Live-cell imaging in human colonic monolayers reveals ERK waves limit the stem cell compartment to maintain epithelial homeostasis

Kelvin W Pond; Julia M Morris; Olga Alkhimenok; Reeba P Varghese; Carly R Cabel; Nathan A Ellis; Jayati Chakrabarti; Yana Zavros; Juanita L Merchant; Curtis A Thorne; Andrew L Paek

doi:10.7554/elife.78837

journal article Open Access Sep 12, 2022

Live-cell imaging in human colonic monolayers reveals ERK waves limit the stem cell compartment to maintain epithelial homeostasis

Kelvin W Pond

Julia M Morris Olga Alkhimenok Reeba P Varghese Carly R Cabel Nathan A Ellis Jayati Chakrabarti

Yana Zavros

Juanita L Merchant Curtis A Thorne

Andrew L Paek

eLife Vol. 11 · eLife Sciences Publications, Ltd

View at Publisher Save 10.7554/elife.78837

Abstract

The establishment and maintenance of different cellular compartments in tissues is a universal requirement across all metazoans. Maintaining the correct ratio of cell types in time and space allows tissues to form patterned compartments and perform complex functions. Patterning is especially evident in the human colon, where tissue homeostasis is maintained by stem cells in crypt structures that balance proliferation and differentiation. Here, we developed a human 2D patient derived organoid screening platform to study tissue patterning and kinase pathway dynamics in single cells. Using this system, we discovered that waves of ERK signaling induced by apoptotic cells play a critical role in maintaining tissue patterning and homeostasis. If ERK is activated acutely across all cells instead of in wave-like patterns, then tissue patterning and stem cells are lost. Conversely, if ERK activity is inhibited, then stem cells become unrestricted and expand dramatically. This work demonstrates that the colonic epithelium requires coordinated ERK signaling dynamics to maintain patterning and tissue homeostasis. Our work reveals how ERK can antagonize stem cells while supporting cell replacement and the function of the gut.

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Details

Published: Sep 12, 2022
Vol/Issue: 11
License: View

Authors

K

Kelvin W Pond

Department of Cellular and Molecular Medicine, University of Arizona; Department of Molecular and Cellular Biology, The University of Arizona; University of Arizona Cancer Center

J

Julia M Morris

Department of Cellular and Molecular Medicine, University of Arizona

O

Olga Alkhimenok

Department of Molecular and Cellular Biology, The University of Arizona

R

Reeba P Varghese

Department of Cellular and Molecular Medicine, University of Arizona; Cancer Biology Graduate Interdisciplinary Program, University of Arizona

C

Carly R Cabel

Department of Cellular and Molecular Medicine, University of Arizona; Cancer Biology Graduate Interdisciplinary Program, University of Arizona

N

Nathan A Ellis

Department of Cellular and Molecular Medicine, University of Arizona; University of Arizona Cancer Center

J

Jayati Chakrabarti

Department of Cellular and Molecular Medicine, University of Arizona

Y

Yana Zavros

Department of Cellular and Molecular Medicine, University of Arizona; University of Arizona Cancer Center

J

Juanita L Merchant

Department of Medicine, The University of Arizona

C

Curtis A Thorne

Department of Cellular and Molecular Medicine, University of Arizona; University of Arizona Cancer Center

A

Andrew L Paek

Department of Molecular and Cellular Biology, The University of Arizona

Funding

Wellcome Trust Award: WT223952/Z/21/Z

National Institutes of Health Award: GM130864

Cite This Article

Kelvin W Pond, Julia M Morris, Olga Alkhimenok, et al. (2022). Live-cell imaging in human colonic monolayers reveals ERK waves limit the stem cell compartment to maintain epithelial homeostasis. eLife, 11. https://doi.org/10.7554/elife.78837

Live-cell imaging in human colonic monolayers reveals ERK waves limit the stem cell compartment to maintain epithelial homeostasis

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