Details

Autor(en) / Beteiligte

• 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.

Titel

Mitochondria Define Intestinal Stem Cell Differentiation Downstream of a FOXO/Notch Axis

Ist Teil von

• Cell metabolism, 2020-11, Vol.32 (5), p.889-900.e7

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2020

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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. 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. [Display omitted] •FOXO1/3 knockdown leads to stem cell differentiation into secretory cells•High and low abundance of mitochondria define stem cells and Paneth cells, respectively•FOXO and NOTCH functionally interact and their inhibition induces mitochondrial fission•Mitochondrial fission is a requisite for differentiation into Paneth and goblet cells Changes in cellular metabolism regulate the stem cell state and differentiation. In particular, intestinal stem cells are enriched in mitochondria when compared to secretory linages. Here, Ludikhuize et al. show that downregulation of FOXO1/3 and Notch1 signaling induces mitochondrial fission, which is a requisite for the differentiation of stem cells into goblet and Paneth cells.