Bone marrow-derived mesenchymal stem cells combined with gonadotropin therapy restore postnatal oogenesis of chemo-ablated ovaries in rats via enhancing very small embryonic-like stem cells

Nesrine Ebrahim,Nicholas R Forsyth,Hanan Tawfeek Emam,Arigue A Dessouky,Ola Mostafa,Ayman Samir Farid,Amira Hassouna,Amani Shaman,Omnia A M Badr,Dina Sabry,Rabab F Salim,Ahmed S Saad,Bayan A Saffaf,Hajir A Al Saihati,Noha I Hussien,Yasmin Seleem

doi:10.1186/s13287-021-02415-5

Abstract

BackgroundVery small embryonic-like stem cells (VSELs) are a rare population within the ovarian epithelial surface. They contribute to postnatal oogenesis as they have the ability to generate immature oocytes and resist the chemotherapy. These cells express markers of pluripotent embryonic and primordial germ cells.ObjectiveWe aimed to explore the capability of VSELs in restoring the postnatal oogenesis of chemo-ablated rat ovaries treated with bone marrow-derived mesenchymal stem cells (BM-MSCs) combined with pregnant mare serum gonadotropin (PMSG).MethodsFemale albino rats were randomly assigned across five groups: I (control), II (chemo-ablation), III (chemo-ablation + PMSG), IV (chemo-ablation + MSCs), and V (chemo-ablation + PMSG + MSCs). Postnatal oogenesis was assessed through measurement of OCT4, OCT4A, Scp3, Mvh, Nobox, Dazl4, Nanog, Sca-1, FSHr, STRA8, Bax, miR143, and miR376a transcript levels using qRT-PCR. Expression of selected key proteins were established as further confirmation of transcript expression changes. Histopathological examination and ovarian hormonal assessment were determined.ResultsGroup V displayed significant upregulation of all measured genes when compared with group II, III or IV. Protein expression confirmed the changes in transcript levels as group V displayed the highest average density in all targeted proteins. These results were confirmed histologically by the presence of cuboidal germinal epithelium, numerous primordial, unilaminar, and mature Graafian follicles in group V.ConclusionVSELs can restore the postnatal oogenesis in chemo-ablated ovaries treated by BM-MSCs combined with PMSG.

Highlights

Mammalian ovaries are responsible for competent mature oocyte formation
Very small embryonic-like stem cells (VSELs) can restore the postnatal oogenesis in chemo-ablated ovaries treated by bone marrow-derived mesenchymal stem cells (BM-Mesenchymal stem cells (MSCs)) combined with pregnant mare serum gonadotropin (PMSG)
Gonadotrophin and BM-MSC supplementation promote elevated serum estradiol E levels Following on from ovarian chemo-ablation by combined administration of busulfan daily for 4 days and 100 mg/ kg cyclophosphamide on the first 2 days, we sought to determine whether gonadotrophin and BM-MSCs carried with them a therapeutic effect

Summary

Introduction

Mammalian ovaries are responsible for competent mature oocyte formation. They are responsible for the secretion of a variety of hormones, growth factors and cytokines that contribute to key signaling pathways of oogenesis and folliculogenesis. POF is manifested by amenorrhea, sex steroid hormone deficiency with elevated (menopausal) levels of serum gonadotropins, before the age of 40 years [2]. It is not a rare condition with an occurrence of approximately 6% in women of less than 40 years of age [3]. Very small embryonic-like stem cells (VSELs) are a rare population within the ovarian epithelial surface. They contribute to postnatal oogenesis as they have the ability to generate immature oocytes and resist the chemotherapy. These cells express markers of pluripotent embryonic and primordial germ cells

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