Published online Dec 26, 2018. doi: 10.4252/wjsc.v10.i12.196
Peer-review started: October 17, 2018
First decision: October 26, 2018
Revised: November 14, 2018
Accepted: December 4, 2018
Article in press: December 5, 2018
Published online: December 26, 2018
Homeostasis of intracellular pHi (pHi) affects many cellular functions, such as cell proliferation and differentiation. However, the knowledge of pHi regulation mechanism in human pluripotent stem cells still unknown.
The changes of acid-base kinetic were observed during the loss of pluripotency in mouse embryonic stem cells. Moreover, the balance of intracellular and extracellular pH significantly affected the reprogramming efficiency and culture quality of human induced pluripotent stem cells (hiPSCs).
We aimed to establish the pHi regulation mechanism model and investigate the relationship of pHi regulation and pluripotency in hiPSCs.
In the pluripotent state and during the loss of pluripotency in hiPSCs, we observed the activity of pHi regulation mechanism by acutely induced intracellular acidification and alkalization in the physiological buffered solution.
In hiPSCs, the Na+-H+ exchanger (NHE), the Na+-HCO3- cotransporter (NBC) and vacuolar-ATPase (V-ATPase) were the main active acid extruders that were activated against intracellular acidification. In contrast, the acid-equivalent loaders, such as the Cl--HCO3- anion exchanger (AE) and the Cl--OH- exchanger (CHE), were activated to prevent intracellular alkalization. In addition to the classic pHi regulators NHE, NBC, V-ATPase, AE and CHE, we also demonstrated the functional existence of unknown acid-extruder(s) and –loader(s) in hiPSCs. Moreover, the pHi and acid-extruding mechanism were decreased during the loss of pluripotency in hiPSCs.
For the first time, we established a model of the pHi regulation mechanism in hiPSCs. The higher resting pHi and acid-extruding mechanism might be the specific feature to adaptive the cancer-like cellular function and pluripotency in hiPSCs.
In summary, we characterized the pHi regulation mechanism and its functional/expressional roles in maintenance of pluripotency of hiPSCs. We proposed that targeting either pHi regulators or pH environments of culture medium could be an effective way to modify the pluripotency state of hiPSCs, which may contribute the differentiation efficiency or culture quality.