Abstract
Abstract Transforming growth factor beta signaling has important roles in stem cell behavior, differentiation, cell motility, cell cycle and apoptosis. Here, we have utilized a novel mouse model that facilitates the sporadic inactivation of TgfβR2 via frameshift reversion of Cre in single, isolated cells and concomitant lineage tracing with a Cre-reporter. Short-term lineage tracing of TgfβR2-deficient crypts revealed reduced expansion suggesting a growth disadvantage among crypts. In contrast, long-term lineage tracing of TgfβR2-deficient crypts revealed an increased number suggesting a growth advantage within the crypt. To reconcile these apparently contradictory findings, we studied the dynamics of proliferative, Lgr5+ stem cells following TgfβR2 loss. We found that TgfβR2-deficient stem cell lineages required more time to reach monoclonality within the crypt. Using mathematical modeling of stem cell neutral drift, we found that increased “stemness” or a greater probability of a self-renewing asymmetrical outcome for TgfβR2-deficient stem cells was more consistent with our experimental results. Further analysis of TgfβR2-deficient stem cells in vivo revealed a decreased production of Paneth cells, a finding we corroborated in cultured intestinal organoids by treating with either a TgfβR1/2 inhibitor or low levels of the Tgfβ1 ligand. Recent studies by others suggested that quiescent stem cells are intermediaries between proliferative Lgr5+ stem cells and Paneth cells and that Tgfβ signaling is important in the formation of quiescent stem cells in other tissues. Therefore, we are currently asking whether Tgfβ signaling is important in the formation of quiescent stem cells in the intestine. Citation Format: Jared M. Fischer, Ashleigh Miller, Peter P. Calabrese, Darryl Shibata, R Michael Liskay. Transforming growth factor beta signaling regulates the fate of intestinal stem cells. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A14.
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