Intracellular pH dynamics regulates intestinal stem cell lineage specification

Yi Liu, Efren Reyes, David Castillo-Azofeifa, Ophir D. Klein, Todd Nystul () and Diane L. Barber ()
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Yi Liu: University of California San Francisco
Efren Reyes: University of California San Francisco
David Castillo-Azofeifa: University of California San Francisco
Ophir D. Klein: University of California San Francisco
Todd Nystul: University of California San Francisco
Diane L. Barber: University of California San Francisco

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Intracellular pH dynamics is increasingly recognized to regulate myriad cell behaviors. We report a finding that intracellular pH dynamics also regulates adult stem cell lineage specification. We identify an intracellular pH gradient in mouse small intestinal crypts, lowest in crypt stem cells and increasing along the crypt column. Disrupting this gradient by inhibiting H+ efflux by Na+/H+ exchanger 1 abolishes crypt budding and blocks differentiation of Paneth cells, which are rescued with exogenous WNT. Using single-cell RNA sequencing and lineage tracing we demonstrate that intracellular pH dynamics acts downstream of ATOH1, with increased pH promoting differentiation toward the secretory lineage. Our findings indicate that an increase in pH is required for the lineage specification that contributes to crypt maintenance, establishing a role for intracellular pH dynamics in cell fate decisions within an adult stem cell lineage.

Date: 2023
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DOI: 10.1038/s41467-023-39312-9

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