Increased intracellular pH is necessary for adult epithelial and embryonic stem cell differentiation

• DOI: 10.1083/jcb.201606042
• Publication Date: 2016-11-07T14:43:11Z
• Authors: Bryne Ulmschneider; Bree K. Grillo-Hill; Marimar Benitez; Dinara R. Azimova; Diane L. Barber; Todd G. Nystul
• Keywords: 0301 basic medicine; 570; Aging; Biomedical and clinical sciences; 1.1 Normal biological development and functioning; Intracellular Space; 610; Stem Cell Research - Embryonic - Non-Human; Regenerative Medicine; Medical and Health Sciences; Mice; 03 medical and health sciences; Ovarian Follicle; Animals; Drosophila Proteins; Cell Lineage; Hedgehog Proteins; Research Articles; Biomedical and Clinical Sciences; Cell Differentiation; Epithelial Cells; Mouse Embryonic Stem Cells; Biological Sciences; Hydrogen-Ion Concentration; Stem Cell Research; Biological sciences; Drosophila melanogaster; Stem Cell Research - Nonembryonic - Non-Human; Female; Biochemistry and Cell Biology; Generic health relevance; Developmental Biology; Signal Transduction

Despite extensive knowledge about the transcriptional regulation of stem cell differentiation, less is known about the role of dynamic cytosolic cues. We report that an increase in intracellular pH (pHi) is necessary for the efficient differentiation of Drosophila adult follicle stem cells (FSCs) and mouse embryonic stem cells (mESCs). We show that pHi increases with differentiation from FSCs to prefollicle cells (pFCs) and follicle cells. Loss of the Drosophila Na+–H+ exchanger DNhe2 lowers pHi in differentiating cells, impairs pFC differentiation, disrupts germarium morphology, and decreases fecundity. In contrast, increasing pHi promotes excess pFC cell differentiation toward a polar/stalk cell fate through suppressing Hedgehog pathway activity. Increased pHi also occurs with mESC differentiation and, when prevented, attenuates spontaneous differentiation of naive cells, as determined by expression of microRNA clusters and stage-specific markers. Our findings reveal a previously unrecognized role of pHi dynamics for the differentiation of two distinct types of stem cell lineages, which opens new directions for understanding conserved regulatory mechanisms.