Abstract
BackgroundHuman amniotic epithelial cells (hAECs) are attractive candidates for regenerative medical therapy, with the potential to replace deficient cells and improve functional recovery after injury. Previous studies have demonstrated that transplantation of hAECs effectively alleviate chemotherapy-induced ovarian damage via inhibiting granulose cells apoptosis in animal models of premature ovarian failure/insufficiency (POF/POI). However, the underlying molecular mechanism accounting for hAECs-mediated ovarian function recovery is not fully understood.MethodsTo investigate whether hAECs-secreting cytokines act as molecular basis to attenuate chemotherapy-induced ovarian injury, hAECs or hAEC-conditioned medium (hAEC-CM) was injected into the unilateral ovary of POF/POI mouse. Follicle development was evaluated by H&E staining at 1, 2 months after hAECs or hAEC-CM treatment. In addition, we performed a cytokine array containing 507 human cytokines on hAECs-derived serum-free conditioned medium. Finally, we further investigated whether hAECs could affect chemotherapy-induced apoptosis in primary human granulosa-lutein (hGL) cells and the tube formation of human umbilical vein endothelial cells (hUVECs) via a co-culture system in vitro.ResultsWe observed the existence of healthy and mature follicles in ovaries treated with hAECs or hAEC-CM, whereas seriously fibrosis and many atretic follicles were found in the contralateral untreated ovaries of the same mouse. To distinguish cytokines involved in the process of hAECs-restored ovarian function, hAEC-CM was analyzed with a human cytokines array. Results revealed that 109 cytokines in hAEC-CM might participate in a variety of biological processes including apoptosis, angiogenesis, cell cycle and immune response. In vitro experiments, hAECs significantly inhibited chemotherapy-induced apoptosis and activated TGF-β/Smad signaling pathway within primary granulosa-lutein cells in paracrine manner. Furthermore, hAEC-CM was shown to promote angiogenesis in the injured ovaries and enhance the tube formation of human umbilical vein endothelial cells (hUVECs) in co-culture system.ConclusionsThese findings demonstrated that paracrine might be a key pathway in the process of hAECs-mediating ovarian function recovery in animal models of premature ovarian failure/insufficiency (POF/POI).
Highlights
Human amniotic epithelial cells are attractive candidates for regenerative medical therapy, with the potential to replace deficient cells and improve functional recovery after injury
Injection of Human amniotic epithelial cells (hAECs) or hAEC-conditioned medium (CM) restored ovarian function in chemotherapy-induced POF/POI mice The hAECs represented a cobblestone-like morphology (Additional file 1: Figure S1A, a). hAECs expressed the high level of epithelial markers CK19 and E-cadherin, low level of mesenchymal marker N-cadherin, and did not express granulosa cell-specific marker follicle-stimulating hormone receptor (FSHR) (Additional file 1: Figure S1A, b)
To further elucidate whether hAEC-mediated the recovery of ovarian function is achieved by improving the local ovarian microenvironment, hAECs or hAEC-conditioned medium (hAEC-CM) was injected into the unilateral ovary using a microinjection needle at 7 days after the administration of chemotherapy drugs (Additional file 1: Figure S1C, a)
Summary
Human amniotic epithelial cells (hAECs) are attractive candidates for regenerative medical therapy, with the potential to replace deficient cells and improve functional recovery after injury. Previous studies have demonstrated that transplantation of hAECs effectively alleviate chemotherapy-induced ovarian damage via inhibiting granulose cells apoptosis in animal models of premature ovarian failure/insufficiency (POF/POI). There is no satisfying protective strategy to avoid chemotherapy-induced premature ovarian failure/insufficiency (POF/POI). Many studies in the field of regenerative medicine showed that stem cells transplantation might provide an important methodology for restoring ovarian function. Human amniotic epithelial cells (hAECs) derived from fetal membranes represent a viable source of stem cells. These cells have low immunogenicity and avoid the ethical issues of embryonic stem cells [2]. HAECs have been shown to be capable of differentiating into functional hepatocyte-like cells [3], neural cells [4] and cardiomyocyte-like cells [5], which exert regenerative function in injured tissues
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