Human amniotic mesenchymal stem cells improve ovarian function in natural aging through secreting hepatocyte growth factor and epidermal growth factor

Abstract

BackgroundAlthough many reports show that various kinds of stem cells have the ability to recover function in premature ovarian aging, few studies have looked at stem cell treatment of natural ovarian aging (NOA). We designed this experimental study to investigate whether human amniotic mesenchymal stem cells (hAMSCs) retain the ability to restore ovarian function, and how hAMSCs work in this process.MethodsTo build the NOA mouse model, the mice were fed for 12–14 months normally with young fertile female mice as the normal control group (3–5 months old). Hematoxylin and eosin staining permitted follicle counting and showed the ovarian tissue structure. An enzyme-linked immunosorbent assay was used to detect the serum levels of the sex hormones estradiol (E2), anti-mullerian hormone (AMH), and follicle-stimulating hormone (FSH). The proliferation rate and marker expression level of human ovarian granule cells (hGCs) (ki67, AMH, FSH receptor, FOXL2, and CYP19A1) were measured by flow cytometry (FACS). Cytokines (growth factors) were measured by a protein antibody array methodology. After hepatocyte growth factor (HGF) and epidermal growth factor (EGF) were co-cultured with hGCs, proliferation (ki67) and apoptosis (Annexin V) levels were analyzed by FACS. After HGF and EGF were injected into the ovaries of natural aging mice, the total follicle numbers and hormone levels were tested.ResultsAfter the hAMSCs were transplanted into the NOA mouse model, the hAMSCs exerted a therapeutic activity on mouse ovarian function by improving the follicle numbers over four stages. In addition, our results showed that hAMSCs significantly promoted the proliferation rate and marker expression level of ovarian granular cells that were from NOA patients. Meanwhile, we found that the secretion level of EGF and HGF from hAMSCs was higher than other growth factors. A growth factor combination (HGF with EGF) improved the proliferation rate and inhibited the apoptosis rate more powerfully after a co-culture with hGCs, and total follicle numbers and hormone levels were elevated to a normal level after the growth factor combination was injected into the ovaries of the NOA mouse model.ConclusionsThese findings provide insight into the notion that hAMSCs play an integral role in resistance to NOA. Furthermore, our present study demonstrates that a growth factor combination derived from hAMSCs plays a central role in inhibiting ovarian aging. Therefore, we suggest that hAMSCs improve ovarian function in natural aging by secreting HGF and EGF.Electronic supplementary materialThe online version of this article (10.1186/s13287-018-0781-9) contains supplementary material, which is available to authorized users.

Vitamin C improves the therapeutic potential of human amniotic epithelial cells in premature ovarian insufficiency disease

“…In support of our findings, recent studies have suggested the paracrine mechanism of mesenchymal stem cell therapy [44]. Our previous study also demonstrated that hepatocyte growth factor (HGF) and epidermal growth factor (EGF) secreted from hAMSCs play a critical role in reversing ovarian aging [17]. In this study, VC-hAECs secreted more trophic factors than hAECs, including HGF and EGF (Fig.…”

“…To date, various kinds of stem cells have been investigated to treat POI, including adipose-derived mesenchymal stem cells (hADSCs) [6], fetal liver mesenchymal stem cells [9], bone marrow mesenchymal stem cells (hBMSCs) 2 [10], human umbilical cordderived mesenchymal stem cells (hUCMSCs) [11,12], human amniotic epithelial cells (hAECs) [13,14], human amniotic fluid stem cells [15], and human amniotic mesenchymal stem cells (hAMSCs) [16,17]. Previous studies have indicated that human amnionderived stem cells are easier, less invasive, and more cost-effective than to obtain hADSCs and hBMSCs because amniotic tissues are discarded after delivery [16,18].…”

The role of EGFR signaling in age‐related osteoporosis in mouse cortical bone

“…Inactivating it in mice by EGFR-specific inhibitors or knockdown of EGFR in osteoprogenitors and osteoblastic cells results in bone loss because of a decreased number of bone marrow mesenchymal progenitors (18). Recently, it was reported that EGFR signaling protected cells from senescence and inhibited tissue aging (19)(20)(21), and blocking EGFR signaling promoted cell senescence and tissue aging (21). These studies strongly suggest that the EGFR signaling in osteoprogenitors might be important in prevention of cell senescence and regulation of cortical bone metabolism.…”

Human Amniotic Fluid Mesenchymal Stem Cells Improve Ovarian Function During Physiological Aging by Resisting DNA Damage

“…Current studies have indicated that, in the normal developmental period of the ovarian follicular cycle, all phases of follicular atresia are closely related to the activity levels of granulosa cells (Sun et al, 2012). Moreover, apoptosis in granulosa cells is the principal mechanism driving follicular atresia and arrest (Ding et al, 2018b). It has been speculated that abnormal folliculogenesis is probably due to increased apoptosis and decreased proliferation of granulosa cells (Ding et al, 2018c).…”