Paracrine effects of human amniotic epithelial cells protect against chemotherapy-induced ovarian damage

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).Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0721-0) contains supplementary material, which is available to authorized users.

Exosomes derived from human adipose mesenchymal stem cells improve ovary function of premature ovarian insufficiency by targeting SMAD

“…8 ). These current findings are consistent with the results of a previous study showing that mesenchymal stem cells recover the ovarian function of POI by regulating the SMAD pathway [ 25 ]. Several lines of evidence support this result and indicate that SMAD knockdown induced follicle loss by increasing the expression levels of apoptosis genes (Fas, FasL, caspase-3, and caspase-8) [ 19 , 26 ].…”

Kannabinoid Tip 2 Reseptör Agonistinin Sıçanlarda Over İskemi/reperfüzyon Hasarına Karşı Koruyucu Etkisi

“…12,31 Many studies have shown that the activation of the CB2 receptor causes immunomodulatory eff ects. 24,32 As in previous studies with paracrine, 33 it was observed that the cytokine levels produced by ovarian damage were reduced by the activation of the CB2 receptor agonist. Recent studies with the activation of the CB2 receptor agonist on some diseases such as asthma, colitis, rheumatoid arthritis, rat paw infl ammation, and infl ammatory bowel disease show that it inhibits proinfl ammatory cytokine production, such as TNF-α and IL-1β, and protects it from ovarian injuries.…”

Recent advances in understanding primary ovarian insufficiency

“…Another recent study used an alternative stem cell source: endometrial mesenchymal stem cells (MSCs) injected into mice with chemo-induced POI resulted in higher circulating levels of anti-Mullerian hormone (AMH, a known marker of ovarian reserve), greater number of developing follicles, and higher ovulation and live birth rates 46 . Furthermore, the therapeutic benefit of stem cells from other tissues, including adipose, umbilical cord blood, and amniotic epithelial cells, has been explored [47][48][49][50] . Recent research has begun to explore how stem cells specifically affect the ovarian microenvironment and restore ovarian function through the use of exosomes derived from stem cells in chemotherapy-induced POI models 51,52 .…”