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Identification of the precise molecular pathways involved in oncogene-induced transformation may help us gain a better understanding of tumor initiation and promotion. Here, we demonstrate that SOX2+ foregut epithelial cells are prone to oncogenic transformation upon mutagenic insults, such as KrasG12D and p53 deletion. GFP-based lineage-tracing experiments indicate that SOX2+ cells are the cells-of-origin of esophagus and stomach hyperplasia. Our observations indicate distinct roles for oncogenic KRAS mutation and P53 deletion. p53 homozygous deletion is required for the acquisition of an invasive potential, and KrasG12D expression, but not p53 deletion, suffices for tumor formation. Global gene expression analysis reveals secreting factors upregulated in the hyperplasia induced by oncogenic KRAS and highlights a crucial role for the CXCR2 pathway in driving hyperplasia. Collectively, the array of genetic models presented here demonstrate that stratified epithelial cells are susceptible to oncogenic insults, which may lead to a better understanding of tumor initiation and aid in the design of new cancer therapeutics. Electronic supplementary material The online version of this article (10.1007/s13238-019-0630-3) contains supplementary material, which is available to authorized users.

Farnesoid X receptor (FXR) agonists are emerging as important potential therapeutics for the treatment of nonalcoholic steatohepatitis (NASH) patients, as they exert positive effects on multiple aspects of the disease. FXR agonists reduce lipid accumulation in the liver, hepatocellular inflammation, hepatic injury, and fibrosis. While there are currently no approved therapies for NASH, the bile acid-derived FXR agonist obeticholic acid (OCA; 6-ethyl chenodeoxycholic acid) has shown promise in clinical studies. Previously, we described the discovery of tropifexor (LJN452), the most potent non-bile acid FXR agonist currently in clinical investigation. Here, we report the discovery of a novel chemical series of non-bile acid FXR agonists based on a tricyclic dihydrochromenopyrazole core from which emerged nidufexor (LMB763), a compound with partial FXR agonistic activity in vitro and FXR-dependent gene modulation in vivo. Nidufexor has advanced to Phase 2 human clinical trials in patients with NASH and diabetic nephropathy.

Cancer comprises heterogeneous cells, ranging from highly proliferative immature precursors to more differentiated cell lineages. The emergence of the "cancer stem cell" (CSC) hypothesis that they are the cells responsible for resistance, metastasis and secondary tumor appearance identifies these populations as novel obligatory targets for the treatment of cancer. CSCs, like their normal tissue-specific stem cell counterparts, are multipotent, partially differentiated, self-sustaining, yet transformed cells. To date, most studies on CSC biology have relied on the use of murine models and primary human material. In spite of much progress, the use of primary material presents several limitations that limit our understanding of the mechanisms underlying CSC formation, the similarities between normal stem cells and CSCs and ultimately, the possibility for developing targeted therapies. Recently, different strategies for controlling cell fate have been applied to the modeling of human cancer initiation and for the generation of human CSC models. Here we will summarize recent developments in the establishment and application of reprogramming strategies for the modeling of human cancer initiation and CSC formation.

Cancer stem cells (CSCs) have been implicated in the initiation and maintenance of tumour growth as well as metastasis. Recent reports link stemness to epithelial–mesenchymal transition (EMT) in cancer. However, there is still little knowledge about the molecular markers of those events. In silico analysis of RNA profiles of 36 pancreatic ductal adenocarcinomas (PDAC) reveals an association of the expression of CD95 with EMT and stemness that was validated in CSCs isolated from PDAC surgical specimens. CD95 expression was also higher in metastatic pancreatic cells than in primary PDAC. Pharmacological inhibition of CD95 activity reduced PDAC growth and metastasis in CSC-derived xenografts and in a murine syngeneic model. On the mechanistic level, Sck was identified as a novel molecule indispensable for CD95's induction of cell cycle progression. This study uncovers CD95 as a marker of EMT and stemness in PDAC. It also addresses the molecular mechanism by which CD95 drives tumour growth and opens tantalizing therapeutic possibilities in PDAC.

The generation of human induced pluripotent stem cells (iPS) has raised enormous expectations within the biomedical community due to their potential vast implications in regenerative and personalized medicine. However, reprogramming to iPS is still not fully comprehended. Difficulties found in ascribing specific molecular patterns to pluripotent cells (PSCs), and inherent inter-line and intra-line variability between different PSCs need to be resolved. Additionally, and despite multiple assumptions, it remains unclear whether the current in vitro culturing conditions for the maintenance and differentiation of PSCs do indeed recapitulate the developmental processes observed in vivo. As a consequence, basic questions such as what is the actual nature of PSCs remain unanswered and different theories have emerged in regards to the identity of these valuable cell population. Here we discuss on the published theories for defining PSC identity, the implications that the different postulated models have for the reprogramming field as well as speculate on potential future directions that might be opened once a precise knowledge on the nature of PSCs is accomplished.

Somatic cell nuclear reprogramming is opening new doors for the modeling of human disease phenotypes in vitro, the identification of novel therapeutic compounds and diagnostic factors as well as future autologous cell replacement therapies. Despite the potential that reprogramming technologies bring, there are remaining concerns preventing their broad application in the short-term. One of them is the safety concern associated with the use of stem cell derivatives, those generated by reprogramming or even when embryonic stem cells are employed. Here we summarize the current knowledge in the field of stem cells and reprogramming with a particular focus on the pitfalls preventing rapid translation of stem cell technologies into the clinic. We discuss the most recent findings on immunogenicity and tumorigenicity of reprogrammed cells. We additionally provide an overview on the potential applications that reprogramming approaches might bring to the immunological field and elaborate on the use of induced pluripotent stem cells (iPSCs) with pre-arranged immune receptors for the development of future immunotherapeutic approaches. The use of reprogramming approaches can represent and provide groundbreaking strategies previously unachievable for stem cell engineering aimed at modulating immune responses. In summary, we provide an overview on the different topics related to the use of stem cells and highlight the most provocative, yet perhaps currently underappreciated, aspect of combining immunological and reprogramming strategies for the treatment of human disease.

Lineage conversion of one somatic cell type into another constitutes an attractive approach for research and clinical use. Lineage conversion can proceed in a direct manner, in the absence of proliferation and multipotent progenitor generation, or in an indirect manner, by the generation of expandable multipotent progenitor states. Here we report on the development of a combined reprogramming methodology that, transitioning through a plastic intermediate state, allows for the generation of human mesodermal progenitor cells while circumventing the traditional hallmarks of pluripotency. Converted mesodermal progenitor cells demonstrated bi-potent differentiation potential and were able to generate endothelial and smooth muscle lineages. Importantly, human fibroblasts can be converted into angioblast-like progenitor cells by non-integrative approaches. Differentiated angioblast-like cells exhibit neo-angiogenesis and anastomosis in vivo. The methodology for indirect lineage conversion to angioblast-like cells described here adds to the armamentarium of reprogramming approaches aimed at the clinical treatment of ischemic pathologies.

SummaryInjury to the central nervous system initiates an uncontrolled inflammatory response that results in both tissue repair and destruction. Here, we showed that, in rodents and humans, injury to the spinal cord triggered surface expression of CD95 ligand (CD95L, FasL) on peripheral blood myeloid cells. CD95L stimulation of CD95 on these cells activated phosphoinositide 3-kinase (PI3K) and metalloproteinase-9 (MMP-9) via recruitment and activation of Syk kinase, ultimately leading to increased migration. Exclusive CD95L deletion in myeloid cells greatly decreased the number of neutrophils and macrophages infiltrating the injured spinal cord or the inflamed peritoneum after thioglycollate injection. Importantly, deletion of myeloid CD95L, but not of CD95 on neural cells, led to functional recovery of spinal injured animals. Our results indicate that CD95L acts on peripheral myeloid cells to induce tissue damage. Thus, neutralization of CD95L should be considered as a means to create a controlled beneficial inflammatory response.

SummaryAdult neurogenesis persists in the subventricular zone and the dentate gyrus and can be induced upon central nervous system injury. However, the final contribution of newborn neurons to neuronal networks is limited. Here we show that in neural stem cells, stimulation of the “death receptor” CD95 does not trigger apoptosis but unexpectedly leads to increased stem cell survival and neuronal specification. These effects are mediated via activation of the Src/PI3K/AKT/mTOR signaling pathway, ultimately leading to a global increase in protein translation. Induction of neurogenesis by CD95 was further confirmed in the ischemic CA1 region, in the naive dentate gyrus, and after forced expression of CD95L in the adult subventricular zone. Lack of hippocampal CD95 resulted in a reduction in neurogenesis and working memory deficits. Following global ischemia, CD95-mediated brain repair rescued behavioral impairment. Thus, we identify the CD95/CD95L system as an instructive signal for ongoing and injury-induced neurogenesis.

Despite the profound and rapid advancements in reprogramming technologies since the generation of the first induced pluripotent stem cells (iPSCs) in 2006[1], the molecular basics of the process and its implications are still not fully understood. Recent work has suggested that a subset of TFs, so called "Pioneer TFs", play an important role during the stochastic phase of iPSC reprogramming [2-6]. Pioneer TFs activities differ from conventional transcription factors in their mechanism of action. They bind directly to condensed chromatin and elicit a series of chromatin remodeling events that lead to opening of the chromatin. Chromatin decondensation by pioneer factors progressively occurs during cell division and in turn exposes specific gene promoters in the DNA to which TFs can now directly bind to promoters that are readily accessible[2, 6]. Here, we will summarize recent advancements on our understanding of the molecular mechanisms underlying reprogramming to iPSC as well as the implications that pioneer Transcription Factor activities might play during different lineage conversion processes.

Background— Long noncoding RNAs (lncRNAs) have emerged as critical epigenetic regulators with important functions in development and disease. Here, we sought to identify and functionally characterize novel lncRNAs critical for vertebrate development. Methods and Results— By relying on human pluripotent stem cell differentiation models, we investigated lncRNAs differentially regulated at key steps during human cardiovascular development with a special focus on vascular endothelial cells. RNA sequencing led to the generation of large data sets that serve as a gene expression roadmap highlighting gene expression changes during human pluripotent cell differentiation. Stage-specific analyses led to the identification of 3 previously uncharacterized lncRNAs, TERMINATOR , ALIEN , and PUNISHER , specifically expressed in undifferentiated pluripotent stem cells, cardiovascular progenitors, and differentiated endothelial cells, respectively. Functional characterization, including localization studies, dynamic expression analyses, epigenetic modification monitoring, and knockdown experiments in lower vertebrates, as well as murine embryos and human cells, confirmed a critical role for each lncRNA specific for each analyzed developmental stage. Conclusions— We have identified and functionally characterized 3 novel lncRNAs involved in vertebrate and human cardiovascular development, and we provide a comprehensive transcriptomic roadmap that sheds new light on the molecular mechanisms underlying human embryonic development, mesodermal commitment, and cardiovascular specification.

Hypoxia is a hallmark of solid tumors that drives malignant progression by altering epigenetic controls. In breast tumors, aberrant DNA methylation is a prevalent epigenetic feature associated with increased risk of metastasis and poor prognosis. However, the mechanism by which hypoxia alters DNA methylation or other epigenetic controls that promote breast malignancy remains poorly understood. We discovered that hypoxia deregulates TET1 and TET3, the enzymes that catalyze conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), thereby leading to breast tumor–initiating cell (BTIC) properties. TET1/3 and 5hmC levels were closely associated with tumor hypoxia, tumor malignancy, and poor prognosis in breast cancer patients. Mechanistic investigations showed that hypoxia leads to genome-wide changes in DNA hydroxymethylation associated with upregulation of TNFα expression and activation of its downstream p38–MAPK effector pathway. Coordinate functions of TET1 and TET3 were also required to activate TNFα–p38–MAPK signaling as a response to hypoxia. Our results reveal how signal transduction through the TET–TNFα–p38–MAPK signaling axis is required for the acquisition of BTIC characteristics and tumorigenicity in vitro and in vivo, with potential implications for how to eradicate BTIC as a therapeutic strategy. Cancer Res; 75(18); 3912–24. ©2015 AACR.

SummaryMitochondrial diseases include a group of maternally inherited genetic disorders caused by mutations in mtDNA. In most of these patients, mutated mtDNA coexists with wild-type mtDNA, a situation known as mtDNA heteroplasmy. Here, we report on a strategy toward preventing germline transmission of mitochondrial diseases by inducing mtDNA heteroplasmy shift through the selective elimination of mutated mtDNA. As a proof of concept, we took advantage of NZB/BALB heteroplasmic mice, which contain two mtDNA haplotypes, BALB and NZB, and selectively prevented their germline transmission using either mitochondria-targeted restriction endonucleases or TALENs. In addition, we successfully reduced human mutated mtDNA levels responsible for Leber’s hereditary optic neuropathy (LHOND), and neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP), in mammalian oocytes using mitochondria-targeted TALEN (mito-TALENs). Our approaches represent a potential therapeutic avenue for preventing the transgenerational transmission of human mitochondrial diseases caused by mutations in mtDNA.PaperClip

Glioblastoma multiforme (GBM) remains the most aggressive brain tumor, fatal within two years from diagnosis in most patients. Oncolytic viruses, such as oncolytic herpes simplex viruses (oHSVs), constitute a promising therapeutic approach in cancer (1). Yet, direct delivery of oHSV has shown clinical limitations in terms of efficacy. Duebgen et al. analyzed the role of oHSVs for the treatment of GBM by employing cell delivery systems based on the use of mesenchymal stem cells (MSCs) encapsulated in synthetic extracellular matrices (sECMs). Loading of MSCs with oHSVs demonstrated statistically significant advantages over direct delivery of oHSVs, in terms of efficacy, in clinical animal models of GBM (2). Engineering of oHSVs with tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL) molecules further enhanced antitumoral responses and led to increased survival. While the study by Duebgen et al. represents a substantial advancement on the development of therapies against GBM, we also find issues that require further consideration. First, MSCs have demonstrated immunomodulatory roles affecting T-cells, B-cells, and dendritic cells (DCs) (3), as well as brain immunity through regulation of microglia (4). Immune cells synthesize cytokines mediating tissue inflammation, and inflammation has been linked to immune evasion, migration, and growth of several cancer types, including brain tumors (5). Therefore, the immunodeficient xenograft models used in this study might not fully recapitulate human physiology and, accordingly, the responses that MSCs might elicit in human patients. Indeed, it is widely accepted that inflammation should be considered when aiming at developing novel anticancer therapies. As MSCs can be readily isolated from rodents, autologous immunocompetent models might provide important information parallel to the use of xenograft heterologous transplantation experiments. Therefore, evaluating the role of inflammation remains critical for the future development of autologous therapies in humans, as suggested by the authors. Second, we also wondered whether the use of oHSVs-MSCs might provide additional beneficial effects in combination with standard strategies. MSCs are sensitive to various types of anticancer drugs (6) that could provoke changes in their behavior (eg, differentiation), or even induce apoptosis. An alternative possibility is that radio and chemotherapy effectively target the differentiated tumoral mass, whereas oHSVs-MSCs might provide a beneficial effect against glioma stem cells, populations presumably resistant to conventional therapies and responsible for tumor relapse, as well as patient death upon migration into the contralateral hemisphere. Last, TNF family members have demonstrated to drive basal glioma migration in syngeneic animal models (7). However, the study by Duebgen et al. (2) relies on the use of human cancer lines that hardly recapitulate the infiltrative properties of GBM. Therefore, it would be of interest to evaluate the antitumoral responses elicited upon TRAIL-loaded oHSVs in models more faithfully recapitulating human GBM infiltrative behavior.

Reprogramming technologies have emerged as a promising approach for future regenerative medicine. Here, we report on the establishment of a novel methodology allowing for the conversion of human fibroblasts into hematopoietic progenitor-like cells with macrophage differentiation potential. SOX2 overexpression in human fibroblasts, a gene found to be upregulated during hematopoietic reconstitution in mice, induced the rapid appearance of CD34+ cells with a concomitant upregulation of mesoderm-related markers. Profiling of cord blood hematopoietic progenitor cell populations identified miR-125b as a factor facilitating commitment of SOX2-generated CD34+ cells to immature hematopoietic-like progenitor cells with grafting potential. Further differentiation toward the monocytic lineage resulted in the appearance of CD14+ cells with functional phagocytic capacity. In vivo transplantation of SOX2/miR-125b-generated CD34+ cells facilitated the maturation of the engrafted cells toward CD45+ cells and ultimately the monocytic/macrophage lineage. Altogether, our results indicate that strategies combining lineage conversion and further lineage specification by in vivo or in vitro approaches could help to circumvent long-standing obstacles for the reprogramming of human cells into hematopoietic cells with clinical potential. Stem Cells 2014;32:2923–2938

International audience; This protocol presents recently developed methodologies for the differentiation of human pluripotent stem cells (hPSCs) into ureteric bud (UB) progenitor-like cells. Differentiation of human PSCs to UB progenitor-like cells allows for the generation of chimeric kidney cultures in which the human cells can self-assemble into chimeric 3D structures in combination with embryonic mouse kidney cells over a period of 18 d. UB progenitor-like cells are generated by a two-step process that combines in vitro commitment of human PSCs, whether embryonic stem cells (ESCs) or induced PSCs (iPSCs), under chemically defined culture conditions, with ex vivo cultures for the induction of 3D organogenesis. The models described here provide new opportunities for investigating human kidney development, modeling disease, evaluating regenerative medicine strategies, as well as for toxicology studies.

c-Myc and phosphatidylinositol 3-OH kinase (PI3K) both participate in diverse cellular processes, including cell cycle control and tumorigenic transformation. They also contribute to preserving embryonic stem cell (ESC) characteristics. However, in spite of the vast knowledge, the molecular relationship between c-Myc and PI3K in ESCs is not known. Herein, we demonstrate that c-Myc and PI3K function cooperatively but independently to support ESC self-renewal when murine ESCs are cultured under conventional culture condition. Interestingly, culture of ESCs in 2i-condition including a GSK3β and MEK inhibitor renders both PI3K and Myc signaling dispensable for the maintenance of pluripotent properties. These results suggest that the requirement for an oncogenic proliferation-dependent mechanism sustained by Myc and PI3K is context dependent and that the 2i-condition liberates ESCs from the dependence of this mechanism. Stem Cells 2015;33:713–725

International audience; Heart failure is a leading cause of mortality and morbidity in the developed world, partly because mammals lack the ability to regenerate heart tissue. Whether this is due to evolutionary loss of regenerative mechanisms present in other organisms or to an inability to activate such mechanisms is currently unclear. Here we decipher mechanisms underlying heart regeneration in adult zebrafish and show that the molecular regulators of this response are conserved in mammals. We identified miR-99/100 and Let-7a/c and their protein targets smarca5 and fntb as critical regulators of cardiomyocyte dedifferentiation and heart regeneration in zebrafish. Although human and murine adult cardiomyocytes fail to elicit an endogenous regenerative response after myocardial infarction, we show that in vivo manipulation of this molecular machinery in mice results in cardiomyocyte dedifferentiation and improved heart functionality after injury. These data provide a proof of concept for identifying and activating conserved molecular programs to regenerate the damaged heart.

International audience; Diseases affecting the kidney constitute a major health issue worldwide. Their incidence and poor prognosis affirm the urgent need for the development of new therapeutic strategies. Recently, differentiation of pluripotent cells to somatic lineages has emerged as a promising approach for disease modelling and cell transplantation. Unfortunately, differentiation of pluripotent cells into renal lineages has demonstrated limited success. Here we report on the differentiation of human pluripotent cells into ureteric-bud-committed renal progenitor-like cells. The generated cells demonstrated rapid and specific expression of renal progenitor markers on 4-day exposure to defined media conditions. Further maturation into ureteric bud structures was accomplished on establishment of a three-dimensional culture system in which differentiated human cells assembled and integrated alongside murine cells for the formation of chimeric ureteric buds. Altogether, our results provide a new platform for the study of kidney diseases and lineage commitment, and open new avenues for the future application of regenerative strategies in the clinic.

International audience; Reprogramming strategies allow for the generation of virtually any cell type of the human body, which could be useful for cell-based therapy. Among the different reprogramming technologies available, direct lineage conversion offers the possibility to change the phenotype of a cell type to another one without pushing cells backwards to a plastic/proliferative stage. This approach has raised the possibility to apply a similar process in vivo in order to compensate for functional cell loss. Historically, the cerebral tissue is a prime choice for developing cell-based treatments. As local pericyte accumulation is observed after central nervous system injury, it can be reasoned that this cell type might be a good candidate for the conversion into new neurons in vivo. In this article, and by focusing on recent observations from Karow and colleagues demonstrating the possibility to convert human brain-derived pericytes into functional neurons, we present a brief overview of the state of the art and attempt to offer perspective as to how these interesting laboratory findings could be translated in the clinic.

Lineage conversion has recently attracted increasing attention as a potential alternative to the directed differentiation of pluripotent cells to obtain cells of a given lineage. Different means allowing for cell identity switch have been reported. Lineage conversion relied initially on the discovery of specific transcription factors generally enriched and characteristic of the target cell, and their forced expression in cells of a different fate. This approach has been successful in various cases, from cells of the hematopoietic systems to neurons and cardiomyocytes. Furthermore, recent reports have suggested the possibility of establishing a general lineage conversion approach bypassing pluripotency. This requires a first phase of epigenetic erasure achieved by short overexpression of the factors used to reprogram cells to a pluripotent state (such as a combination of Sox2, Klf4, c-Myc and Oct4), followed by exposure to specific developmental cues. Here we present these different direct conversion methodologies and discuss their potential as alternatives to using induced pluripotent stem cells and differentiation protocols to generate cell populations of a given fate.

One of the current chief goals of regenerative medicine involves finding a way to overcome the lack of efficient treatments for thousands of diseases. Recently, increasing evidence indicates that genetic defects observed in patient somatic cells could be erased and/or alleviated by direct reprogramming toward pluripotency and recapitulated upon directed differentiation to specific cell lineages. Therefore, major efforts have been put forth to establish efficient models of disease by the use of induced pluripotent stem cells (iPSCs). In addition to disease modeling, iPSC technology also paved the way for the development of methods allowing for the generation of transplantable cellular products to reduce/halt the progression of disease symptoms or even ultimately to cure diseases. It is likely that, in the near future, these two strategies will be complementary in the discovery of new alternative treatments. However and despite enormous enthusiasm, iPSC technology still presents several pitfalls that have to be circumvented. In the present work, we will summarize the present state of iPSC technologies alongside several alternatives to the use of iPSCs that could contribute to the establishment of cell therapies.

Pluripotent stem cells possess the capacity for self-renewal and the ability to differentiate into all cell types of the three embryonic germ layers. Accordingly, given their potential use in regenerative medicine, they have long attracted the attention of researchers. Embryonic stem cells (ESCs) represent the model pluripotent stem cell population. However, the use of ESCs in regenerative therapies faces major hurdles—namely, immune rejection and the necessity to use early-stage embryos for ESC isolation. Clinical Pharmacology & Therapeutics (2011) 89 5, 746–749. doi:10.1038/clpt.2010.341

Apoptosis or programmed cell-death is an important process involved in tissue homeostasis, development and a variety of immune responses.(1) The apoptotic program can be activated via transmembrane receptors stimulated by their cognate ligands. The presence of a well-conserved region of 80 amino acids in their intracellular tail, the Death-Domain (DD), has conferred those receptors the general name of "death receptors". Death receptors are a subfamily of the TNF receptor superfamily, which includes the TNF receptor-I (TNFR1), TRAMP, DR3/APO-3, TRAIL-receptor 1 (TRAIL-R1/DR4), TRAIL-receptor 2 (TRAIL-R1/DR5), DR6 and CD95 (Fas/Apo-1). The pro-apoptotic properties of the CD95 system have been extensively studied during the past decades. Nevertheless, CD95 has now emerged as an important activator of other major signaling pathways leading to a variety of phenotypes. In the last years, stimulation of CD95 has been described to activate the MAPK pathways p38, JNK and ERK. (2-6) CD95 has also been shown to activate the transcription factor NFkB. (67-9) However, the molecular mechanisms leading to activation of such pathways are not fully understood and their contribution to the final phenotype is still unclear. CD95 has been shown to be particularly involved in tumor cell invasion, (6) neurite sprouting and outgrowth,(5,10) as well as cell proliferation(11,12)--functions that lay to rest the general assumption of CD95 as a death receptor. In our group we have recently described a novel molecular link between CD95 and the phosphatydilinositol-3-kinase (PI3K) pathway in Glioblastoma multiforme. In the present review we will discuss the past and present knowledge of the CD95/CD95L system and its role in PI3K signaling.

SummaryInvasion of surrounding brain tissue by isolated tumor cells represents one of the main obstacles to a curative therapy of glioblastoma multiforme. Here we unravel a mechanism regulating glioma infiltration. Tumor interaction with the surrounding brain tissue induces CD95 Ligand expression. Binding of CD95 Ligand to CD95 on glioblastoma cells recruits the Src family member Yes and the p85 subunit of phosphatidylinositol 3-kinase to CD95, which signal invasion via the glycogen synthase kinase 3-β pathway and subsequent expression of matrix metalloproteinases. In a murine syngeneic model of intracranial GBM, neutralization of CD95 activity dramatically reduced the number of invading cells. Our results uncover CD95 as an activator of PI3K and, most importantly, as a crucial trigger of basal invasion of glioblastoma in vivo.

Gene-editing technologies and patient-specific induced pluripotent stem cells (iPSCs) may represent an unprecedented opportunity for merging the stem cell and traditional gene therapy fields to fulfill the promises of regenerative medicine.

Finding a cure for cardiovascular disease remains a major unmet medical need. Recent investigations have started to unveil the mechanisms of mammalian heart regeneration. The study of the regenerative mechanisms in lower vertebrate and mammalian animal models has provided clues for the experimental activation of proregenerative responses in the heart. In parallel, the use of endogenous adult stem cell populations alongside the recent application of reprogramming technologies has created major expectations for the development of therapies targeting heart disease. Together, these new approaches are bringing us closer to more successful strategies for the treatment of heart disease.