Abstract
BackgroundWe have recently reported that human bone marrow-derived mesenchymal stem cells (MSCs) facilitate angiogenesis and prevent follicle loss in xenografted human ovarian tissues. However, the mechanism underlying this effect remains to be elucidated. Thus, determining the paracrine profiles and identifying the key secreted factors in MSCs co-transplanted with ovarian grafts are essential for the future application of MSCs.MethodsIn this study, we used cytokine microarrays to identify differentially expressed proteins associated with angiogenesis in frozen-thawed ovarian tissues co-transplanted with MSCs. The function of specific secreted factors in MSCs co-transplanted with human ovarian tissues was studied via targeted blockade with short-hairpin RNAi and the use of monoclonal neutralizing antibodies.ResultsOur results showed that angiogenin (ANG) was one of the most robustly up-regulated proteins (among 42 protein we screened, 37 proteins were up-regulated). Notably, the targeted depletion of ANG with short-hairpin RNAi (shANG) or the addition of anti-ANG monoclonal neutralizing antibodies (ANG Ab) significantly reversed the MSC-stimulated angiogenesis, increased follicle numbers and protective effect on follicle apoptosis.ConclusionOur results indicate that ANG plays a critical role in regulating angiogenesis and follicle survival in xenografted human ovarian tissues. Our findings provide important insights into the molecular mechanism by which MSCs promote angiogenesis and follicle survival in transplanted ovarian tissues, thus providing a theoretical basis for their further application.
Highlights
We have recently reported that human bone marrow-derived mesenchymal stem cells (MSCs) facilitate angiogenesis and prevent follicle loss in xenografted human ovarian tissues
ANG levels are significantly increased upon co-transplantation of MSCs with ovarian tissues The characterization of MSCs was shown in Additional file 2: Figure S2
We were intrigued that ANG exhibited a marked increase in expression in cotransplanted ovarian tissue and MSCs, as it has been reported that ANG plays an essential role in endothelial cell proliferation and angiogenesis [33]
Summary
We have recently reported that human bone marrow-derived mesenchymal stem cells (MSCs) facilitate angiogenesis and prevent follicle loss in xenografted human ovarian tissues. MSCs have been shown to be a promising therapeutic approach to treat a spectrum of diseases, especially in disorders associated with insufficient angiogenesis [11, 12]. We demonstrated that MSCs from human bone marrow. Zhang et al Reproductive Biology and Endocrinology (2017) 15:18 functioned as a supportive agent for human ovarian tissue transplantation, promoting angiogenesis and follicle survival [13]. A better understanding of how co-transplanted MSCs exert their pro-angiogenic effects on ovarian grafts can help optimize the parameters for clinical applications. In this study, we sought to investigate the possible mechanisms by which human MSCs promote re-vascularization and prevent follicle loss in xenografted ovarian tissues
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