Mitochondria Define Intestinal Stem Cell Differentiation Downstream of a FOXO/Notch Axis
Ludikhuize, Marlies C.; Meerlo, Maaike; Gallego, Marc Pages; Xanthakis, Despina; Burgaya Julià, Mar; Nguyen, Nguyen T.B.; Brombacher, Eline C.; Liv, Nalan; Maurice, Madelon M.; Paik, Ji hye; Burgering, Boudewijn M.T.; Rodriguez Colman, Maria J.
(2020) Cell Metabolism, volume 32, issue 5, pp. 889 - 900.e7
(Article)
Abstract
Differential WNT and Notch signaling regulates differentiation of Lgr5+ crypt-based columnar cells (CBCs) into intestinal cell lineages. Recently we showed that mitochondrial activity supports CBCs, while adjacent Paneth cells (PCs) show reduced mitochondrial activity. This implies that CBC differentiation into PCs involves a metabolic transition toward downregulation of mitochondrial dependency.
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Here we show that Forkhead box O (FoxO) transcription factors and Notch signaling interact in determining CBC fate. In agreement with the organoid data, Foxo1/3/4 deletion in mouse intestine induces secretory cell differentiation. Importantly, we show that FOXO and Notch signaling converge on regulation of mitochondrial fission, which in turn provokes stem cell differentiation into goblet cells and PCs. Finally, scRNA-seq-based reconstruction of CBC differentiation trajectories supports the role of FOXO, Notch, and mitochondria in secretory differentiation. Together, this points at a new signaling-metabolic axis in CBC differentiation and highlights the importance of mitochondria in determining stem cell fate.
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Keywords: differentiation, FOXO, intestine, metabolism, mitochondria, Notch, stem cells, Molecular Biology, Physiology, Cell Biology, Journal Article
ISSN: 1550-4131
Publisher: Cell Press
Note: Funding Information: We thank D. Castigliego and P.H. van der Kraak (UMC Utrecht) for their technical support on IHC stainings; F. de Sauvage (Genentech) for providing DTR-LGR5-GFP mice; T. Dick (DKFZ) for sharing mtGrx1-roGFP; and I. Verlaan (UMC Utrecht) for preparing R-spondin-, Noggin-, and Wnt3a-conditioned medium. This work was financially supported by Dutch Cancer Society ( KWF 2016-I 10471 , KWF 2017-II 11315 ). Funding Information: We thank D. Castigliego and P.H. van der Kraak (UMC Utrecht) for their technical support on IHC stainings; F. de Sauvage (Genentech) for providing DTR-LGR5-GFP mice; T. Dick (DKFZ) for sharing mtGrx1-roGFP; and I. Verlaan (UMC Utrecht) for preparing R-spondin-, Noggin-, and Wnt3a-conditioned medium. This work was financially supported by Dutch Cancer Society (KWF 2016-I 10471, KWF 2017-II 11315). Conceptualization, M.J.R.C. M.C.L. and B.M.T.B.; Methodology and Investigation, M.J.R.C. M.C.L. M.M. M.B.J. E.C.B. N.T.B.N.; Electron microscopy analysis and interpretation, D.X. M.M.M. N.L.; Bioinformatic analysis, M.P.G.; Resources mouse models, J.-h.P.; Manuscript Writing, M.J.R.C. and M.C.L.; Review & Editing, M.J.R.C. and B.M.T.B.; Funding Acquisition, M.J.R.C. and B.M.T.B. The authors declare no competing interests. Publisher Copyright: © 2020 Elsevier Inc.
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