Ovarian tissue damage after grafting: systematic review of strategies to improve follicle outcomes

Abstract

Frozen-thawed human ovarian tissue endures large-scale follicle loss in the early post-grafting period, characterized by hypoxia lasting around 7 days. Tissue revascularization occurs progressively through new vessel invasion from the host and neoangiogenesis from the graft. Such reoxygenation kinetics lead to further potential damage caused by oxidative stress. The aim of the present manuscript is to provide a systematic review of proangiogenic growth factors, hormones and various antioxidants administered in the event of ovarian tissue transplantation to protect the follicle pool from depletion by boosting revascularization or decreasing oxidative stress. While almost all investigated studies revealed an advantage in terms of revascularization and reduction in oxidative stress, far fewer demonstrated a positive impact on follicle survival.Since the cascade of events driven by ischemia after transplantation is a complex process involving numerous players, it appears that acting on specific molecular mechanisms, such as levels of proangiogenic growth factors, is not enough to significantly mitigate tissue damage. Strategies exploiting the activated tissue response to ischemia for tissue healing and remodeling purposes, like use of antiapoptotic drugs and adult stem cells, are also discussed in the present review, since they yielded promising results in terms of follicle pool protection.

Effects of hypoxia-preconditioned HucMSCs on neovascularization and follicle survival in frozen/thawed human ovarian cortex transplanted to immunodeficient mice

“…A series of stressful events caused by hypoxia in grafts are complex and involve various players. Activation of signalling pathways in response to hypoxia and oxidative stress not only allows cells to adapt to this stress, changing cell metabolism and promoting survival but also triggers any subsequent tissue events, such as angiogenesis and tissue remodelling, which strive to reduce tissue injury [ 35 ].…”

“…The ASCs could boost the vascularization of grafts. This strategy can decrease follicle loss that occurs soon after OT by reducing both follicle death and abnormal primordial follicle activation [ 35 ] and be persistent in the long term [ 16 ]. The umbilical cord is discarded after childbirth but compared to MSCs derived from traditional cell sources such as adipose or bone marrow, HucMSCs showed increased pluripotency and elevatory proliferation capacity [ 43 ].…”

“…Its secretome is rich in various growth factors, including VEGF, governing the proangiogenic behaviour of HucMSC [ 29 ]. Boosting neoangiogenesis has proven to improve follicle outcomes [ 35 ]. Hypoxia-preconditioned HucMSCs provide prolonged exposure to growth factors such as VEGFA after transplantation, improving neoangiogenesis enhancement.…”

“…All morphologically normal follicles were analysed. Follicles were considered positive if more than 50% of GCs or oocytes were stained [ 35 ].…”

Proceedings of the Oncofertility Congress of the “Freezing Ovarian Tissue and Oocytes” (FOTO) Consortium Brussels

“…These include the addition of proangiogenic growth factors, hormones, and various antioxidants which have shown to boost revascularization or reduce oxidative stress, although there is little evidence of a positive impact on follicle survival. Luciana Cacciottola (Belgium) addressed the use of adipose tissue-derived stem cells in the context of OTT and showed favorable data of reduced hypoxia, enhanced revascularization, and primordial follicle quiescence [ 3 ].…”