Nahideh Nazdikbin Yamchi
1 
, Farhad Amjadi
1, Rahim Beheshti
2, Mehdi Hassanpour
1, Reza Shirazi
3, Amin Tamadon
4,5 , Reza Rahbarghazi
6,7 , Mahdi Mahdipour
1,8* 1 Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
2 Faculty of Veterinary Medicine, Shabestar Islamic Azad University, Shabestar, Iran
3 Department of Anatomy, School of Medical Sciences, Medicine & Health, UNSW Sydney, Sydney, Australia
4 Percia Vista R&D Co. Shiraz, Iran
5 Department for Scientific Work, West Kazakhstan Marat Ospanov Medical University, Aktobe 030012, Kazakhstan
6 Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
7 Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
8 Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
Abstract
Introduction: Premature ovarian insufficiency (POI) is a challenging issue in terms of reproduction biology. In this study, therapeutic properties of bone marrow CD146+ mesenchymal stem cells (MSCs) and CD144+ endothelial cells (ECs) were separately investigated in rats with POI.
Methods: POI rats were classified into control POI, POI + CD146+ MSCs, and POI + CD144+ ECs groups. Enriched CD146+ MSCs and CD144+ ECs were directly injected into ovarian tissue (15 × 104 cells/10 μL) in relevant groups. After 4 weeks, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) levels were measured in blood samples. Ovarian tissues were collected and subjected to Hematoxylin-Eosin and Masson’s trichrome staining. The expression of angp-2, vegfr-2, smad-2, -4, -6, and tgf-β1 was studied using qRT-PCR analysis. Histopathological examination indicated an increased pattern of atretic follicles in the POI group related to the control rats (P<0.0001).
Results: Data indicated that injection of POI + CD146+ MSCs and CD144+ ECs in POI rats reduced atretic follicles and increased the number of normal follicles (P<0.01). Along with these changes, the content of blue-colored collagen fibers was diminished after cell transplantation. Besides, cell transplantation in POI rats had the potential to reduce increased FSH, and LH levels (P<0.05). In contrast, E2 content was increased in POI + CD146+ MSCs and POI + CD144+ ECs groups compared to control POI rats, indicating restoration of follicular function. CD144+ (smad-2, and -4) and CD146+ (smad-6) cells altered the activity of genes belonging TGF-β signaling pathway. Unlike POI + CD146+ MSCs, aberrant angiogenesis properties were significantly down-regulated in POI + CD144+ ECs related to the control POI group (P<0.05).
Conclusion: The transplantation of bone marrow CD146+ and CD144+ cells can lead to the restoration of ovarian tissue function in POI rats via modulating different mechanisms associated with angiogenesis and fibrosis