Increased intracellular pH is necessary for adult epithelial and embryonic stem cell differentiation.
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.
Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143.|Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94143.
Bryne
http://orcid.org/0000-0002-7116-8842
B
Ulmschneider
Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143.|Department of Biological Sciences, San Jose State University, San Jose, CA 95192.
Bree K
http://orcid.org/0000-0001-6471-7025
BK
Grillo-Hill
Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143.|Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94143.
Marimar
http://orcid.org/0000-0002-1610-6825
M
Benitez
Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143.|Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94143.
Dinara R
DR
Azimova
Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143.
Diane L
http://orcid.org/0000-0001-7185-9435
DL
Barber
Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143 todd.nystul@ucsf.edu.|Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94143.
Todd G
http://orcid.org/0000-0001-8599-6529
TG
Nystul
D000375:Aging / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000166:cytology* / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D005260:Female; D053823:Hedgehog Proteins / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D042541:Intracellular Space / Q000378:metabolism*; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006080:Ovarian Follicle / Q000166:cytology; D015398:Signal Transduction
D029721:Drosophila Proteins; D053823:Hedgehog Proteins