Bone marrow mesenchymal stem cells expressing Neat-1, Hotair-1, miR-21, miR-644, and miR-144 subsided cyclophosphamide-induced ovarian insufficiency by remodeling the IGF-1-kisspeptin system, ovarian apoptosis, and angiogenesis

Amany I Ahmed; Mohamed F Dowidar; Asmaa F Negm; Hussein Abdellatif; Asma Alanazi; Mohammed Alassiri; Walaa Samy; Dina Mohamed Mekawy; Eman M A Abdelghany; Nesma I El-Naseery; Mohamed A Ibrahem; Emad Ali Albadawi; Wed Salah; Mamdouh Eldesoqui; Emil Tîrziu; Iulia Maria Bucur; Ahmed Hamed Arisha; Tarek Khamis

doi:10.1186/s13048-024-01498-x

Bone marrow mesenchymal stem cells expressing Neat-1, Hotair-1, miR-21, miR-644, and miR-144 subsided cyclophosphamide-induced ovarian insufficiency by remodeling the IGF-1-kisspeptin system, ovarian apoptosis, and angiogenesis

J Ovarian Res. 2024 Sep 12;17(1):184. doi: 10.1186/s13048-024-01498-x.

Authors

Amany I Ahmed¹, Mohamed F Dowidar¹, Asmaa F Negm¹, Hussein Abdellatif^{2

3}, Asma Alanazi^{4

5}, Mohammed Alassiri^{5

6}, Walaa Samy⁷, Dina Mohamed Mekawy^{8

9}, Eman M A Abdelghany¹⁰, Nesma I El-Naseery¹¹, Mohamed A Ibrahem¹², Emad Ali Albadawi¹³, Wed Salah¹⁴, Mamdouh Eldesoqui^{15

16}, Emil Tîrziu¹⁷, Iulia Maria Bucur¹⁸, Ahmed Hamed Arisha^{19

20}, Tarek Khamis²¹

Affiliations

¹ Department of Biochemistry, Faculty of Veterinary Medicine, Zagazig University, Zagazig, 44519, Egypt.
² Department of Human and Clinical Anatomy, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Sultanate of Oman.
³ Human Anatomy and Embryology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
⁴ Collage of Medicine, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Riyadh, Saudi Arabia.
⁵ King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.
⁶ Department of Basic Medical Sciences, College of Science and Health Professions (COSHP), King Saud bin Abdulaziz University for Health Sciences, Riyadh, Kingdom of Saudi Arabia.
⁷ Medical biochemistry Department, Faculty of Medicine, Zagazig University, Zagazig, 44519, Egypt.
⁸ Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo, Egypt.
⁹ Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Badr University in Cairo, Badr City, 11829, Egypt.
¹⁰ Human Anatomy and Embryology Department, Faculty of Medicine, Zagazig University, Zagazig, 44519, Egypt.
¹¹ Department of Histology and Cytology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, 44519, Egypt.
¹² Obstetrics and Gynecology Department, Faculty of Medicine, Zagazig University, Zagazig, 44519, Egypt.
¹³ Department of Anatomy, College of Medicine, Taibah University, Medina, Saudi Arabia.
¹⁴ Department of Anatomy, Faculty of Medicine, University of Jeddah, Jeddah, Saudi Arabia.
¹⁵ Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, P.O.Box 71666, Riyadh, 11597, Saudi Arabia.
¹⁶ Department of Anatomy and Embryology, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt.
¹⁷ Department of Animal Production and Veterinary Public Health, Faculty of Veterinary Medicine, University of Life Sciences, "King Mihai I" from Timisoara [ULST], Aradului St. 119, Timisoara, 300645, Romania.
¹⁸ Department of Animal Production and Veterinary Public Health, Faculty of Veterinary Medicine, University of Life Sciences, "King Mihai I" from Timisoara [ULST], Aradului St. 119, Timisoara, 300645, Romania. Iulia.bucur@usvt.ro.
¹⁹ Department of Animal Physiology and Biochemistry, Faculty of Veterinary Medicine, Badr University in Cairo, Badr City, 11829, Egypt. vetahmedhamed@zu.edu.eg.
²⁰ Department of Physiology and Laboratory of Biotechnology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, 44511, Egypt. vetahmedhamed@zu.edu.eg.
²¹ Department of Pharmacology and Laboratory of Biotechnology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, 44519, Egypt. t.khamis@vet.zu.edu.eg.

Abstract

Ovarian insufficiency is one of the common reproductive disorders affecting women with limited therapeutic aids. Mesenchymal stem cells have been investigated in such disorders before yet, the exact mechanism of MSCs in ovarian regeneration regarding their epigenetic regulation remains elusive. The current study is to investigate the role of the bone marrow-derived mesenchymal stem cells (BM-MSCs) lncRNA (Neat-1 and Hotair1) and miRNA (mir-21-5p, mir-144-5p, and mir-664-5p) in mitigating ovarian granulosa cell apoptosis as well as searching BM-MSCs in altering the expression of ovarian and hypothalamic IGF-1 - kisspeptin system in connection to HPG axis in a cyclophosphamide-induced ovarian failure rat model. Sixty mature female Sprague Dawley rats were divided into 3 equal groups; control group, premature ovarian insufficiency (POI) group, and POI + BM-MSCs. POI female rat model was established with cyclophosphamide. The result revealed that BM-MSCs and their conditioned media displayed a significant expression level of Neat-1, Hotair-1, mir-21-5p, mir-144-5p, and mir-664-5p. Moreover, BM-MSCs transplantation in POI rats improves; the ovarian and hypothalamic IGF-1 - kisspeptin, HPG axis, ovarian granulosa cell apoptosis, steroidogenesis, angiogenesis, energy balance, and oxidative stress. BM-MSCs expressed higher levels of antiapoptotic lncRNAs and microRNAs that mitigate ovarian insufficiency.

Keywords: BM-MSCs; Cyclophosphamide; HPG; Premature ovarian failure; lncRNA; microRNAs.

MeSH terms

Angiogenesis
Animals
Apoptosis*
Bone Marrow Cells / metabolism
Cyclophosphamide* / adverse effects
Female
Insulin-Like Growth Factor I* / genetics
Insulin-Like Growth Factor I* / metabolism
Mesenchymal Stem Cells* / metabolism
MicroRNAs* / genetics
MicroRNAs* / metabolism
Ovary / metabolism
Primary Ovarian Insufficiency* / chemically induced
Primary Ovarian Insufficiency* / genetics
Primary Ovarian Insufficiency* / metabolism
RNA, Long Noncoding* / genetics
RNA, Long Noncoding* / metabolism
Rats
Rats, Sprague-Dawley*

Substances

MicroRNAs
Cyclophosphamide
RNA, Long Noncoding
MIRN144 microRNA, rat
Insulin-Like Growth Factor I
HOTAIR long untranslated RNA, rat
mirn21 microRNA, rat
insulin-like growth factor-1, rat

Abstract

MeSH terms

Substances

Grants and funding