Functional and molecular mechanism of intracellular pH regulation in human inducible pluripotent stem cells

doi:10.4252/wjsc.v10.i12.196

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World Journal of Stem Cells

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World J Stem Cells. Dec 26, 2018; 10(12): 196-211
Published online Dec 26, 2018. doi: 10.4252/wjsc.v10.i12.196

Functional and molecular mechanism of intracellular pH regulation in human inducible pluripotent stem cells

Shih-Chi Chao, Gwo-Jang Wu, Shu-Fu Huang, Niann-Tzyy Dai, Hsu-Kai Huang, Mei-Fang Chou, Yi-Ting Tsai, Shiao-Pieng Lee, Shih-Hurng Loh

Shih-Chi Chao, Shih-Hurng Loh, Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11490, Taiwan

Gwo-Jang Wu, Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan

Shu-Fu Huang, Mei-Fang Chou, Shih-Hurng Loh, Department of Pharmacy Practice, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan

Niann-Tzyy Dai, Division of Plastic and Reconstructive Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan

Hsu-Kai Huang, Division of Chest Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan

Yi-Ting Tsai, Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan

Yi-Ting Tsai, Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan

Shiao-Pieng Lee, Division of Oral and Maxillofacial Surgery, Department of Dentistry, School of Dentistry, Tri-Service General Hospital and National Defense Medical Center, Taipei 11490, Taiwan

Shih-Hurng Loh, Department of Pharmacology, National Defense Medical Center, Taipei 11490, Taiwan

Author contributions: Chao SC and Loh SH performed the majority of experiments and analyzed the data; Chao SC, Wu GJ, Dai NT and Loh SH performed conception and design; Wu GJ, Dai NT and Loh SH participated equally in iPSC treatment and providing; Chao SC, Wu GJ, Huang SF, Dai NT, Huang SK, Tsai YT, Lee SP and Loh SH coordinated and interpreted the research; Cha SC and Loh SH wrote the paper; Cha SC, Wu GJ, Huang SF and Loh SH drafted the article or making critical revisions related to important intellectual content of the manuscript; Loh SH final approval of the version of the article to be published.

Supported by Ministry of Science and Technology Grants of Taiwan, No. MOST 106-2320-B-016-003-MY2 (to Loh SH) and No. MOST 106-2314-B-016-037-MY3 (to Tsai YT); National Defense Medical Center Grants of Taiwan, No. MAB-106-033 (to Loh SH), No. MAB-105-043 and No. MAB-106-034 (to Dai NZ); Teh-Tzer Study Group for Human Medical Research Foundation of Taiwan, No. A1061037 and No. A1061054 (to Loh SH).

Institutional review board statement: The manuscript is approved by Institutional Review Board of Tri-Service General Hospital.

Conflict-of-interest statement: All authors declare no potential conflict of interest.

Corresponding author to: Shih-Hurng Loh, DPhil, Director, Full Professor, Department of Pharmacology, and Department of Pharmacy Practice, Tri-Service General Hospital, National Defense Medical Center, No. 161, Sec. 6, Minquan E. Rd., Taipei 11490, Taiwan. shloh@ndmctsgh.edu.tw

Telephone: +886-2-87924861 Fax: +886-2-87924861

Received: October 17, 2018
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
Processing time: 69 Days and 1.1 Hours

ARTICLE HIGHLIGHTS

Research background

Homeostasis of intracellular pH_i (pH_i) affects many cellular functions, such as cell proliferation and differentiation. However, the knowledge of pH_i regulation mechanism in human pluripotent stem cells still unknown.

Research motivation

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).

Research objectives

We aimed to establish the pH_i regulation mechanism model and investigate the relationship of pH_i regulation and pluripotency in hiPSCs.

Research methods

In the pluripotent state and during the loss of pluripotency in hiPSCs, we observed the activity of pH_i regulation mechanism by acutely induced intracellular acidification and alkalization in the physiological buffered solution.

Research results

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 pH_i 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 pH_i and acid-extruding mechanism were decreased during the loss of pluripotency in hiPSCs.

Research conclusions

For the first time, we established a model of the pH_i regulation mechanism in hiPSCs. The higher resting pH_i and acid-extruding mechanism might be the specific feature to adaptive the cancer-like cellular function and pluripotency in hiPSCs.

Research perspectives

In summary, we characterized the pH_i regulation mechanism and its functional/expressional roles in maintenance of pluripotency of hiPSCs. We proposed that targeting either pH_i 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.