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

Xin Mi,Zi-Jiang Chen,Yingying Qin,Yajuan Yang,Wenlin Jiao,Shidou Zhao

doi:10.1007/s12015-022-10335-x

Xin Mi, Zi-Jiang Chen + Show 4 more

Open Access

https://doi.org/10.1007/s12015-022-10335-x

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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

Highlights

The majority of follicles in the mammalian ovary are quiescent, forming the primordial follicle pool, and only a few are gradually recruited into the growth phase. [1]
We further demonstrated that hepatocyte growth factor (HGF) secreted from hUC-mesenchymal stromal cells (MSCs) plays an essential role during this process
The effect of HGF to increase the proportion of activated oocytes with cytoplasmic localization of FOXO3a was blocked by c-Metab (Fig. S2). These results suggest that c-Met localized on granulosa cells is the specific receptor for HGF to promote the activation of the PI3K-AKT pathway

Summary

Introduction

The majority of follicles in the mammalian ovary are quiescent, forming the primordial follicle pool, and only a few are gradually recruited into the growth phase. [1]. Recent studies have found that even POI patients with amenorrhea still have some residual primordial follicles in their ovaries, and this provides a new direction for the treatment of POI patients by promoting the activation of these primordial follicles [9, 10] Based on this hypothesis, Kawamura et al pioneered in vitro activation (IVA) of primordial follicles by treating human ovarian cortical fragments with PI3K-AKT pathway stimulators in vitro to promote the activation of dormant follicles [11]. Kawamura et al pioneered in vitro activation (IVA) of primordial follicles by treating human ovarian cortical fragments with PI3K-AKT pathway stimulators in vitro to promote the activation of dormant follicles [11] This approach has been applied clinically and has resulted in several live births [12]. Considering the potential carcinogenicity of PI3K-AKT pathway stimulators and the invasive surgery, the prospects for the IVA technology are limited, and more effective and safe treatments for patients with POI are needed [13]

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