Huang ZH, Huang C, Ji XR, Zhou WJ, Luo XF, Liu Q, Tang YL, Gong F, Zhu WB. MKK7-mediated phosphorylation of JNKs regulates the proliferation and apoptosis of human spermatogonial stem cells. World J Stem Cells 2021; 13(11): 1797-1812 [PMID: 34909124 DOI: 10.4252/wjsc.v13.i11.1797]
Corresponding Author of This Article
Wen-Bing Zhu, PhD, Professor, Institute of Reproductive and Stem Cell Engineering, Central South University, No. 932 Lushan South Road, Yuelu District, Changsha 410008, Hunan Province, China. zhuwenbing0971@sina.com
Research Domain of This Article
Reproductive Biology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Zeng-Hui Huang, Xi-Ren Ji, Wen-Jun Zhou, Xue-Feng Luo, Qian Liu, Yu-Lin Tang, Fei Gong, Wen-Bing Zhu, Institute of Reproductive and Stem Cell Engineering, Central South University, Changsha 410008, Hunan Province, China
Zeng-Hui Huang, Department of Reproductive Center, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha 410008, Hunan Province, China
Chuan Huang, Department of Sperm Bank, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha 410008, Hunan Province, China
Author contributions: Zhu WB designed the study and supervised the laboratory experiments; Huang ZH conducted the experiments and drafted the manuscript; Huang C, Ji XR, Zhou WJ and Luo XF assisted with the experiments and sample collection; Liu Q, Tang YL and Gong F performed the analysis with constructive discussion and contributed analysis tools.
Supported byChina Postdoctoral Science Foundation, No. 2019M661521; and National Natural Science Foundation of China, No. 82001634.
Institutional review board statement: The Ethics Committee of the Reproductive & Genetic Hospital of CITICXiangya, Basic Medical Science School, Central South University, approved and supervised the present study (Approval No. LL-SC-2020-028).
Conflict-of-interest statement: All authors declared no competing interests.
Data sharing statement: The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Wen-Bing Zhu, PhD, Professor, Institute of Reproductive and Stem Cell Engineering, Central South University, No. 932 Lushan South Road, Yuelu District, Changsha 410008, Hunan Province, China. zhuwenbing0971@sina.com
Received: July 19, 2021 Peer-review started: July 19, 2021 First decision: August 15, 2021 Revised: August 28, 2021 Accepted: September 15, 2021 Article in press: September 15, 2021 Published online: November 26, 2021 Processing time: 128 Days and 20.3 Hours
ARTICLE HIGHLIGHTS
Research background
Human spermatogonial stem cells (SSCs) are the basis of spermatogenesis. However, little is known about the developmental regulatory mechanisms of SSC due to sample origin and species differences.
Research motivation
To investigates the mechanisms involved in the proliferation of human SSCs.
Research objectives
To investigate the functions and mechanisms of mitogen-activated protein kinase kinase 7 (MKK7) during proliferation and apoptosis in human SSCs.
Research methods
The expression of MKK7 in human testis was identified using immunohistochemistry and western blotting (WB). MKK7 was knocked down using small interfering RNA, and cell proliferation and apoptosis were detected by WB, EdU, cell counting kit-8 and fluorescence-activated cell sorting. After bioinformatic analysis, the interaction of MKK7 with c-Jun N-terminal kinases (JNKs) was verified by protein co-immunoprecipitation and WB. The phosphorylation of JNKs was inhibited by SP600125, and the phenotypic changes were detected by WB, cell counting kit-8 and fluorescence-activated cell sorting.
Research results
MKK7 is mainly expressed in human SSCs, and MKK7 knockdown inhibits SSC proliferation and promotes their apoptosis. MKK7 mediated the phosphorylation of JNKs, and after inhibiting the phosphorylation of JNKs, the phenotypic changes of the cells were similar to those after MKK7 downregulation. The expression of MKK7 was significantly downregulated in patients with abnormal spermatogenesis, suggesting that abnormal MKK7 may be associated with spermatogenesis impairment.
Research conclusions
MKK7 regulates the proliferation and apoptosis of human SSC by mediating the phosphorylation of JNKs. Abnormal expression of MKK7 may impair human spermatogenesis.
Research perspectives
This study intended to reveal the role and regulatory mechanism of MKK7 in the regulation of SSC development and spermatogenesis in humans, which can provide a scientific basis for the etiological interpretation and molecular diagnosis of male infertility. It also provided new molecular targets for the clinical treatment of male infertility and the development of contraceptives.
