Mitochondria Define Intestinal Stem Cell Differentiation Downstream of a FOXO/Notch Axis. Academic Article uri icon

Overview

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. 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.

publication date

  • November 3, 2020

Research

keywords

  • Goblet Cells
  • Intestines
  • Mitochondria
  • Paneth Cells
  • Stem Cells

Identity

Scopus Document Identifier

  • 85094586590

Digital Object Identifier (DOI)

  • 10.1016/j.cmet.2020.10.005

PubMed ID

  • 33147486

Additional Document Info

volume

  • 32

issue

  • 5