Rapid Crypt Cell Remodeling Regenerates the Intestinal Stem Cell Niche after Notch Inhibition.

Stem Cell Reports
Natacha BohinLinda C Samuelson

Abstract

Intestinal crypts have great capacity for repair and regeneration after intestinal stem cell (ISC) injury. Here, we define the cellular remodeling process resulting from ISC niche interruption by transient Notch pathway inhibition in adult mice. Although ISCs were retained, lineage tracing demonstrated a marked reduction in ISC function after Notch disruption. Surprisingly, Notch ligand-expressing Paneth cells were rapidly lost by apoptotic cell death. The ISC-Paneth cell changes were followed by a regenerative response, characterized by expansion of cells expressing Notch ligands Dll1 and Dll4, enhanced Notch signaling, and a proliferative surge. Lineage tracing and organoid studies showed that Dll1-expressing cells were activated to function as multipotential progenitors, generating both absorptive and secretory cells and replenishing the vacant Paneth cell pool. Our analysis uncovered a dynamic, multicellular remodeling response to acute Notch inhibition to repair the niche and restore homeostasis. Notably, this crypt regenerative response did not require ISC loss.

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Citations

Aug 14, 2020·Stem Cell Research & Therapy·Xianglin MeiMeiying Li
Feb 12, 2021·Cellular and Molecular Gastroenterology and Hepatology·Breanna J SheahanChristopher M Dekaney
May 6, 2021·Biomolecules·Meera KrishnanPrasad Abnave
Jul 2, 2021·JCI Insight·Izumi KajiJames R Goldenring
Aug 27, 2021·Cellular and Molecular Gastroenterology and Hepatology·Nobukatsu HoritaLinda C Samuelson

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Methods Mentioned

BETA
transgenic
flow cytometry
fluorescence-activated cell sorting
FACS

Software Mentioned

Olympus DP
ImageJ

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