Mesenchymal stem cell-derived angiogenin promotes primodial follicle survival and angiogenesis in transplanted human ovarian tissue

Background: We 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. Methods: In 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. Results: Our 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. Conclusion: Our 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.National Science Foundation of China [31230047, 81471508, 81571386, 81471427, 31429004, 81300456]; National Key Technology R&D Program of China [2015BAI13B06, 2014BAI05B04]; Guangdong Natural Science Foundation [2014A03031379]; Guangdong Medical Scientific Foundation [A2014665]; Research Fund for Distinguished Experts, Guangxi, ChinaSCI(E)ARTICLE1