Single cell lineage tracing reveals a role for Tgf?R2 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 ? receptor 2 (Tgf?R2) mutation to show cell autonomous effects of Tgf?R2 loss on ISC clonal dynamics and differentiation. Specifically, Tgf?R2 mutation in ISCs increased clone survival while lengthening times to monoclonality, suggesting that Tgf? signaling controls both ISC clone extinction and expansion, independent of proliferation. In addition, Tgf?R2 loss in vivo reduced crypt fission, irradiation-induced crypt regeneration, and differentiation toward Paneth cells. Finally, altered Tgf? signaling in cultured mouse and human enteroids supports further the in vivo data and reveals a critical role for Tgf? signaling in generating precursor secretory cells. Overall, our data reveal a key role for Tgf? signaling in regulating ISCs clonal dynamics and differentiation, with implications for cancer, tissue regeneration, and inflammation.

SUBMITTER: Fischer JM 

PROVIDER: S-EPMC5087053 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature