title: Single cell lineage tracing reveals a role for TgfβR2 in intestinal stem cell dynamics and differentiation.
abstract: Intestinal stem cells (ISCs) are maintained by a niche mechanism, in which multiple ISCs undergo differential fates where a single ISC clone ultimately occupies the niche. Importantly, mutations continually accumulate within ISCs creating a potential competitive niche environment. Here we use single cell lineage tracing following stochastic transforming growth factor β receptor 2 (TgfβR2) mutation to show cell autonomous effects of TgfβR2 loss on ISC clonal dynamics and differentiation. Specifically, TgfβR2 mutation in ISCs increased clone survival while lengthening times to monoclonality, suggesting that Tgfβ signaling controls both ISC clone extinction and expansion, independent of proliferation. In addition, TgfβR2 loss in vivo reduced crypt fission, irradiation-induced crypt regeneration, and differentiation toward Paneth cells. Finally, altered Tgfβ signaling in cultured mouse and human enteroids supports further the in vivo data and reveals a critical role for Tgfβ signaling in generating precursor secretory cells. Overall, our data reveal a key role for Tgfβ signaling in regulating ISCs clonal dynamics and differentiation, with implications for cancer, tissue regeneration, and inflammation.
authors: Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239; fischerj@ohsu.edu.
authors: Jared M
authors: 0000-0002-0062-0870
authors: JM
authors: Fischer
authors: Department of Molecular and Computational Biology, University of Southern California, Los Angeles, CA 90089.
authors: Peter P
authors: PP
authors: Calabrese
authors: Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239.
authors: Ashleigh J
authors: AJ
authors: Miller
authors: Department of Interventional Radiology, University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors: Nina M
authors: NM
authors: Muñoz
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109; Department of Medicine, University of Washington Medical School, Seattle, WA 98195.
authors: William M
authors: WM
authors: Grady
authors: Department of Pathology, Norris Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033.
authors: Darryl
authors: D
authors: Shibata
authors: Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239.
authors: R Michael
authors: RM
authors: Liskay
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics; D058948:Cell Tracking; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology; D051379:Mice; D009154:Mutation; D019879:Paneth Cells / Q000166:cytology* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D015398:Signal Transduction; D059010:Single-Cell Analysis / Q000379:methods; D055153:Stem Cell Niche / Q000235:genetics; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: Paneth cell; Tgfβ; TgfβR2; intestinal stem cell; lgr5