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2. Isthmus progenitor cells contribute to homeostatic cellular turnover and support regeneration following intestinal injury

Author

Malagola, Ermanno, primary, Vasciaveo, Alessandro, additional, Ochiai, Yosuke, additional, Kim, Woosook, additional, Zheng, Biyun, additional, Zanella, Luca, additional, Wang, Alexander L.E., additional, Middelhoff, Moritz, additional, Nienhüser, Henrik, additional, Deng, Lu, additional, Wu, Feijing, additional, Waterbury, Quin T., additional, Belin, Bryana, additional, LaBella, Jonathan, additional, Zamechek, Leah B., additional, Wong, Melissa H., additional, Li, Linheng, additional, Guha, Chandan, additional, Cheng, Chia-Wei, additional, Yan, Kelley S., additional, Califano, Andrea, additional, and Wang, Timothy C., additional

Published
2024
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3. Time-resolved fate mapping identifies the intestinal upper crypt zone as an origin of Lgr5+ crypt base columnar cells

Author

Capdevila, Claudia, primary, Miller, Jonathan, additional, Cheng, Liang, additional, Kornberg, Adam, additional, George, Joel J., additional, Lee, Hyeonjeong, additional, Botella, Theo, additional, Moon, Christine S., additional, Murray, John W., additional, Lam, Stephanie, additional, Calderon, Ruben I., additional, Malagola, Ermanno, additional, Whelan, Gary, additional, Lin, Chyuan-Sheng, additional, Han, Arnold, additional, Wang, Timothy C., additional, Sims, Peter A., additional, and Yan, Kelley S., additional

Published
2024
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4. Intestinal Enteroendocrine Lineage Cells Possess Homeostatic and Injury-Inducible Stem Cell Activity

Author

Yan, Kelley S, Gevaert, Olivier, Zheng, Grace XY, Anchang, Benedict, Probert, Christopher S, Larkin, Kathryn A, Davies, Paige S, Cheng, Zhuan-fen, Kaddis, John S, Han, Arnold, Roelf, Kelly, Calderon, Ruben I, Cynn, Esther, Hu, Xiaoyi, Mandleywala, Komal, Wilhelmy, Julie, Grimes, Sue M, Corney, David C, Boutet, Stéphane C, Terry, Jessica M, Belgrader, Phillip, Ziraldo, Solongo B, Mikkelsen, Tarjei S, Wang, Fengchao, von Furstenberg, Richard J, Smith, Nicholas R, Chandrakesan, Parthasarathy, May, Randal, Chrissy, Mary Ann S, Jain, Rajan, Cartwright, Christine A, Niland, Joyce C, Hong, Young-Kwon, Carrington, Jill, Breault, David T, Epstein, Jonathan, Houchen, Courtney W, Lynch, John P, Martin, Martin G, Plevritis, Sylvia K, Curtis, Christina, Ji, Hanlee P, Li, Linheng, Henning, Susan J, Wong, Melissa H, and Kuo, Calvin J

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Stem Cell Research, Stem Cell Research - Nonembryonic - Non-Human, Regenerative Medicine, Digestive Diseases, 1.1 Normal biological development and functioning, Underpinning research, Animals, Antigens, Differentiation, Enteroendocrine Cells, Gene Expression Regulation, Intestinal Mucosa, Jejunum, Mice, Mice, Transgenic, Stem Cells, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Several cell populations have been reported to possess intestinal stem cell (ISC) activity during homeostasis and injury-induced regeneration. Here, we explored inter-relationships between putative mouse ISC populations by comparative RNA-sequencing (RNA-seq). The transcriptomes of multiple cycling ISC populations closely resembled Lgr5+ ISCs, the most well-defined ISC pool, but Bmi1-GFP+ cells were distinct and enriched for enteroendocrine (EE) markers, including Prox1. Prox1-GFP+ cells exhibited sustained clonogenic growth in vitro, and lineage-tracing of Prox1+ cells revealed long-lived clones during homeostasis and after radiation-induced injury in vivo. Single-cell mRNA-seq revealed two subsets of Prox1-GFP+ cells, one of which resembled mature EE cells while the other displayed low-level EE gene expression but co-expressed tuft cell markers, Lgr5 and Ascl2, reminiscent of label-retaining secretory progenitors. Our data suggest that the EE lineage, including mature EE cells, comprises a reservoir of homeostatic and injury-inducible ISCs, extending our understanding of cellular plasticity and stemness.

Published
2017

6. Identification and Specification of the Mouse Skeletal Stem Cell

Author

Chan, Charles KF, Seo, Eun Young, Chen, James Y, Lo, David, McArdle, Adrian, Sinha, Rahul, Tevlin, Ruth, Seita, Jun, Vincent-Tompkins, Justin, Wearda, Taylor, Lu, Wan-Jin, Senarath-Yapa, Kshemendra, Chung, Michael T, Marecic, Owen, Tran, Misha, Yan, Kelley S, Upton, Rosalynd, Walmsley, Graham G, Lee, Andrew S, Sahoo, Debashis, Kuo, Calvin J, Weissman, Irving L, and Longaker, Michael T

Subjects
Medical Biotechnology, Biomedical and Clinical Sciences, Stem Cell Research - Embryonic - Non-Human, Genetics, Stem Cell Research - Nonembryonic - Non-Human, Transplantation, Pediatric, Regenerative Medicine, Stem Cell Research, Stem Cell Research - Nonembryonic - Human, 1.1 Normal biological development and functioning, Development of treatments and therapeutic interventions, Underpinning research, 5.2 Cellular and gene therapies, 2.1 Biological and endogenous factors, Aetiology, Musculoskeletal, Animals, Bone Morphogenetic Proteins, Bone and Bones, Cartilage, Cell Lineage, Crosses, Genetic, Mesenchymal Stem Cells, Mice, Mice, Inbred C57BL, Signal Transduction, Biological Sciences, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

How are skeletal tissues derived from skeletal stem cells? Here, we map bone, cartilage, and stromal development from a population of highly pure, postnatal skeletal stem cells (mouse skeletal stem cells, mSSCs) to their downstream progenitors of bone, cartilage, and stromal tissue. We then investigated the transcriptome of the stem/progenitor cells for unique gene-expression patterns that would indicate potential regulators of mSSC lineage commitment. We demonstrate that mSSC niche factors can be potent inducers of osteogenesis, and several specific combinations of recombinant mSSC niche factors can activate mSSC genetic programs in situ, even in nonskeletal tissues, resulting in de novo formation of cartilage or bone and bone marrow stroma. Inducing mSSC formation with soluble factors and subsequently regulating the mSSC niche to specify its differentiation toward bone, cartilage, or stromal cells could represent a paradigm shift in the therapeutic regeneration of skeletal tissues.

Published
2015

7. BHLHA15-Positive Secretory Precursor Cells Can Give Rise to Tumors in Intestine and Colon in Mice

Author

Hayakawa, Yoku, Tsuboi, Mayo, Asfaha, Samuel, Kinoshita, Hiroto, Niikura, Ryota, Konishi, Mitsuru, Hata, Masahiro, Oya, Yukiko, Kim, Woosook, Middelhoff, Moritz, Hikiba, Yohko, Higashijima, Naoko, Ihara, Sozaburo, Ushiku, Tetsuo, Fukayama, Masashi, Tailor, Yagnesh, Hirata, Yoshihiro, Guha, Chandan, Yan, Kelley S., Koike, Kazuhiko, and Wang, Timothy C.

Published
2019
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10. Gluten induces rapid reprogramming of natural memory αβ and γδ intraepithelial T cells to induce cytotoxicity in celiac disease

Author

Kornberg, Adam, primary, Botella, Theo, additional, Moon, Christine S., additional, Rao, Samhita, additional, Gelbs, Jared, additional, Cheng, Liang, additional, Miller, Jonathan, additional, Bacarella, Alyssa M., additional, García-Vilas, Javier A., additional, Vargas, Justin, additional, Yu, Xuechen, additional, Krupska, Izabela, additional, Bush, Erin, additional, Garcia-Carrasquillo, Reuben, additional, Lebwohl, Benjamin, additional, Krishnareddy, Suneeta, additional, Lewis, Suzanne, additional, Green, Peter H. R., additional, Bhagat, Govind, additional, Yan, Kelley S., additional, and Han, Arnold, additional

Published
2023
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13. Immature myeloid cells are indispensable for intestinal regeneration post irradiation injury

Author

Jiang, Zhengyu, Waterbury, Quin T., Fu, Na, Kim, Woosook, Malagola, Ermanno, Guha, Chandan, Shawber, Carrie J., Yan, Kelley S., and Wang, Timothy C.

Subjects
Article
Abstract

SUMMARYThe intestinal epithelium functions both in nutrient absorption and as a barrier, separating the luminal contents from a network of vascular, fibroblastic, and immune cells underneath. Following injury to the intestine, multiple different cell populations cooperate to drive regeneration of the mucosa. Immature myeloid cells (IMCs), marked by histidine decarboxylase (Hdc), participate in regeneration of multiple organs such as the colon and central nervous system. Here, we found that IMCs infiltrate the injured intestine and promote epithelial regeneration and modulate LEC activity. IMCs produce prostaglandin E2 (PGE2), which promotes LEC lymphangiogenesis and upregulation of pro-regenerative factors including RSPO3. Moreover, we found that IMC recruitment into the intestine is driven by invading microbial signals. Accordingly, antibiotic eradication of the intestinal microbiome prior to WB-IR inhibits IMC recruitment, and consequently, intestinal recovery. We propose that IMCs play a critical role in intestinal repair and implicate gut microbes as mediators of intestinal regeneration.

Published
2023

16. R-SPONDIN2 mesenchymal cells form the bud tip progenitor niche during human lung development

Author

Hein, Renee F.C., primary, Wu, Joshua H., additional, Holloway, Emily M., additional, Frum, Tristan, additional, Conchola, Ansley S., additional, Tsai, Yu-Hwai, additional, Wu, Angeline, additional, Fine, Alexis S., additional, Miller, Alyssa J., additional, Szenker-Ravi, Emmanuelle, additional, Yan, Kelley S., additional, Kuo, Calvin J., additional, Glass, Ian, additional, Reversade, Bruno, additional, and Spence, Jason R., additional

Published
2022
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17. R-SPONDIN2(+) mesenchymal cells form the bud tip progenitor niche during human lung development

Author

Reversade, Bruno, Hein, Renee F. C.; Wu, Joshua H.; Holloway, Emily M.; Frum, Tristan; Conchola, Ansley S.; Tsai, Yu-Hwai; Wu, Angeline; Fine, Alexis S.; Miller, Alyssa J.; Szenker-Ravi, Emmanuelle; Yan, Kelley S.; Kuo, Calvin J.; Glass, Ian; Frum, Tristan; Glass, Ian; Spence, Jason R., School of Medicine, Reversade, Bruno, Hein, Renee F. C.; Wu, Joshua H.; Holloway, Emily M.; Frum, Tristan; Conchola, Ansley S.; Tsai, Yu-Hwai; Wu, Angeline; Fine, Alexis S.; Miller, Alyssa J.; Szenker-Ravi, Emmanuelle; Yan, Kelley S.; Kuo, Calvin J.; Glass, Ian; Frum, Tristan; Glass, Ian; Spence, Jason R., and School of Medicine

Abstract

The human respiratory epithelium is derived from a progenitor cell in the distal buds of the developing lung. These ""bud tip progenitors'' are regulated by reciprocal signaling with surrounding mesenchyme; however, mesenchymal heterogeneity and function in the developing human lung are poorly understood. We interrogated single-cell RNA sequencing data from multiple human lung specimens and identified a mesenchymal cell population present during development that is highly enriched for expression of theWNT agonist RSPO2, and we found that the adjacent bud tip progenitors are enriched for the RSPO2 receptor LGR5. Functional experiments using organoid models, explant cultures, and FACS-isolated RSPO2(+) mesenchyme show that RSPO2 is a critical niche cue that potentiates WNT signaling in bud tip progenitors to support their maintenance and multipotency., This project has been made possible in part by grant number CZF2019-002440 from the Chan Zuckerberg Initiative DAF, an advised fund from the Silicon Valley Community Foundation, and in part by the NIH-NHLBI (R01HL119215) funding to J.R.S.; R.F.C.H. was supported by a NIH Tissue En- gineering and Regenerative Medicine Training Grant (NIH-NIDCR T32DE 007057) and by a Ruth L. Kirschstein Predoctoral Individual National Research Service Award (NIH-NHLBI F31HL152531); A.J.M. was supported by a Ruth L. Kirschstein Predoctoral Individual National Research Service Award (NIH- NHLBI F31HL142197); E.M.H. was supported by a Ruth L. Kirschstein Predoc- toral Individual National Research Service Award (NIH-NHBLI F31HL146162); T.F. was supported by a NIH Tissue Engineering and Regenerative Medicine Training Grant (NIH-NIDCR T32DE007057); A.S.C. was supported by the T32 Michigan Medical Scientist Training Program (5T32GM007863-40); I.G. and the University of Washington Laboratory of Developmental Biology was supported by NIH award number 5R24HD000836 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). B.R. is a fellow of the Branco Weiss Foundation (Switzerland) and the National Research Foundation (Singapore), and an A*STAR and EMBO Young Investi- gator. This work was supported by an inaugural Use-Inspired Basic Research (UIBR) central fund from the Agency for Science, Technology and Research (A*STAR) and National Medical Research Council Open Fund– Individual Research Grants (OF-YIRG,#OFYIRG18May-0053; and OF-IRG, #OFIRG20- Nov-0057), to E.S.-R and B.R., respectively. We would like to thank Judy Opp and the University of Michigan Advanced Genomics core for the operation of the 103 chromium single-cell capture plat- form, the University of Michigan Microscopy core for providing access to confocal microscopes, the Flow Cytometry core for providing access to flow cytometers, and the Vector core for providing lentivirus production and ad

Published
2022

19. Multiplexed single-cell analysis reveals prognostic and nonprognostic T cell types in human colorectal cancer

Author

Masuda, Kazuya, primary, Kornberg, Adam, additional, Miller, Jonathan, additional, Lin, Sijie, additional, Suek, Nathan, additional, Botella, Theo, additional, Secener, Kerim A., additional, Bacarella, Alyssa M., additional, Cheng, Liang, additional, Ingham, Matthew, additional, Rosario, Vilma, additional, Al-Mazrou, Ahmed M., additional, Lee-Kong, Steven A., additional, Kiran, Ravi P., additional, Stoeckius, Marlon, additional, Smibert, Peter, additional, Del Portillo, Armando, additional, Oberstein, Paul E., additional, Sims, Peter A., additional, Yan, Kelley S., additional, and Han, Arnold, additional

Published
2022
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20. Deconstructing T Cell Clonal Dynamics in Response to Immune-Checkpoint Blockade

Author

Rao, Samhita, primary, Obradovic, Aleksandar, additional, Gharib, Karim, additional, Kornberg, Adam, additional, Botella, Theo, additional, Moon, Christine, additional, Ghasemzadeh, Ali, additional, Lin, Sijie, additional, Krupska, Izabela, additional, Bush, Erin, additional, Korman, Alan J., additional, Yan, Kelley S., additional, Drake, Charles G., additional, Califano, Andrea, additional, and Han, Arnold, additional

Published
2022
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23. Restriction of intestinal stem cell expansion and the regenerative response by YAP

Author

Barry, Evan R., Morikawa, Teppei, Butler, Brian L., Shrestha, Kriti, de la Rosa, Rosemarie, Yan, Kelley S., Fuchs, Charles S., Magness, Scott T., Smits, Ron, Ogino, Shuji, Kuo, Calvin J., and Camargo, Fernando D.

Subjects
Regeneration (Biology) -- Research, Cellular signal transduction -- Research, Wnt proteins -- Properties -- Observations, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

A remarkable feature of regenerative processes is their ability to halt proliferation once an organ's structure has been restored. The Wnt signalling pathway is the major driving force for homeostatic [...]

Published
2013

25. R-SPONDIN2+Mesenchymal Cells Form the Bud Tip Progenitor Niche During Human Lung Development

Author

Hein, Renee F.C., primary, Wu, Joshua H., additional, Tsai, Yu-Hwai, additional, Wu, Angeline, additional, Miller, Alyssa J., additional, Holloway, Emily M., additional, Frum, Tristan, additional, Conchola, Ansley S., additional, Szenker-Ravi, Emmanuelle, additional, Reversade, Bruno, additional, Yan, Kelley S., additional, Kuo, Calvin J., additional, and Spence, Jason R., additional

Published
2021
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26. Surrogate Wnt agonists that phenocopy canonical Wnt and -catenin signalling

Author

Janda, Claudia Y., Dang, Luke T., You, Changjiang, Chang, Junlei, de Lau, Wim, Zhong, Zhendong A., Yan, Kelley S., Marecic, Owen, Siepe, Dirk, Li, Xingnan, Moody, James D., Williams, Bart O., Clevers, Hans, Piehler, Jacob, Baker, David, Kuo, Calvin J., and Garcia, K. Christopher

Subjects
Wnt proteins -- Health aspects, Phenotypes -- Health aspects, Cellular signal transduction -- Health aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Claudia Y. Janda [1]; Luke T. Dang [2]; Changjiang You [3]; Junlei Chang [4]; Wim de Lau [5]; Zhendong A. Zhong [6]; Kelley S. Yan [4]; Owen Marecic [7]; [...]

Published
2017
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27. Non-equivalence of Wnt and R-spondin ligands during Lgr5+ intestinal stem-cell self-renewal

Author

Yan, Kelley S., Janda, Claudia Y., Chang, Junlei, Zheng, Grace X. Y., Larkin, Kathryn A., Luca, Vincent C., Chia, Luis A., Mah, Amanda T., Han, Arnold, Terry, Jessica M., Ootani, Akifumi, Roelf, Kelly, Lee, Mark, Yuan, Jenny, Li, Xiao, Bolen, Christopher R., Wilhelmy, Julie, Davies, Paige S., Ueno, Hiroo, von Furstenberg, Richard J., Belgrader, Phillip, Ziraldo, Solongo B., Ordonez, Heather, Henning, Susan J., Wong, Melissa H., Snyder, Michael P., Weissman, Irving L., Hsueh, Aaron J., Mikkelsen, Tarjei S., Garcia, K. Christopher, and Kuo, Calvin J.

Subjects
Ligands (Biochemistry) -- Health aspects, Stem cells -- Health aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Kelley S. Yan [1, 2]; Claudia Y. Janda [3]; Junlei Chang [1]; Grace X. Y. Zheng [4]; Kathryn A. Larkin [1]; Vincent C. Luca [3]; Luis A. Chia [1]; [...]

Published
2017
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28. Structure and conserved RNA binding of the PAZ domain

Author

Yan, Kelley S., Yan, Sherry, Farooq, Amjad, Han, Arnold, Zeng, Lei, and Zhou, Ming-Ming

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Kelley S. Yan; Sherry Yan; Amjad Farooq; Arnold Han; Lei Zeng; Ming-Ming Zhou (corresponding author) The discovery of RNA-mediated gene-silencing pathways, including RNA interference [1, 2, 3], highlights a [...]

Published
2003
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29. The functional and phenotypic diversity of single T-cell infiltrates in human colorectal cancer as correlated with clinical outcome

Author

Masuda, Kazuya, primary, Kornberg, Adam, additional, Lin, Sijie, additional, Ho, Patricia, additional, Secener, Kerim, additional, Suek, Nathan, additional, Bacarella, Alyssa M., additional, Ingham, Matthew, additional, Rosario, Vilma, additional, Al-Masrou, Ahmed M., additional, Lee-Kong, Steven A., additional, Kiran, P. Ravi, additional, Yan, Kelley S., additional, Stoeckius, Marlon, additional, Smibert, Peter, additional, Oberstein, Paul E., additional, Sims, Peter A., additional, and Han, Arnold, additional

Published
2020
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33. Non-equivalence of Wnt and R-spondin ligands during Lgr5+ intestinal stem-cell self-renewal

Author

Belgrader, Phillip, Ueno, Hiroo, Yuan, Jenny, Henning, Susan J., Lee, Mark, Terry, Jessica M., Wong, Melissa H., Ziraldo, Solongo B., Han, Arnold, Li, Xiao, Larkin, Kathryn A., Luca, Vincent C., Ootani, Akifumi, Von Furstenberg, Richard J., Snyder, Michael P., Ordonez, Heather, Kuo, Calvin J., Weissman, Irving L., Chang, Junlei, Hsueh, Aaron J., Yan, Kelley S., Chia, Luis A., Zheng, Grace X. Y., Wilhelmy, Julie, Roelf, Kelly, Garcia, K. Christopher, Janda, Claudia Y., Mikkelsen, Tarjei S., Davies, Paige S., Bolen, Christopher R., and Mah, Amanda T.

Abstract

The canonical Wnt/β-catenin signaling pathway governs diverse developmental, homeostatic and pathologic processes. Palmitoylated Wnt ligands engage cell surface Frizzled (Fzd) receptors and Lrp5/6 co-receptors enabling β-catenin nuclear translocation and Tcf/Lef-dependent gene transactivation1–3. Mutations in Wnt downstream signaling components have revealed diverse functions presumptively attributed to Wnt ligands themselves, although direct attribution remains elusive, as complicated by redundancy between 19 mammalian Wnts and 10 Fzds1 and Wnt hydrophobicity2,3. For example, individual Wnt ligand mutations have not revealed homeostatic phenotypes in the intestinal epithelium4, an archetypal canonical Wnt pathway-dependent rapidly self-renewing tissue whose regeneration is fueled by proliferative crypt Lgr5+ intestinal stem cells (ISCs)5–9. R-spondin ligands (Rspo1–4) engage distinct Lgr4-6 and Rnf43/Znrf3 receptor classes10–13, markedly potentiate canonical Wnt/β-catenin signaling and induce intestinal organoid growth in vitro and Lgr5+ ISCs in vivo8,14–17. However, the interchangeability, functional cooperation and relative contributions of Wnt versus Rspo ligands to in vivo canonical Wnt signaling and ISC biology remain unknown. Here, we deconstructed functional roles of Wnt versus Rspo ligands in the intestinal crypt stem cell niche. We demonstrate that the default fate of Lgr5+ ISCs is lineage commitment, escape from which requires both Rspo and Wnt ligands. However, gain-of-function studies using Rspo versus a novel non-lipidated Wnt analog reveal qualitatively distinct, non-interchangeable roles for these ligands in ISCs. Wnts are insufficient to induce Lgr5+ ISC self-renewal, but rather confer a basal competency by maintaining Rspo receptor expression that enables Rspo to actively drive and specify the extent of stem cell expansion. This functionally non-equivalent yet cooperative interplay between Wnt and Rspo ligands establishes a molecular precedent for regulation of mammalian stem cells by distinct priming and self-renewal factors, with broad implications for precision control of tissue regeneration.

Published
2017
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36. Surrogate Wnt agonists that phenocopy canonical Wnt and β-catenin signalling

Author

Janda, Claudia Y., Dang, Luke T., You, Changjiang, Chang, Junlei, Lau, Wim De, Zhong, Zhendong A., Yan, Kelley S., Marecic, Owen, Siepe, DIrk, Li, Xingnan, Moody, James D., Williams, Bart O., Clevers, Hans, Piehler, Jacob, Baker, David, Kuo, Calvin J., Garcia, K. Christopher, Janda, Claudia Y., Dang, Luke T., You, Changjiang, Chang, Junlei, Lau, Wim De, Zhong, Zhendong A., Yan, Kelley S., Marecic, Owen, Siepe, DIrk, Li, Xingnan, Moody, James D., Williams, Bart O., Clevers, Hans, Piehler, Jacob, Baker, David, Kuo, Calvin J., and Garcia, K. Christopher

Published
2017

38. Surrogate Wnt agonists that phenocopy canonical Wnt and β-catenin signalling

Author

Janda, Claudia Y., primary, Dang, Luke T., additional, You, Changjiang, additional, Chang, Junlei, additional, de Lau, Wim, additional, Zhong, Zhendong A., additional, Yan, Kelley S., additional, Marecic, Owen, additional, Siepe, Dirk, additional, Li, Xingnan, additional, Moody, James D., additional, Williams, Bart O., additional, Clevers, Hans, additional, Piehler, Jacob, additional, Baker, David, additional, Kuo, Calvin J., additional, and Garcia, K. Christopher, additional

Published
2017
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40. Identification and specification of the mouse skeletal stem cell.

Author

Chan, Charles K. F., Chan, Charles KF, Seo, Eun Young, Chen, James Y, Lo, David, McArdle, Adrian, Sinha, Rahul, Tevlin, Ruth, Seita, Jun, Vincent-Tompkins, Justin, Wearda, Taylor, Lu, Wan-Jin, Senarath-Yapa, Kshemendra, Chung, Michael T, Marecic, Owen, Tran, Misha, Yan, Kelley S, Upton, Rosalynd, Walmsley, Graham G, Lee, Andrew S, Sahoo, Debashis, Kuo, Calvin J, Weissman, Irving L, Longaker, Michael T, Chan, Charles K. F., Chan, Charles KF, Seo, Eun Young, Chen, James Y, Lo, David, McArdle, Adrian, Sinha, Rahul, Tevlin, Ruth, Seita, Jun, Vincent-Tompkins, Justin, Wearda, Taylor, Lu, Wan-Jin, Senarath-Yapa, Kshemendra, Chung, Michael T, Marecic, Owen, Tran, Misha, Yan, Kelley S, Upton, Rosalynd, Walmsley, Graham G, Lee, Andrew S, Sahoo, Debashis, Kuo, Calvin J, Weissman, Irving L, and Longaker, Michael T

Abstract

How are skeletal tissues derived from skeletal stem cells? Here, we map bone, cartilage, and stromal development from a population of highly pure, postnatal skeletal stem cells (mouse skeletal stem cells, mSSCs) to their downstream progenitors of bone, cartilage, and stromal tissue. We then investigated the transcriptome of the stem/progenitor cells for unique gene-expression patterns that would indicate potential regulators of mSSC lineage commitment. We demonstrate that mSSC niche factors can be potent inducers of osteogenesis, and several specific combinations of recombinant mSSC niche factors can activate mSSC genetic programs in situ, even in nonskeletal tissues, resulting in de novo formation of cartilage or bone and bone marrow stroma. Inducing mSSC formation with soluble factors and subsequently regulating the mSSC niche to specify its differentiation toward bone, cartilage, or stromal cells could represent a paradigm shift in the therapeutic regeneration of skeletal tissues.

Published
2015

42. Non-equivalence of Wnt and R-spondin ligands during Lgr5+ intestinal stem-cell self-renewal.

Author

Yan, Kelley S., Janda, Claudia Y., Chang, Junlei, Zheng, Grace X. Y., Larkin, Kathryn A., Luca, Vincent C., Chia, Luis A., Mah, Amanda T., Han, Arnold, Terry, Jessica M., Ootani, Akifumi, Roelf, Kelly, Lee, Mark, Yuan, Jenny, Li, Xiao, Bolen, Christopher R., Wilhelmy, Julie, Davies, Paige S., Ueno, Hiroo, and von Furstenberg, Richard J.

Abstract

The canonical Wnt/β-catenin signalling pathway governs diverse developmental, homeostatic and pathological processes. Palmitoylated Wnt ligands engage cell-surface frizzled (FZD) receptors and LRP5 and LRP6 co-receptors, enabling β-catenin nuclear translocation and TCF/LEF-dependent gene transactivation. Mutations in Wnt downstream signalling components have revealed diverse functions thought to be carried out by Wnt ligands themselves. However, redundancy between the 19 mammalian Wnt proteins and 10 FZD receptors and Wnt hydrophobicity have made it difficult to attribute these functions directly to Wnt ligands. For example, individual mutations in Wnt ligands have not revealed homeostatic phenotypes in the intestinal epithelium-an archetypal canonical, Wnt pathway-dependent, rapidly self-renewing tissue, the regeneration of which is fueled by proliferative crypt Lgr5+ intestinal stem cells (ISCs). R-spondin ligands (RSPO1-RSPO4) engage distinct LGR4-LGR6, RNF43 and ZNRF3 receptor classes, markedly potentiate canonical Wnt/β-catenin signalling, and induce intestinal organoid growth in vitro and Lgr5+ ISCs in vivo. However, the interchangeability, functional cooperation and relative contributions of Wnt versus RSPO ligands to in vivo canonical Wnt signalling and ISC biology remain unknown. Here we identify the functional roles of Wnt and RSPO ligands in the intestinal crypt stem-cell niche. We show that the default fate of Lgr5+ ISCs is to differentiate, unless both RSPO and Wnt ligands are present. However, gain-of-function studies using RSPO ligands and a new non-lipidated Wnt analogue reveal that these ligands have qualitatively distinct, non-interchangeable roles in ISCs. Wnt proteins are unable to induce Lgr5+ ISC self-renewal, but instead confer a basal competency by maintaining RSPO receptor expression that enables RSPO ligands to actively drive and specify the extent of stem-cell expansion. This functionally non-equivalent yet cooperative interaction between Wnt and RSPO ligands establishes a molecular precedent for regulation of mammalian stem cells by distinct priming and self-renewal factors, with broad implications for precise control of tissue regeneration. [ABSTRACT FROM AUTHOR]

Published
2017
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46. Non-equivalence of Wnt and R-spondin ligands during Lgr5+intestinal stem-cell self-renewal

Author

Yan, Kelley S., Janda, Claudia Y., Chang, Junlei, Zheng, Grace X. Y., Larkin, Kathryn A., Luca, Vincent C., Chia, Luis A., Mah, Amanda T., Han, Arnold, Terry, Jessica M., Ootani, Akifumi, Roelf, Kelly, Lee, Mark, Yuan, Jenny, Li, Xiao, Bolen, Christopher R., Wilhelmy, Julie, Davies, Paige S., Ueno, Hiroo, von Furstenberg, Richard J., Belgrader, Phillip, Ziraldo, Solongo B., Ordonez, Heather, Henning, Susan J., Wong, Melissa H., Snyder, Michael P., Weissman, Irving L., Hsueh, Aaron J., Mikkelsen, Tarjei S., Garcia, K. Christopher, and Kuo, Calvin J.

Abstract

The canonical Wnt/β-catenin signalling pathway governs diverse developmental, homeostatic and pathological processes. Palmitoylated Wnt ligands engage cell-surface frizzled (FZD) receptors and LRP5 and LRP6 co-receptors, enabling β-catenin nuclear translocation and TCF/LEF-dependent gene transactivation. Mutations in Wnt downstream signalling components have revealed diverse functions thought to be carried out by Wnt ligands themselves. However, redundancy between the 19 mammalian Wnt proteins and 10 FZD receptors and Wnt hydrophobicity have made it difficult to attribute these functions directly to Wnt ligands. For example, individual mutations in Wnt ligands have not revealed homeostatic phenotypes in the intestinal epithelium—an archetypal canonical, Wnt pathway-dependent, rapidly self-renewing tissue, the regeneration of which is fueled by proliferative crypt Lgr5+intestinal stem cells (ISCs). R-spondin ligands (RSPO1–RSPO4) engage distinct LGR4–LGR6, RNF43 and ZNRF3 receptor classes, markedly potentiate canonical Wnt/β-catenin signalling, and induce intestinal organoid growth in vitro and Lgr5+ISCs in vivo. However, the interchangeability, functional cooperation and relative contributions of Wnt versus RSPO ligands to in vivo canonical Wnt signalling and ISC biology remain unknown. Here we identify the functional roles of Wnt and RSPO ligands in the intestinal crypt stem-cell niche. We show that the default fate of Lgr5+ISCs is to differentiate, unless both RSPO and Wnt ligands are present. However, gain-of-function studies using RSPO ligands and a new non-lipidated Wnt analogue reveal that these ligands have qualitatively distinct, non-interchangeable roles in ISCs. Wnt proteins are unable to induce Lgr5+ISC self-renewal, but instead confer a basal competency by maintaining RSPO receptor expression that enables RSPO ligands to actively drive and specify the extent of stem-cell expansion. This functionally non-equivalent yet cooperative interaction between Wnt and RSPO ligands establishes a molecular precedent for regulation of mammalian stem cells by distinct priming and self-renewal factors, with broad implications for precise control of tissue regeneration.

Published
2017
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47. The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations

Author

Yan, Kelley S., primary, Chia, Luis A., additional, Li, Xingnan, additional, Ootani, Akifumi, additional, Su, James, additional, Lee, Josephine Y., additional, Su, Nan, additional, Luo, Yuling, additional, Heilshorn, Sarah C., additional, Amieva, Manuel R., additional, Sangiorgi, Eugenio, additional, Capecchi, Mario R., additional, and Kuo, Calvin J., additional

Published
2011
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48. Erratum: Structure and conserved RNA binding of the PAZ domain

Author

Yan, Kelley S., Yan, Sherry, Farooq, Amjad, Han, Arnold, Zeng, Lei, and Zhou, Ming-Ming

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Kelley S. Yan; Sherry Yan; Amjad Farooq; Arnold Han; Lei Zeng; Ming-Ming Zhou Nature 426, 469-474 (2003). In this Letter, the last two sentences of the second paragraph of [...]

Published
2004
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