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Intracellular pH dynamics regulates intestinal stem cell lineage specification.

Yi Liu1, Efren Reyes2, David Castillo-Azofeifa2,3

  • 1Department of Cell and Tissue Biology, University of California San Francisco, San Francisco, CA, 94143, USA.

Nature Communications
|June 23, 2023
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Summary
This summary is machine-generated.

Intracellular pH gradients regulate adult stem cell fate in the mouse intestine. Disrupting this pH gradient blocks stem cell budding and Paneth cell differentiation, crucial for intestinal maintenance.

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Area of Science:

  • Cell Biology
  • Stem Cell Biology
  • Gastrointestinal Physiology

Background:

  • Intracellular pH dynamics are crucial regulators of diverse cellular functions.
  • Adult stem cell lineage specification is critical for tissue homeostasis and regeneration.
  • The role of intracellular pH in adult stem cell fate decisions remains largely unexplored.

Purpose of the Study:

  • To investigate the role of intracellular pH dynamics in adult stem cell lineage specification within the mouse small intestinal crypts.
  • To identify specific mechanisms and molecular players involved in pH-mediated stem cell fate decisions.

Main Methods:

  • Utilized mouse small intestinal crypts to analyze intracellular pH gradients.
  • Employed Na+/H+ exchanger 1 (NHE1) inhibition to disrupt pH gradients.
  • Applied exogenous WNT to assess rescue effects.
  • Performed single-cell RNA sequencing and lineage tracing to elucidate molecular pathways.

Main Results:

  • Identified a distinct intracellular pH gradient in intestinal crypts, lowest in stem cells and increasing along the crypt axis.
  • Inhibition of H+ efflux via NHE1 abolished crypt budding and Paneth cell differentiation.
  • Exogenous WNT treatment rescued the observed defects in crypt budding and Paneth cell differentiation.
  • Demonstrated that intracellular pH dynamics acts downstream of ATOH1, with elevated pH promoting secretory lineage differentiation.

Conclusions:

  • Intracellular pH dynamics play a critical role in regulating adult stem cell lineage specification in the intestinal crypt.
  • An increase in intracellular pH is essential for lineage specification, contributing to crypt maintenance.
  • These findings establish a novel role for intracellular pH dynamics in governing cell fate decisions within adult stem cell populations.