foundation for current and future analyses. Her influence will no doubt be evident in HSC work presented at this year’s ISSCR meeting. I am sure I speak for the entire Cell Stem Cell team when I say that we look forward to sharing all of our stem cell experiences with you, at this meeting and beyond. As always, we welcome your feedback and input about the journal and the field overall.

It is hard to believe that the International Society for Stem Cell Research (ISSCR) is 10 years old, and that coincident with this is the fifth-year anniversary of Cell Stem Cell. Having participated in the creation and development of the society and the journal, the success of both has made me appreciate my matchmaking skills.When I founded the ISSCR, I was responding to a call from stem cell researchers to bring investigators together and form a community. The annual meeting served this purpose from its fledgling initial meeting in Washington, D.C., with about 550 people, to this year's meeting in Yokohama with about 4,000 individuals. There is a tremendous need for scientific interactions, and the community is vibrant and operates at a very high level.One of my initial thoughts for the ISSCR was that it needed a journal. A key driver was the stem cell research community's call for a dedicated forum to publish stem cell research and to discuss issues faced by the field—a high-quality and high-visibility journal to give the field credibility and capture the highest profile papers. In this endeavor, after a long negotiation, we affiliated with Cell Press to start Cell Stem Cell. I am pleased to have been integral in the discussions that resulted in the strong partnership between ISSCR and Cell Stem Cell.Cell Stem Cell has accomplished all of its goals admirably from its initiation, and Debbie Sweet has been a pioneering editor with great vision. With a 2010 impact factor of 25.9, it is clearly a high-end journal that publishes impactful papers. The reviews are fantastic and comprehensive. The ISSCR section of the journal is one of its unique features, presenting key undertakings of the society such as committee activities, task force initiatives, and professional guidance. The ISSCR meeting reviews are greatly welcomed.When Cell Stem Cell needed to become nimble, decisions were made to create new sections that reflect the progress in the field. I am particularly interested in the Clinical Progress section that allows data to be put into the journal that bridges basic research and clinical application. There is also a diversity of articles in Cell Stem Cell. This includes the tremendous literature on induced pluripotent stem cells (a field in itself and one that will greatly contribute to science and medicine in the future). The journal, in short, has been a great success, has had wonderful interactions with the ISSCR, and has moved the field forward in a palpable and self-renewing manner.The ISSCR has tackled many issues in its first 10 years. One of the most important aspects was mentoring. It is clear that young investigators have found a home in the ISSCR. The society has a special committee for junior investigators and there is a formal mentoring session at each annual meeting. I remember the time period before induced pluripotent stem cells were available when young investigators were unclear if any funding would be available for human pluripotent stem cell studies on the only available technology, human embryonic stem cells. It was hard to have the courage to start a lab working on pluripotent cells, and now with many advances, the field is vibrant with many junior investigators.The ISSCR has highlighted ethical questions in various ways, including having Laurie Zoloth make a presidential session speech at one of the annual meetings. The society has also made a strong effort to reach out to patient advocates and policy-makers, and few will forget the powerful speech that one such advocate, Charles Sabine, gave at the 2011 meeting. The ethics of working with stem cells were brought to the forefront because of a Presidential executive order. Many of us from the leadership of the ISSCR have appeared on radio, on TV, and in other contexts to inform and educate the public about stem cell research.The stem cell field has also had to deal with some difficult issues over the past 10 years. We found out that human cloning was not in fact performed in Korea despite prior publication. In Europe, a landmark legal decision about patenting of human embryonic stem cells changed the landscape for future research and commercial development. U.S. researchers weathered considerable uncertainty when a judicial process based on a lawsuit brought by investigators who do not support research on embryonic stem cells shut down federal funding for a period of time. The society responded by defining its role in embryonic stem cell research (a role that not everyone in the field embraces, but one that is practical and informative). At this point, it seems as though embryonic stem cells are becoming less of a “big issue” and there is broader recognition that they are important for the future of the field. In vitro fertilization was once a huge source of ethical disagreement, but is now mainstream. I hope that embryonic stem cells will achieve a similar status.The ISSCR has also provided information and expert opinions to help many governments address their stem cell issues. As part of that effort, the society produced an international document on the practical use and ethical use of stem cells. In addition, counseling of individual governments facilitated the set-up of stem cell institutes in various countries. Government policy has been strongly influenced by the advice of several ISSCR presidents and leaders.The public efforts of the ISSCR revolve around a single topic chosen every year by the president. In my case, I focused on education of the public. More recently, there has been a decision to examine questionable clinics that do stem cell research. Such “snake oil salesmen” often promise major clinical success for therapies that are not scientifically based. The society is in the process of evaluating how to call out companies that are involved in such efforts and how to inform the public of such behavior. In the interim, we have created a web page to provide information to patients who seek to evaluate new stem cell therapies (http://www.closerlookatstemcells.org).It has been interesting to watch the leadership transitions that occur through the ISSCR. Each year a new president takes the helm and brings their unique perspective to the role. Greg Schultz, the founding executive director, was absolutely critical in the process in the early days, and Nancy Witty, our current executive director, has done a wonderful job over the past 6 years. It is clearly through Nancy's leadership that the mission of the ISSCR has been truly executed.I see a number of future opportunities for the field of stem cell research and regenerative medicine in which the ISSCR and Cell Stem Cell can play a vital role. One of those is clinical translation. Existing successes include limbal stem cells being transplanted to treat corneal eye diseases and the expansion of blood stem cells. The study of patient-specific induced pluripotent stem cells or “diseases in a dish” will undoubtedly yield information that will be brought to the clinic. The need for a facilitation of this process is very important and a journal is critical. I feel that Cell Stem Cell could have a pioneering role in promoting translation of stem cell research. There are many issues yet to be overcome, including ones related to safety, manufacturing, and access to stem cell treatments.Another issue for the field is to maintain the quality of the research it produces. With the increasing number of researchers getting involved, it is critical to remain rigorous, and to ensure that published conclusions are well supported by data. The field has already seen its share of retractions and controversy. I hope that everyone working in this area will continue to produce fantastic research that builds to a crescendo of clinical relevance.Here is what I said at the very first meeting at the end of my presidential speech:“I am very enthusiastic about the Society, and I hope that 20 years from now we will be utilizing stem cells in the clinic as routine medical therapy for many genetic and degenerative disorders, that the basic genetics and molecular biology and cell biology of the stem cell will be largely understood, and that the Society will be filled with wonderful young trainees and old investigators such as myself.”We are now at the halfway mark, celebrating the ISSCR's 10th Annual Meeting where we are hearing a wealth of progress towards this goal, presented by a truly global community of all ages.I want to raise a toast to ISSCR and Cell Stem Cell: to a happy birthday and continued success.

If you have looked at the cover of this issue, you may be wondering why we chose a picture of an engineer repairing telephone wires. The link to stem cells might not be immediately apparent. However, if you look closely, you will see that there is an underlying theme. The telephone wires represent communication, and the drawing incorporates various elements of the interconnected network of ethical and practical considerations involved in regenerative medicine, some of which are highlighted in our issue (see if you can guess the artist whose work we are subtly emulating!). The engineer has a role to play too—as a depiction of the stem cell-based approaches that are tapping into that network to help make progress toward repair and regeneration.The underlying prompt for the cover theme came from this month's review section, which looks at the importance of communication at different stages of the research enterprise. In their Forum, Erica Haimes and Ken Taylor advocate for strong connections between researchers, clinicians, and patients to help ensure smooth and effective provision of materials for scientific research. Once materials are available, discussion and exchange of reagents is more straightforward if information about them is presented clearly. To that end, the two Letters both comment and build upon a Forum that appeared in our April issue calling for a standardized approach to nomenclature for human pluripotent stem cell lines (Luong et al., 2011xLuong, M.X., Auerbach, J., Crook, J.M., Daheron, L., Hei, D., Lomax, G., Loring, J.F., Ludwig, T., Schlaeger, T.M., Smith, K.P. et al. Cell Stem Cell. 2011; 8: 357–359Abstract | Full Text | Full Text PDF | PubMed | Scopus (15)See all ReferencesLuong et al., 2011). The Perspective from Christopher Goldring and colleagues arose from communication, as it is based on discussions between authors from a broad range of academic institutions and companies at a workshop. This article outlines the many different factors that need to be taken into account for assessing the safety of any stem cell-based therapy, regardless of the cell type and source being used. Richard Maziarz and Dawn Driscoll look at the other end of the process by outlining the need for early interaction between those developing treatments and the health care organizations that will ultimately be asked to pay for them. Last but not least, we also focus on the importance of communication with the general public, through patient advocate Brooke Ellison, who gives us an overview of a new book, “Stem Cell Hope” by TIME Magazine reporter Alice Park; and through outgoing ISSCR President Elaine Fuchs, who in her President's Note emphasizes the importance of active engagement with lay audiences to promote understanding and appreciation of stem cell research.In the context of a journal, the concept of communication is always relevant—it is our raison d'etre. We are therefore happy to be “communicating” a strong selection of new research findings in this issue, ranging from regulation of lung stem cells to suppression of aberrant transcripts in ESCs. Some papers were available online ahead of the issue date; others are newly available now. As always, you can find a summary of these studies and how they relate to each other on our Editors' Notes page. Last month, we partnered with our sister journal Neuron to bring you a focus on neural stem cells. This focus had two parts, the first being a collection of review articles and primary research papers in our May issue. Then, later in the month, Neuron published a special review feature covering a variety of different topics related to neural stem cells and adult neurogenesis. This month, Cell will also be publishing a collection of stem cell-related review articles. As I discussed last year (Sweet, 2010xSweet, D.J. Cell Stem Cell. 2010; 6: 493Abstract | Full Text | Full Text PDF | PubMed | Scopus (2)See all ReferencesSweet, 2010), Cell Stem Cell aims to follow the progress of the stem cell field toward clinical translation, and the most recent addition to our article type repertoire, “Clinical Progress,” fosters communication in that realm by presenting high-quality work that bridges the divide between basic research and clinical application. In this regard, we were pleased to see that last month Thomson Reuters highlighted Cell Stem Cell as a Rising Star in the field of Clinical Medicine, based on its citation record. Later this year, we hope to promote interaction in a different way, by cohosting a Cell Symposium on Stem Cell Programming and Reprogramming in Lisbon, Portugal, from December 8th to 10th. You can find information about the confirmed speakers and how to register to attend online at http://bit.ly/i9UZBs. Alternatively, if you prefer your missives about stem cell research in a more succinct form, you may want join our growing band of followers on Twitter (@CellStemCell).As I write this Editorial, we are making preparations for the ISSCR 2011 Annual Meeting. At the meeting itself, we are delighted to be partnering with the University Health Network – Toronto and the ISSCR to bring you a free half-day symposium to honor the scientific legacy of Ernest McCulloch (see Iscove, 2011xIscove, N. Cell Stem Cell. 2011; 8: 250–251Abstract | Full Text | Full Text PDF | PubMedSee all ReferencesIscove, 2011). All registered attendees for the ISSCR meeting are welcome to join us for this Focus Session, which will take place from 9:00 a.m. to 12:30 p.m. on Wednesday, June 15th. You can find more information about it and register your interest on the premeeting events page of the ISSCR website. Cell Press will have an exhibition booth at the meeting (#811), and we invite you to visit us to learn more about our various initiatives, including the special issues mentioned above, to meet Scientific Editors from Cell and Cell Stem Cell, and to enter to win an iPad 2 by connecting with us on Facebook. At the booth, we will also announce the results of our website-based “Best Paper” contest, so you can find out which of the six finalists was the most popular among our voters. In addition, you will be able to learn about an exciting new Cell Press tool designed to take authors “behind the scenes” in the publication process. When you pick up your delegate bag, you will see that it contains a copy of this issue of Cell Stem Cell (perhaps that is even where you found this Editorial). We are very grateful to Stemgent for providing the sponsorship that made it possible for us to distribute these journal copies. Stemgent focuses on developing cutting-edge products for the stem cell community, including a new mRNA-based reprogramming protocol based on a paper that Cell Stem Cell published last year (Warren et al., 2010xWarren, L., Manos, P.D., Ahfeldt, T., Loh, Y.-H., Li, H., Lau, F., Ebina, W., Mandal, P.K., Smith, Z.D., Meissner, A. et al. Cell Stem Cell. 2010; 7: 618–630Abstract | Full Text | Full Text PDF | PubMed | Scopus (1007)See all ReferencesWarren et al., 2010).In closing, I'd like to offer congratulations in advance to Robert Blelloch for receiving the ISSCR Outstanding Young Investigator Award this year, and to the winners of two new awards: Kazutoshi Takahashi and Shinya Yamanaka, receiving the McEwen Centre Award for Innovation, and Robert Klein, receiving the Public Service Award. As always, I look forward to communicating with as many of you as possible during the course of the ISSCR meeting, and of course to hearing about all of the latest and best research. See you there!

Irving Weissman, the incoming president of the International Society for Stem Cell Research (ISSCR), promises not to shy away from speaking his mind during his term. His goal to serve as a vocal advocate for the society should come as no surprise, given that he has been outspoken throughout his 50+ years in the stem cell field.Weissman was no ordinary teenager. As a high-school student of just 16, he began his scientific career when he spent a summer helping out in the laboratory of renowned pathologist Ernst Eichwald at what was then the Montana Deaconess Hospital in Great Falls, Montana. He liked it so much, he worked after school and the following summer, and when he graduated from high school in 1957, he already had two scientific papers to his name. Others soon followed, so that by the time he'd completed his premedical studies at Montana State University in 1961, he could boast a string of publications. It was this track record rather than any academic accolades that won Weissman a place at Stanford School of Medicine. “At no stage in my career did I ever get into the top 10% of my class by grades,” he says. “The only reason I got admitted to Stanford was the papers I'd written.”Weissman picks out one in particular that pointed him toward the stem cell field. In 1955, Eichwald and a colleague had found that skin grafts performed between inbred mice were mostly accepted by the recipient, but not if the donor was male and the host female. It was the first clear evidence of a male-specific antigen, and Weissman set out to see if he could induce tolerance of male-to-female transplants in these mice. Inspired by the pioneering work of Rupert Billingham, Leslie Brent, and Peter Medawar on transplantation immunity, Weissman transplanted bone marrow and spleen cells from males into newborn or immunosuppressed females, making their immune systems accept all subsequent grafts from the donor male. “It made me wonder what it was in bone marrow that could persist for the life of the host,” he says. “It was this experiment that really hooked me into science.”This result opened up therapeutic opportunities that were immediately obvious to Weissman. Over lunch with his mother, he made the bold prediction that within 5 years patients would be receiving bone marrow on a routine basis, preparing the immune system of an adult to receive a transplant of virtually any tissue from any unrelated individual. “What I didn't reckon on was how hard it is to move things from science to medicine,” he says.It's not for want of trying. After the first clear evidence that stem cells are present in mouse bone marrow was reported, Weissman spent 9 invaluable months in Jim Gowans' laboratory at Oxford University in the UK. His express mission was to find out more about the role of the thymus in the maturation of T cells from bone marrow cells. “Gowans' approach to discover that lymphocytes were the specific cells of the immune system was to purify, purify, purify,” says Weissman. He was able to purify lymphocytes from the thoracic duct, label them, and return them to live rats to discover where they went and what they did.In time, Weissman's obsession with purification and in vivo verification led to several publications of major consequence for the stem cell field. In July 1988, he and his colleagues became the first to purify mouse hematopoietic stem cells and demonstrate their multipotent properties (something he would repeat in humans in 1992). “We showed that transplanting blood-forming stem cells to lethally irradiated mice could reconstitute all blood cell types and save the lives of all the animals,” says Weissman.The next logical step was to find a way to study analogous human stem cells in an animal system, ultimately with a view to rolling stem cell therapy out into clinical trials. Also in 1988, Weissman, Michael McCune, and colleagues generated a model of the human immune system by transplanting human fetal blood-forming and lymphocyte-forming organs into severe combined immunodeficient (SCID) mice.Weissman had a lot planned for those early SCID-human (SCID-hu) chimeric mice, including studying HIV-infected cells of the human immune system in vivo and testing the efficacy of drugs to combat the virus. But getting the funding for such edgy experiments proved harder than he had imagined. Enter Systemix, which Weissman cofounded with McCune and New York venture capitalist Eli Jacobs to realize the promise of the SCID-hu mouse. With plenty of funds and the freedom to carry out the experiments, things began well.When the Swiss drug and chemical giant Sandoz Ltd bought a hefty stake in Systemix in 1992, the future looked even brighter. “I thought that a lot of our problems were over because Sandoz was committed to a lot of the same things,” says Weissman. “But what I didn't reckon on was that leadership changes in the pharmaceutical industry and the people who saw this as something that you should rush to make real in humans were gone within a year of the sale and we had a whole new group of executives to deal with.”Although this turnover slowed down the research, in 1996 Sandoz began three clinical trials involving stem cells, with the goal of improving the survival of cancer patients by regenerating their blood-forming systems with cancer-free stem cells after high-dose chemotherapy. “At last we were going to do human stem cell transplants. We had a chance we were going to improve the therapy. We had a company backing us, with the money in place to do it.”But within months of starting the trials, the whims of the business world interfered once more, when Sandoz merged with Ciba-Geigy to form Novartis. “Their goals were not the same as ours, so even before the results of those three clinical trials started coming out, they decided they weren't going to back this work any further,” says Weissman. Worse still, Novartis held all the patents necessary for taking the research forward, either licensed to them from Stanford University or invented at Systemix or Sandoz. In the meantime, the transplant team at Stanford, led by Robert Negrin, was beginning to see the benefits of receiving purified stem cell transplants after high-dose chemotherapy. “At three years in the stage IV breast cancer patients, instead of 6% alive without disease from a similar study using unpurified mobilized peripheral blood (MPB), the patient group receiving breast cancer-free stem cells was 45% alive without disease,” says Weissman.He had another shot at developing stem cell therapies within the commercial sector, this time at California-based Cellerant Therapeutics. But he experienced only further frustration: “I have now resigned as a director, sold off all my shares, and removed any consulting activities I have with them on stem cells.” The patents too have nearly come full circle. “We are engaged in negotiations to bring the know-how and the isolating antibodies back to Stanford University and the California Institute of Regenerative Medicine,” he says. These institutions may fund key clinical trials that he hopes will act as proof of the therapeutic principle, finally pushing stem cells into the medical mainstream and giving companies the confidence to take on the development of stem cell products.There are other reasons for being upbeat. After a decade of tireless advocacy of stem cell research during the Bush era, Weissman is clearly delighted at the tone set by the new US administration and the funds that are beginning to flow toward stem cell research. But as the new president of the ISSCR, he is likely to be as outspoken as ever in favor of further reform. In particular, he is critical of current NIH guidelines to fund research into cell lines developed by the iPSC method but not those developed by nuclear transfer. “It sounds like they have taken the stance that this is a worthy gamble” he says. “I don't want to gamble when patients' lives could be the stake.”Weissman is also likely to use his presidency to go on the offensive against those using the potential of stem cells to sell unverified treatments. Of particular concern are those cases where cells are being given to patients with only faint prospects of stimulating local blood vessel activation, let alone regenerating entire tissues. Worse still, says Weissman, are those using the promise of stem cells to prey on the vulnerability of patients with incurable diseases. “If I have my way, we will look at the entire spectrum of these abuses and, like the American Cancer Society, investigate and list groups that use unproven stem cell therapies,” he says.It's been a longer journey than Weissman ever imagined. “It just makes me realize how naive I was when I sat down with my mom and said this is going to happen in the next 5 years. It's 50 years later.” Now at the age of 69, will he live to see the day when his teenaged fantasy becomes a reality and stem cell therapies have become routine? “You betcha,” he says.Photo by Sean Morrison.View Large Image | View Hi-Res Image | Download PowerPoint Slide

In the paper by Levine published in the June issue of Cell Stem Cell (Levine, 2008xLevine, A. Cell Stem Cell. 2008; 2: 521–524Abstract | Full Text | Full Text PDF | PubMed | Scopus (23)See all ReferencesLevine, 2008), the author investigated the contribution of individual countries to the field of hESC research in relation to another scientific field, research involving RNAi. Under- and overperforming countries with respect to hESC research were designated according to this means, and a positive correlation between stem cell policies and the extent of hESC research was postulated.Levine's study was based on a literature analysis for “journal articles” that cited the first hESC paper (Thomson et al., 1998xThomson, J.A., Itskovitz-Eldor, J., Shapiro, S.S., Waknitz, M.A., Swiergiel, J.J., Marshall, V.S., and Jones, J.M. Science. 1998; 282: 1145–1147Crossref | PubMedSee all ReferencesThomson et al., 1998). This literature search resulted in a data set containing 1112 articles through the year 2006. The author termed the subject of these papers as “research related to hESCs” and used this paper set for his subsequent analyses. However, we have some concern on the data and the methodology used in this study.First, although the author indicates clearly that the papers included in his analysis are not limited to primary hESC research reports, in our view the approach used is questionable because of the equivocal assumption that articles citing the Thomson paper would represent those research activities that are possibly influenced by national stem cell policies. This approach does not take into account the negligible impact of a country's stem cell policy on the number of reviews or papers on ethical or legal issues of hESC research, which are often designated as journal articles and which often cite the Thomson paper. Therefore, rating a country's contribution to the scientific field of hESC research should only consider the number and, particularly, the scientific impact of research papers describing original experimental work involving hESCs.To determine the number of experimental hESC research papers, we performed a literature analysis using the method described earlier (Guhr et al., 2006xGuhr, A., Kurtz, A., Friedgen, K., and Loser, P. Stem Cells. 2006; 24: 2187–2191Crossref | PubMed | Scopus (66)See all ReferencesGuhr et al., 2006). Inspection of about 3300 papers published through 2006 and identified by our literature search revealed that only 453 of them described experimental work involving hESCs (Guhr et al., 2006xGuhr, A., Kurtz, A., Friedgen, K., and Loser, P. Stem Cells. 2006; 24: 2187–2191Crossref | PubMed | Scopus (66)See all References, Loser and Wobus, 2007xLoser, P. and Wobus, A.M. Naturwiss. Rundsch. 2007; 60: 229–247See all References; Table 1Table 1). Other articles included reviews, book articles, reports on work with murine ESCs or human EC and EG cells, and articles on ethical or legal aspects of hESC research.Table 1Contribution of Individual Countries to hESC Research as Determined by the Number of Experimental Research Publications for the Years 2000–2006 and 20072000–20062000–20032004200520062007Number of hESC research papers4535692133172229Share in Overall hESC Research Paper Number (%)USA40.639.342.436.843.038.4UK10.110.79.810.69.98.3Israel9.930.414.15.34.65.7Korea8.13.67.612.86.46.6Singapore5.13.64.36.05.28.3Sweden4.91.85.43.46.45.2China (and Taiwan)4.41.81.17.54.63.9Australia4.23.62.26.04.74.3Canada2.01.84.31.51.22.1Japan2.002.22.32.33.1Germany1.501.12.31.73.0Netherlands1.33.601.51.20.4Belgium1.101.10.81.70.4India00001.22.1France000001.3Italy000001.3Other4.805.43.25.95.4Data for individual years are given (data for 2000–2003 are merged). Relevant papers were identified using the method described by Guhr et al. (2006)xGuhr, A., Kurtz, A., Friedgen, K., and Loser, P. Stem Cells. 2006; 24: 2187–2191Crossref | PubMed | Scopus (66)See all ReferencesGuhr et al. (2006), including an inspection for reported experimental use of hESCs. Assignment of papers to a country was according to the address of the corresponding author. In the few cases of two corresponding authors, papers were assigned to the country of the first one.The obvious difference between our data pool and Levine's (453 versus 1112 papers) is most likely due to the fact that the latter also includes papers that describe results of other than experimental hESC research or may represent “noise” according to Levine. Strikingly, we are aware of only seven original research articles on hESCs that were published in print by German groups through 2006 (plus five articles that were available online already in 2006 but appeared in print in 2007). In contrast, Levine put the number of articles from Germany reporting “research related to hESCs” at 63, which is a 9-fold overestimation. Furthermore, our search did not reveal any experimental hESC paper from France or Italy published in print before 2007, while the numbers of hESC-related papers found by Levine through 2006 were 32 and 16, respectively. On the other hand, the overestimation for U.S.-based work by Levine relative to our results is only 2.2-fold (401 hESC-related papers versus 184 hESC research papers). In addition, 89 of the 453 hESC research papers published through 2006 (19.6%) did not cite the Thomson paper, and the citation was incorrect in a few others (“Thompson” instead of “Thomson,” 6 of 453, 1.3%). These 95 papers are consequently lacking from Levine's data set. Furthermore, citation attitudes may change over time. While 80.4% of hESC research papers published through 2006 cited the initial Thomson paper, this value decreased to 57.6% for papers published in 2007. Therefore, caution should be exercised when assessing the quantity of research activities by citation analysis.A second concern that we raise with respect to the Levine article is that the impact of research should be taken into account when rating a country's contribution to a given scientific field. While most of the 453 hESC research papers published through 2006 are too young to allow an analysis of their citation frequency, the impact of the publications can be estimated by using the ISI citation impact factors of the journals in which the papers were published. Whereas the weighted average of the 2006 impact factors for journals that published the said 453 papers was 6.917 ± 6.285 (mean ± SD), this value was considerably lower for papers originating from some of the countries that overperformed in hESC research according to Levine (e.g., China, 3.310 ± 2.175; Singapore, 4.613 ± 4.865). In contrast, hESC work from U.S. groups was published in journals with a higher average impact factor (8.848 ± 7.731). Thus, hESC research results produced in the U.S. (the “largest underperformer” in hESC research) were published more often in highly influential international journals than work originating from most other countries. This finding is similar to that from an earlier study (Owen-Smith and McCormick, 2006xOwen-Smith, J. and McCormick, J. Nat. Biotechnol. 2006; 24: 391–392Crossref | PubMed | Scopus (38)See all ReferencesOwen-Smith and McCormick, 2006).We agree with Levine that it would be useful to relate hESC research activities to a different scientific field in order to determine a country's relative performance. However, we feel that it remains to be discussed whether work using RNAi (which is applied in many fields of biological research as a mere tool to downregulate gene expression) is a suitable standard of comparison.In conclusion, we suggest that meta-analyses of research activities in a given scientific field should be performed only on data sets of articles that have been individually inspected prior to inclusion. This would allow for more substantiated statements, especially when dealing with politically sensitive areas of research such as hESCs.

The skin epidermis is constantly renewed by epidermal stem cells. In a recent Science paper, Rompolas et al. utilize live imaging to track epidermal stem cells over their lifetimes. Their findings provide new insights into epidermal stem cell behaviors and unravel how newly generated cells are integrated into pre-existing tissues.

It's easy to be excited about stem cell research. Even setting aside the sometimes hyperbolic coverage in the mainstream media, it is clear from what we already know about the properties and pervasiveness of stem cells that they hold great promise for elucidating many aspects of basic biology and for potential therapeutic strategies. Indeed, some stem cell-based treatments are already part of mainstream medicine, most notably bone marrow transplants, which save lives on a regular basis. Others, such as treatment of neurodegenerative diseases or diabetes, are still more distant goals, but ones that seem increasingly realistic as our understanding grows. Recently, it has also become clear that our insights into stem cell biology may even help us devise more effective cancer therapies and better human disease models for the development of new pharmaceuticals. Underlying this advancing knowledge base is, of course, a burgeoning community of stem cell researchers, producing a rapidly expanding body of work that needs to be reviewed and distributed. Mirroring the trend, in the 5 years since it was founded the International Society for Stem Cell Research (ISSCR) has developed into a major international scientific organization. This is the energizing backdrop against which we are proud to introduce the latest addition to the Cell Press family of journals, Cell Stem Cell.The overall aim of Cell Stem Cell is to provide a forum for the dissemination of important new information about stem cell research. The publication topics will range from fundamental advances in our understanding of stem cell biology, in a wide range of organisms, to new findings of direct clinical relevance. Like all Cell Press journals, we will have a strong focus on high-quality research articles, as exemplified by the five papers included in this inaugural issue. They cover topics ranging from regulation of pluripotency to age-related decline, and I hope you will enjoy reading them. Going forward, we will publish standard and short research Article formats plus Resource articles describing technical advances or other information sources that will be of broad interest to the stem cell community. Each issue of Cell Stem Cell will also feature a wide variety of review material. The review section will cover current research topics, as illustrated by the article from Shinya Yamanaka in this issue, and will also frequently include contributions about ethical and policy issues relating to stem cell research. Initiating this aspect of our coverage are Commentary articles from Anne McLaren and Lord Robert Winston, two widely respected researchers from the UK who have played prominent roles in ethical and policy discussions related to stem cells. For more information about the articles featured in this issue, plus our online comment forum relating to the history of the term “stem cell,” see the Editors' Notes page that follows the Table of Contents.As editors and publishers, we consider many factors when making a decision to launch a new journal, but the most prominent by far is whether there is an indication from researchers that a new communication platform is needed. The path that led us to Cell Stem Cell involved something of a “meeting of minds” between Cell Press and the stem cell research community, as represented by the ISSCR. At Cell Press, we had observed the explosive growth of the stem cell field and the resulting rapid increase in the number of papers being published. At the same time, the society's members had indicated through a survey that they would like to see it initiate a new journal to serve the stem cell research community. Based on this information and feedback from a wide range of stem cell researchers, we and the ISSCR both concluded that the field would benefit greatly from a new high-quality forum for stem cell research, setting the stage for the launch of Cell Stem Cell. We chose the name Cell Stem Cell to provide a clear association with the Cell family of journals, to be clearly distinct from existing publications, and to encapsulate the intended aim of covering the entire field of stem cell biology. As for all Cell Press journals, access to Cell Stem Cell content will be free online from one year after publication. On the Cell Stem Cell website (http://www.cellstemcell.com), we are also featuring free access to a selection of stem cell papers published in other Cell Press journals and will post new articles online ahead of issue dates.We are delighted that the ISSCR has chosen to endorse Cell Stem Cell as its official affiliated journal. This is an unprecedented relationship for a Cell Press journal, so it merits some clarification. Like most other Cell Press journals, Cell Stem Cell will be run by an in-house team of scientific editors who will determine the content in terms of the research manuscripts and the review material in the journal. As respected researchers in the field, the ISSCR leadership will contribute to the peer review process for this material in the same way as other reviewers and Editorial Board members. In addition, in a feature that is unique to Cell Stem Cell, there will be a special dedicated section in the journal with content provided by the society. This section will provide a forum for the ISSCR to publish information that it would like to distribute to its members and the broader scientific community, including, for example, messages from the President, policy statements, and the results of committee discussions. In this issue, the ISSCR section includes a President's Note from Paul Simmons, giving his perspective on stem cell research from his time as ISSCR president, and a Committee Forum article from Douglas Sipp, the Chair of the International Committee, on the society's international scope. The articles that are provided by the ISSCR are clearly delineated in the journal by both the article header and the colored tab at the top of the page: green for editorial review material, tan for the society section, and blue for research articles. Overall, the affiliation agreement between Cell Stem Cell and the ISSCR is one of mutual support between two independent organizations. As part of the agreement, ISSCR members will receive a substantial discount on personal subscriptions to the journal. Also, although this inaugural issue of Cell Stem Cell is dated July 2007, it was published early for distribution to the attendees at the ISSCR annual meeting in Cairns, Australia, which runs from June 17th to 20th.Despite the excitement that surrounds our vision for this new journal, it would be somewhat disingenuous not to acknowledge that the stem cell field has produced perhaps more than its fair share of controversial publications in recent years. At Cell Stem Cell, we recognize our responsibility to make all reasonable efforts to ensure the veracity of the information that we publish. We will therefore, of course, subject all research articles published in Cell Stem Cell to rigorous peer review and hold authors to high standards in terms of documentation and presentation of their data. In the spirit of open communication, we will be happy to receive informative Correspondence articles about papers we have published, and we will have a Matters Arising format for challenges to published papers should the need occur. Furthermore, we will occasionally publish articles that investigate a controversial issue but lead to a negative conclusion, as we appreciate that such studies, if conducted rigorously, can be important for the ongoing progress of the field.The in-house editorial team of Cell Stem Cell will comprise three scientists. As the Editor, I come to Cell Stem Cell with over 10 years of editorial experience and have been at Cell Press since 1999. During my tenure here I have worked as a scientific editor on Cell, Molecular Cell, and Developmental Cell, and I have been the Editor of Developmental Cell since 2003. Before becoming an editor, I received my PhD at the MRC-LMB in Cambridge, UK, and was a postdoctoral fellow at The Scripps Research Institute in La Jolla, CA. I am joined by Heather Fleming, who as the Reviews Editor is responsible for organizing the review and opinion material in each issue. Heather joined us from a postdoctoral position at Massachusetts General Hospital in Boston and before that did graduate work at the Ontario Cancer Institute. The third member of the team will be Christina Lilliehook, who will be joining us as a Scientific Editor later this summer from the University of Rochester, following postdoctoral work at the Weill Medical College of Cornell University and graduate school at Mount Sinai School of Medicine. I am extremely grateful for the advice and support provided by the ISSCR, and particularly the Publications Committee, who formed the Cell Stem Cell ISSCR Advisory Committee and have participated actively in planning the journal. Last, but most definitely not least, I also want to express my appreciation for the support and assistance provided by the distinguished members of the Editorial Board, who are generous with their time in assessing submissions and helping to determine appropriate publication standards.Support and development of the field is the underlying goal of any journal, and Cell Stem Cell is no exception. Currently the stem cell field has tremendous momentum and is the focus of great anticipation within the research community and beyond. We hope you will enjoy reading and contributing to Cell Stem Cell, or CSC as we sometimes call it, and that with your input we can play a part in ensuring that this exciting area of biology fulfils its remarkable potential.

Welcome to the special issue marking the fifth anniversary of the launch of Cell Stem Cell. The inaugural issue of the journal, dated July 2007, was published in early June for the ISSCR annual meeting in Cairns, Australia. We have therefore chosen to celebrate the anniversary in June, and to distribute this issue at the ISSCR annual meeting in Yokohama, Japan. We are very grateful to Stemgent, Life Technologies, Lonza, and StemCell Technologies for providing the sponsorship support that enables us to send a copy for every attendee at the meeting. For this special issue, we have focused on progress in the stem cell field over the past 5 years and outstanding issues that remain through a series of Perspective and Forum articles. For the Perspectives, we asked the authors to summarize key developments in different areas of stem cell research since Cell Stem Cell launched. The approaches they have chosen to take vary—some have focused on one or two key points and discuss them in depth, while others have provided more of an overview of major areas of progress. In the Forum section, we gave each author free rein to express their opinion on a topic that they consider important for the field. Again, the contributions in this section vary, in terms of subject covered and degree of speculation involved. We hope that all of these articles from leaders in the field will prove thought-provoking and informative, and that together they provide a snapshot of the current status and future directions. In honor of the location of the 2012 ISSCR meeting, we have also chosen to feature three research articles from Japan. These papers, from the groups of Akira Onishi, Yoshiki Sasai, and Jun Yamashita, provide a fitting illustration of the strong contributions that Japanese scientists are making to the stem cell field. The cover of the issue has a connection to Japan as well, because the winning entry from the competition we held earlier this year is from Mai Kimoto, a doctoral student at Hokkaido University. Mai's beautiful hand-drawn image depicts a broad range of tissues in which stem cells have been identified and characterized in a design inspired by marine ecosystems.As Leonard Zon discusses in his accompanying editorial, this 5 year anniversary for Cell Stem Cell coincides with the 10 year anniversary of the founding of the ISSCR. Like the journal, the society has evolved significantly since its first inception, and has become a major force within the stem cell field and beyond as society at large grapples with how to support and regulate the stem cell field. You will see a short montage depicting the society's activities in this issue, and information about the winners of the society's 2012 awards, all of whom we heartily congratulate. We at Cell Stem Cell very much appreciate the mutually supportive relationship that we have with the ISSCR, and look forward to it continuing in the future.In running a journal for the stem cell field, our primary goal at all times is to make a positive contribution to scientific progress. We are well aware that all scientists, but particularly those working in a fast-moving field such as stem cells, want the process of publication to be as rapid and straightforward as possible. There are many factors to balance, including author and reviewer time commitment and the desire to ensure that we hold papers to appropriate scientific standards without having unreasonable expectations about experimental content. It has always been our policy to take papers through just one major round of revision to avoid protracted review processes, and the supplemental material guidelines that Cell Press introduced 2 years ago have helped rein in expectations about the amount of information needed for a given publication. We strive to ensure that our consideration processes are timely and thoughtful, and that we both explain our decisions and minimize the time spent for everybody involved. We also aim to be accessible to authors and to provide appropriate advice to help navigate the publication process as smoothly as possible. We have therefore been very happy about the amount of positive feedback we have received from the community about the quality of the editorial service provided by Cell Stem Cell and the role that the journal has played in the stem cell field, both anecdotally and through a broader survey that Cell Press sent out earlier this year.Our ability to make this type of positive contribution depends on support and assistance from many different members of the scientific community, and we are very grateful to everyone who has helped Cell Stem Cell over the past 5 years. The journal would be nothing without the articles it contains, so we appreciate all of the authors who entrusted us with presenting their work to the broader community. The members of the editorial board and ISSCR advisory committee have provided valuable support and guidance as we have developed Cell Stem Cell and its coverage. Peer reviewers are also a vital component of any journal's operation. Over 1,300 individuals have acted as referees for research and review articles submitted to Cell Stem Cell since early 2007, and we are grateful to each and every one of them for the time and effort they put in. Because they are anonymous, for good reason, reviewers are often “unsung heroes” in the publication process. In an effort to redress that balance, I'd like to take this opportunity to recognize their contribution. Rapid, discerning, thoughtful, and constructive reviews help us as editors decide which papers are appropriate for publication and help the authors involved improve their work. The scientific enterprise benefits as a result.I am often asked where Cell Stem Cell, and the field more generally, will go in the future. The honest answer is that I don't know, but that is part of what makes it so exciting! All of the articles in this issue serve to illustrate the rapid pace of progress in the stem cell field, and the energy that surrounds it as it continues to grow. I personally have felt and continue to feel privileged to be part of this vibrant and fascinating area of science. I am sure I speak for Christina, Sheila, and everyone else involved in Cell Stem Cell when I say that we very much look forward to continuing to work with the research community and to doing our part in helping the stem cell field continue to succeed. Please come and visit us during the ISSCR meeting in Yokohama at booth 208 to learn more about Cell Stem Cell and the many exciting initiatives going on at Cell Press.

Although the use of citations to develop data sets for analysis has a lengthy history, Loser et al. (2008)xLoser, P., Guhr, A., Kurtz, A., and Wobus, A.M. Cell Stem Cell. 2008; 3: 129–130Abstract | Full Text | Full Text PDF | PubMed | Scopus (5)See all ReferencesLoser et al. (2008) are correct to point out—as I acknowledged—that these data sets are inherently noisy. In this case, I made a deliberate choice to use citation linkages to define my data sets because of the opportunity these linkages offered to use an identical methodology to develop data sets not just for hESC- and RNAi-related research but also for research related to 50 other influential biomedical research articles. In my view, this ability to make comparisons between fields and countries outweighed the loss of precision present in hand-collated data sets in previous studies (Guhr et al., 2006xGuhr, A., Kurtz, A., Friedgen, K., and Loser, P. Stem Cells. 2006; 24: 2187–2191Crossref | PubMed | Scopus (66)See all References, Owen-Smith and McCormick, 2006xOwen-Smith, J. and McCormick, J. Nat. Biotechnol. 2006; 24: 391–392Crossref | PubMed | Scopus (38)See all References).I did not claim, nor intend to imply, that my data set consisted entirely of experimental work involving hESCs. Rather, throughout my paper, and indeed in its title, I referred to my data sets as research related to hESCs and RNAi, and I clearly articulated the importance of this phrasing. This distinction is not mere semantics. Many of the non-hESC articles included in my hESC-related data set report primary research using embryonic stem cells in animal models or other human stem cells. I do not consider these articles false positives. Many important advances in hESC science have been based on just this sort of related research. Furthermore, scientists starting hESC research programs may opt to work with mouse cells initially and transition to hESCs over time. Although not all articles in related fields cite the initial hESC article, I believe those that do are disproportionately likely to report relevant work. My data set also includes some review material that summarizes existing research or introduces hESC science to related fields. Though not primary research, these articles serve an important scientific purpose, clearly related to hESC science. I do agree that articles on the ethical and legal implications of hESC research are false positives. Due to time limitations, I chose not to manually review each of ∼22,000 articles in my three data sets to systematically remove these articles. A preliminary search of the titles of articles in my hESC-related set for keywords relevant to ethical, legal, and policy issues identified 24 papers (∼2%) divided among nine countries. Excluding these articles has essentially no impact on my identification of over- and underperforming countries in research related to hESCs.Loser et al.'s letter highlights a point that should have, in retrospect, been drawn out more clearly. The inclusion of research related to, but not explicitly using, hESCs into my data set reduced the magnitude of the signal my study aimed to detect because the distribution of this related research is more likely to mirror the control set. The conservative nature of this signal means my approach will tend to underestimate the magnitude of underperformance in countries, such as Germany, France, and Japan, that have relatively strong developmental biology research communities.If anything, given the different methodologies, I interpret Loser et al.'s analysis as confirmatory rather than contradictory. Indeed, if their data on country shares of experimental hESC research are compared to my biomedical control set, the set of seven overperforming countries are the same, as are four of the top five underperforming countries (the only change is the substitution of Germany for Switzerland). Thus, although the order of the countries and the magnitude of the under- and overperformance differs, both analyses paint broadly similar pictures of the development of this field.Incorporating measures of research quality would be an interesting extension to my analysis of country-level research output. However, because citation distributions are skewed to the point that a journal's impact factor is not particularly representative of any individual article (Garfield, 2006xGarfield, E. JAMA. 2006; 295: 90–93Crossref | PubMed | Scopus (839)See all References, Seglen, 1997xSeglen, P.O. BMJ. 1997; 314: 498–502Crossref | PubMedSee all References), country-level weighted average journal impact factors may not be an appropriate strategy to accomplish this task. Furthermore, the journal selection and publication process is influenced by social as well as scientific factors, particularly given the single-blind review system common in the life sciences. Loser et al. should not discount the possibility that the differences they find reflect, in part, the social structure of science that may make it easier for western and English-speaking scientists to gain access to high-impact journals (Link, 1998xLink, A.M. JAMA. 1998; 280: 246–247Crossref | PubMed | Scopus (148)See all References, Ross et al., 2006xRoss, J.S., Gross, C.P., Desai, M.M., Hong, Y., Grant, A.O., Daniels, S.R., Hachinski, V.C., Gibbons, R.J., Gardner, T.J., and Krumholz, H.M. JAMA. 2006; 295: 1675–1680Crossref | PubMed | Scopus (70)See all References).I commend Loser et al. for their efforts developing a verified data set of confirmed experimental hESC articles—a hugely valuable resource. Policy analysis is most effective when it builds upon multiple data sources, and I believe both approaches can contribute to the growing understanding of the influence of public policy on the development of hESC and related research.

Summary The adult Drosophila midgut is maintained by intestinal stem cells (ISCs) that generate both self-renewing and differentiating daughter cells. How this asymmetry is generated is currently unclear. Here, we demonstrate that asymmetric ISC division is established by a unique combination of extracellular and intracellular polarity mechanisms. We show that Integrin-dependent adhesion to the basement membrane induces cell-intrinsic polarity and results in the asymmetric segregation of the Par proteins Par-3, Par-6, and aPKC into the apical daughter cell. Cell-specific knockdown and overexpression experiments suggest that increased activity of aPKC enhances Delta/Notch signaling in one of the two daughter cells to induce terminal differentiation. Perturbing this mechanism or altering the orientation of ISC division results in the formation of intestinal tumors. Our data indicate that mechanisms for intrinsically asymmetric cell division can be adapted to allow for the flexibility in lineage decisions that is required in adult stem cells., Graphical Abstract Highlights ► Par complex segregates asymmetrically in dividing Drosophila intestinal stem cells ► Par complex inhibition leads to tumor-like intestinal stem cell overproliferation ► aPKC overactivation alters levels of Notch activity, causing stem cell loss ► Integrins regulate spindle orientation and Par protein localization, This paper extends the role of Par proteins in asymmetric cell division to an adult stem cell lineage—the Drosophila intestinal stem cell—and implicates integrins in regulating Par asymmetry in this context.

Gupta and colleagues highlight recent work, including their own, that suggested based on lineage tracing that mural cells are adipogenic, contrasting with the conclusions of a recent Cell Stem Cell paper.

Induced pluripotent stem cells (iPSCs) hold great promise for autologous cell therapies, but significant roadblocks remain to translating iPSCs to the bedside. For example, concerns about the presumed autologous transplantation potential of iPSCs have been raised by a recent paper demonstrating that iPSC-derived teratomas were rejected by syngeneic hosts. Additionally, the reprogramming process can alter genomic and epigenomic states, so a key goal at this point is to determine the clinical relevance of these changes and minimize those that prove to be deleterious. Finally, thus far few studies have examined the efficacy and tumorigenicity of iPSCs in clinically relevant transplantation scenarios, an essential requirement for the FDA. We discuss potential solutions to these hurdles to provide a roadmap for iPSCs to "jump the dish" and become useful therapies.

Disease-specific induced pluripotent stem cells (iPSCs) are invaluable tools for studying genetic disorders in a dish. A recent paper by Wang et al. (2014) powerfully combines analysis of human iPSCs with genome editing and tissue engineering, in conjunction with biochemical and physiological assays, to provide insights into Barth-syndrome-associated cardiomyopathy.

Although previous reports suggested that canonical Wnt signaling has opposing effects on epidermal and hair follicle stem cells, two recent papers (Choi et al., 2013; Lim et al., 2013) now show that Wnt signaling promotes proliferation in both stem cell populations, revealing new insights into regeneration of both skin compartments.

There is near consensus that Wnt family molecules establish important gradients within niches where hematopoietic stem cells (HSC) reside. We review recent papers suggesting that a delicate balance is required between competing Wnt ligands and corresponding signaling pathways to maintain HSC integrity. Some steps in the transitions from HSC to lymphoid progenitor seem to be partially reversible and under the influence of Wnts. In addition, it has been recently suggested that HSC can oscillate between dormant versus active or lineage-biased states. We speculate that Wnts control a reflux process that may sustain stem cell self-renewal and differentiation potential.

Glycolysis is an essential component of cellular metabolism associated with pluripotent stem cells (PSCs). Two new papers, one by Gu et al. (2016) in this issue of Cell Stem Cell and one by Zhang et al. (2016) in Cell Reports, demonstrate that glycolytic flux is dynamically increased in human primed PSCs upon feeder-free cultivation or conversion into the naive state.

Two papers (Rezvani et al., 2016; Song et al., 2016) in this issue of Cell Stem Cell use transcription-factor-mediated reprogramming to convert liver myofibroblasts into hepatocyte-like cells in mice. Moreover, murine models of fibrotic and cholestatic liver injury were used to demonstrate that this approach has potential for treatment of liver cirrhosis.

Growing evidence shows that stem cells are modulated by systemic factors that are integrated with local signals in response to physiological status. Two recent Cell (Chell and Brand, 2010) and Nature (Sousa-Nunes et al., 2011) papers reveal that Drosophila neural stem cell proliferation is controlled by a diet-dependent insulin/TOR signaling relay between tissues.

Two Matters Arising articles in this issue challenge the conclusions of a previous Cell Stem Cell paper that found extensive transcriptional differences between hESCs and hiPSCs. The original authors provide a response and set in motion a discussion in the field about appropriate methods for microarray data analysis.

Two recent papers outline improvements in gene editing technology that may facilitate the analysis of signaling networks important for development. The systems developed by both Thyagarajan and coworkers (Thyagarajan et al., 2007) in Nature Biotechnology, and Lombardo and colleagues (Lombardo et al., 2007) in Stem Cells, have the potential to advance our understanding of human embryonic stem cells.

Although spermatogonial stem cell niches have been defined in lower organisms, their definitive localization in mammalian seminiferous tubules has been elusive. In a recent Science paper, Yoshida et al. (2007) elegantly demonstrated a vascular and interstitial tissue-associated niche for undifferentiated spermatogonia in the mouse.

Understanding the molecular mechanisms underlying activation of quiescent neural stem cells (NSCs) is complicated by heterogeneity in coexisting NSC pools. Two papers in this issue of Cell Stem Cell (Llorens-Bobadilla et al., 2015; Shin et al., 2015) report sequencing of single NSCs, providing insights into the transition from quiescence to activation and highlighting common themes in NSCs from distinct brain regions.

This SnapShot presents a timeline of key advances in directed differentiation and disease modeling using human pluripotent stem cells. The selected papers are color-coded for different systems and show progress in the field, from making disease- and tissue-specific hiPSC derivatives to the development of disease models for drug screening and therapeutics and the generation of complex systems that mimic tissue architecture and self-organized structures. To view this SnapShot, open or download the PDF.

Facultative liver stem cells have long been thought to be an important source of new hepatocytes during chronic liver injury. This longstanding paradigm is being challenged by two papers discussed herein (Schaub et al., 2014; Yanger et al., 2014).

Targeted genome editing using engineered nucleases can reliably generate defined genetic mutations, although the range of off-target lesions caused by these techniques is unclear. Recent papers in Cell Stem Cell perform high-coverage whole-genome sequencing to demonstrate the feasibility of obtaining correctly targeted pluripotent stem cell clones with minimal unintended modifications.

A recent paper published by Rodgers et al. describes a novel phase of stem cell quiescence, termed GAlert, that serves to prime cells in response to injury-induced signals. These stem cells are located distal to the site of injury and require mTORC1 activity to elicit the alert response.

Two recent papers in Nature describe a remarkable new technique for reprogramming somatic cells back to the embryonic state. Obokata et al. (2014a, 2014b) show that applying stressful stimuli can convert mature cells into progenitors capable of generating all three embryonic germ layer lineages, as well as placental tissue.

In a recent paper in Nature, Vierbuchen et al. (2010) show that fibroblasts can be directly converted into functional neurons by defined factors. This finding sheds new light on the biology underlying cell-fate restrictions and might offer a new avenue for studying neurological diseases.

This issue of Cell Stem Cell includes an unusual Forum article from Leonard Zon and a member of his group, Pulin Li (Li and Zon, 2010xLi, P. and Zon, L. Cell Stem Cell. 2010; 6: 199–202Abstract | Full Text | Full Text PDF | PubMed | Scopus (34)See all ReferencesLi and Zon, 2010). Their article describes the course and outcome of a collaborative discussion approach initiated by Dr. Zon that aimed to resolve the differences of opinion that exist about whether N-cadherin is expressed in hematopoietic stem cells (HSCs) and, if so, whether it plays a functional role in that context. Accompanying the Forum article is a Brief Report from Hosokawa et al. (2010)xHosokawa, K., Arai, F., Yoshihara, H., Iwasaki, H., Hembree, M., Yin, T., Nakamura, Y., Gomei, Y., Takubo, K., Shiaba, H. et al. Cell Stem Cell. 2010; 6: 194–198Abstract | Full Text | Full Text PDF | PubMed | Scopus (60)See all References)Hosokawa et al. (2010), containing experiments that are relevant to part of the discussion. In addition, although it has a different focus and does not cover N-cadherin specifically, Timm Schroeder's Minireview about HSC purification and subpopulations is related to some of the issues that are raised (Schroeder, 2010xSchroeder, T. Cell Stem Cell. 2010; 6: 203–207Abstract | Full Text | Full Text PDF | PubMed | Scopus (60)See all ReferencesSchroeder, 2010).Li and Zon's article describes their perspective on the N-cadherin discussion process and its outcome clearly, so I will not go into details here. Watching the process from the sidelines over the past year has prompted me to think at a broader level about how research fields, and the journals that serve them, can best handle scientific disagreements when they do arise. Many are settled in a rapid and informal way, with scientists discussing their results in detail, exchanging reagents if necessary, and coming to a joint conclusion. In an ideal world, one would like to think that all scientific disagreements could be resolved in this way. However, in the real world, it is not always possible to do so. In most, and perhaps eventually all, cases, over the course of time additional data and new approaches make it possible to reconcile data that previously seemed discrepant. However, in the interim, contradictory results can be confusing and even misleading for the field. It was this type of situation that Dr. Zon set out to address with a mediated interactive discussion approach. Compared to some of the questions faced by the stem cell field, the role of N-cadherin in HSCs is of interest to a relatively small subset of researchers, but it has nevertheless been the subject of conflicting presentations and publications. Addressing it in this way therefore provided both a “test case” of the overall approach and benefit to the field overall. I think it is clear from Li and Zon's article and the discrete conclusions they draw that there is value in this type of process and that it can resolve disagreements. However, I think it is also clear that mediating and overseeing such a process is difficult and time consuming, and reaching agreement on major issues can be very challenging.From the perspective of a journal such as Cell Stem Cell, it seems to me that the only fair approach is to remain neutral in any conflict and to publish studies that meet editorial criteria and peer reviewer standards even if they seem to conflict with previous work. However, there comes a time in many scientific disagreements where additional experiments along similar lines to those published previously do not provide significant new insights. As Li and Zon outline in their article, analysis of the role of N-cadherin in HSCs seems to have reached that point. In addition, many journals, Cell Stem Cell included, have options for community feedback on papers, through online comment systems, letters, and more formal data-supported challenges to published work. With a view to encouraging this type of dialogue, we increased the prominence of our online comment feature in the new “Article of the Future” format that we launched in January this year (for more information, see Marcus, 2009xMarcus, E. Cell. 2009; 139: 11Abstract | Full Text | Full Text PDF | PubMed | Scopus (8)See all ReferencesMarcus, 2009). I encourage all of you, as our readers, to use this feature and provide your perspective on articles that we have published. More informal online venues such as blogs, society-sponsored networks such as the ISSCR groups on LinkedIn and Facebook, and even Twitter, also provide mechanisms for scientific discussion about published work and its interpretation that can help highlight issues for the benefit of the field overall.At a broader level, I think it is also important to bear in mind that, even though scientific disagreements can sometimes be a source of tension, they are, in fact, a good thing. Controversies prompt everyone to rethink their assumptions and devise new experiments to address outstanding issues. Ultimately, therefore, disagreements help drive progress.

Regenerative mechanisms involving either stem cell differentiation or dedifferentiation of mature cells have been described in various systems, but the relationship between such disparate mechanisms is unclear. Two recent papers, one by Sandoval-Guzmán et al. (2013) and one by Tata et al. (2013), address fundamental questions about the universality of reparative regeneration and whether mammals share any properties seen in lower vertebrates.

Summary In a recent Nature Cell Biology paper, Taddei et al. (2008) reveal that deletion of β1 integrin from K5-expressing mammary epithelial basal cells specifically attenuates ductal stem cell activity, without dramatically altering the basal cell layer, or morphogenesis overall.