1. Medium acidosis drives cardiac differentiation during mesendoderm cell fate specification from human pluripotent stem cells.
- Author
-
Liu W, Hsieh HT, He Z, Xiao X, Song C, Lee EX, Dong J, Lei CL, Wang J, and Chen G
- Subjects
- Humans, Hydrogen-Ion Concentration, Acidosis metabolism, Endoderm cytology, Endoderm metabolism, Cell Lineage drug effects, Mesoderm cytology, Mesoderm metabolism, Culture Media pharmacology, Culture Media chemistry, Signal Transduction drug effects, Cell Line, AMP-Activated Protein Kinases metabolism, Cell Differentiation drug effects, Glycolysis, Pluripotent Stem Cells metabolism, Pluripotent Stem Cells cytology, Pluripotent Stem Cells drug effects, Myocytes, Cardiac metabolism, Myocytes, Cardiac cytology, Myocytes, Cardiac drug effects
- Abstract
Effective lineage-specific differentiation is essential to fulfilling the great potentials of human pluripotent stem cells (hPSCs). In this report, we investigate how modulation of medium pH and associated metabolic changes influence mesendoderm differentiation from hPSCs. We show that daily medium pH fluctuations are critical for the heterogeneity of cell fates in the absence of exogenous inducers. Acidic environment alone leads to cardiomyocyte generation without other signaling modulators. In contrast, medium alkalinization is inhibitory to cardiac fate even in the presence of classic cardiac inducers. We then demonstrate that acidic environment suppresses glycolysis to facilitate cardiac differentiation, while alkaline condition promotes glycolysis and diverts the differentiation toward other cell types. We further show that glycolysis inhibition or AMPK activation can rescue cardiac differentiation under alkalinization, and glycolysis inhibition alone can drive cardiac cell fate. This study highlights that pH changes remodel metabolic patterns and modulate signaling pathways to control cell fate., Competing Interests: Declaration of interests W.L. and G.C. filed a patent application based on cardiomyocyte differentiation that is induced by acidic pH., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF