Bone Marrow-Derived Mesenchymal Stem Cells Reverse Radiotherapy-Induced Premature Ovarian Failure: Emphasis on Signal Integration of TGF-β, Wnt/β-Catenin and Hippo Pathways

Radiotherapy is an indispensable cancer treatment approach. However, it is associated with hazardous consequences on multiple organs characterized by insidious worsening severity over time. This study aimed to examine the potential therapeutic effects of bone marrow mesenchymal stem cells (BM-MSCs) in radiation-induced premature ovarian failure (POF). Exposing female rats to 3.2 Gy whole-body Upsilon-rays successfully induced POF. One week later, a single intravenous injection of BM-MSCs (2*10(6)) cells was administered. BM-MSCs perfectly home to the damaged ovaries, enhanced ovarian follicle pool, and preserved the ovarian function manifested by restoring serum estradiol and follicle stimulating hormone levels, besides, rescuing the fertility outcomes of irradiated rats. These events have been associated with inhibiting ovarian apoptosis (Bax/Bcl2, caspase 3) and enhancing proliferation (PCNA). Interestingly, BM-MSCs reversed the inhibition of ovarian FOXO3 expression induced by radiation which resulted in increased primordial follicles stock. Moreover, BM-MSCs recovered the suppressed folliculogenesis process induced by radiation through upregulating FOXO1, GDF-9, and Fst genes expression accompanied by downregulating TGF-beta which enhanced granulosa cells proliferation and secondary follicle development. Mechanistically, BM-MSCs miRNAs epigenetically upregulate Wnt/beta-catenin and Hippo signaling pathways which are implicated in ovarian follicles growth and maturation. Therefore, BM-MSCs presented a ray of hope in the treatment of radiation-associated POF through genetic and epigenetic modulation of the integrated TGF-beta, Wnt/beta-catenin, and Hippo pathways which control apoptosis, proliferation, and differentiation of ovarian follicles.