Basic Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Aug 26, 2020; 12(8): 857-878
Published online Aug 26, 2020. doi: 10.4252/wjsc.v12.i8.857
Human embryonic stem cell-derived mesenchymal stem cells improved premature ovarian failure
Khadijeh Bahrehbar, Mojtaba Rezazadeh Valojerdi, Fereshteh Esfandiari, Rouhollah Fathi, Seyedeh-Nafiseh Hassani, Hossein Baharvand
Khadijeh Bahrehbar, Fereshteh Esfandiari, Seyedeh-Nafiseh Hassani, Hossein Baharvand, Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Tehran 1665659911, Iran
Khadijeh Bahrehbar, Hossein Baharvand, Department of Developmental Biology, University of Science and Culture, Tehran 1665659911, Iran
Mojtaba Rezazadeh Valojerdi, Rouhollah Fathi, Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Tehran 1665659911, Iran
Mojtaba Rezazadeh Valojerdi, Department of Anatomy, Faculty of Medical Science, Tarbiat Modares University, Tehran 1665659911, Iran
Author contributions: Bahrehbar K and Esfandiari F were involved in collection and/or assembly of the data and manuscript writing; Bahrehbar K, Rezazadeh Valojerdi M, Baharvand H, Fathi R and Hassani SN were involved in data analysis and interpretation; Esfandiari F, Fathi R and Hassani SN were involved in conception and design; Rezazadeh Valojerdi M and Baharvand H were co-corresponding authors and were involved in conducting the experiments, manuscript proof, administrative and financial support.
Supported by Royan Institute, the National Institute for Medical Research Development, No. 963255; and the Ministry of Health and Medical Education, No. 700/147.
Institutional review board statement: This study was reviewed and approved by the Institutional Review Board at Royan Institute.
Institutional animal care and use committee statement: All animal experiments of the study were reviewed and approved by the Institutional Ethical Committee at Royan Institute.
Conflict-of-interest statement: The authors declare that they have no competing interests.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared according to these guidelines.
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:
Corresponding author: Hossein Baharvand, PhD, Full Professor, Department of Stem Cells and Developmental Biology, Royan Institute for Stem Cell Biology and Technology, Banihashem St., Tehran 1665659911, Iran.
Received: February 22, 2020
Peer-review started: February 22, 2020
First decision: April 29, 2020
Revised: June 1, 2020
Accepted: July 18, 2020
Article in press: July 18, 2020
Published online: August 26, 2020
Research background

Premature ovarian failure (POF) is characterized by amenorrhea, hypoestrogenemia, high gonadotropins and infertility in women under 40-years-old. Previous reports demonstrated that various tissue-specific stem cells could restore ovarian function and folliculogenesis in chemotherapy-induced POF mice.

Research motivation

Human embryonic stem cell-derived MSC (ES-MSC) have advantages, such as higher proliferation, more potent anti-inflammatory properties and lack of obstacles of harvesting tissue-specific MSCs that make them attractive candidates for restoring fertility in patients with POF.

Research objectives

The aim of this study was to evaluate the therapeutic efficacy of ES-MSCs in a model of chemotherapy-induced POF.

Research methods

In this study, we initially established a mouse POF model by administration of cyclophosphamide and busulfan, then we transplanted ES-MSCs and bone marrow-derived MSC (BM-MSC) into a mouse model of POF to investigate the role of these cells and mechanisms of action for improvement of POF.

Research results

The POF model established by the 100 mg/kg dose of cyclophosphamide showed significant decreases in body weight, follicle count and estradiol level but had an increased follicle-stimulating hormone level. ES-MSC and/or BM-MSC transplantation significantly improved body weight, follicle count, hormone secretion, survival rate and reproductive function in POF mice. Gene expression and Western blot analysis, terminal deoxynucleotidyl transferase mediated 2-deoxyuridine 5-triphosphate nick end labelling assay and immunohistochemistry indicated that the ES-MSCs or BM-MSCs reduced apoptosis in the follicles and restored fertility in chemotherapy-induced POF mice. The results of this study indicated that the effects of ES-MSCs and BM-MSCs in restoring ovarian function appear via the paracrine mechanisms of cytokines.

Research conclusions

Our findings demonstrated that human ES-MSCs, similar to BM-MSCs, improved ovarian function and restored fertility in a mouse POF model.

Research perspectives

Our present study results suggest that human ES-MSCs could be a promising source for stem cell therapy in individuals with POF.