HGF Secreted by Mesenchymal Stromal Cells Promotes Primordial Follicle Activation by Increasing the Activity of the PI3K-AKT Signaling Pathway

Abstract

Primordial follicle activation is fundamental for folliculogenesis and for the maintenance of fertility. An effective therapeutic strategy for patients with premature ovarian insufficiency (POI) is to promote the activation of residual primordial follicles. The secretome of human umbilical cord mesenchymal stromal cells (hUC-MSC-sec) contains several components that might promote the activation of primordial follicles. In the present study, we revealed that treatment with the hUC-MSC-sec significantly increased the proportion of activated primordial follicles in mouse ovaries both in vitro and in vivo. The activating effects of hUC-MSC-sec on primordial follicles were attributed to the activation of the PI3K-AKT signaling pathway by hepatocyte growth factor (HGF). While the effect of the hUC-MSC-sec was attenuated by the neutralizing antibodies against HGF, application of exogenous HGF alone also promoted the activation of primordial follicles. Furthermore, we demonstrated that HGF promoted the expression of KITL in granulosa cells by binding with the HGF receptor c-Met, thereby increasing the activity of the PI3K-AKT signaling pathway to activate primordial follicles. Taken together, our findings demonstrate that hUC-MSC-sec promotes primordial follicle activation through the functional component HGF to increase the PI3K-AKT signaling activity, highlighting the application of the hUC-MSC-sec or HGF for the treatment of POI patients. Graphical abstract

Bone marrow mesenchymal stem cells in premature ovarian failure: Mechanisms and prospects

“…Xin Mi et al also found that the secretome of hUMSCs helped effectively to activate primordial follicle both in vivo and vitro. And furthermore, hUMSCs-derived HGF upregulated the expression of KIT ligand in GCs, thereby promoting the activation of PI3K/Akt signaling pathway in dormant oocytes (194). Li Z et al revealed that hUMSCs-derived exosome significantly ameliorated ovarian function and reproductive ability of POF mice models through promoting GCs proliferation via the Hippo signaling pathway (195).…”

“…also found that the secretome of hUMSCs helped effectively to activate primordial follicle both in vivo and vitro. And furthermore, hUMSCs-derived HGF upregulated the expression of KIT ligand in GCs, thereby promoting the activation of PI3K/Akt signaling pathway in dormant oocytes ( 194 ). Li Z et al.…”

Aging conundrum: A perspective for ovarian aging

“…The lifespan of the ovary depends on the delicate balance between the survival and death of oocytes. PMF activation is the basis for ovarian folliculogenesis and maintenance of fertility (121). However, damage during ovarian folliculogenesis, including the activation, recruitment, and development of early follicles, has a complex relationship with ovarian aging.…”

Signaling pathway intervention in premature ovarian failure

“…A study revealed that the ovarian reserve function of rats' was improved and the number of follicles rose after receiving transplantation human umbilical cord mesenchymal stem cells (hUCMSCs) (115). The hepatocyte growth factor, which is secreted from hUCMSCs, can increase the activity of the PI3K/Akt signaling in dormant oocytes (116). By transplanting hUCMSCs into mice with POF, Lv et al (120) found that multiple hUCMSCs transplantations had a better effect on the recovery of ovarian function than single hUCMSCs transplantation (120).…”