Enhancement of Neoangiogenesis and Follicle Survival by Sphingosine-1-Phosphate in Human Ovarian Tissue Xenotransplants

Abstract

Ovarian transplantation is one of the key approaches to restoring fertility in women who became menopausal as a result of cancer treatments. A major limitation of human ovarian transplants is massive follicular loss during revascularization. Here we investigated whether sphingosine-1-phosphate or its receptor agonists could enhance neoangiogenesis and follicle survival in ovarian transplants in a xenograft model. Human ovarian tissue xenografts in severe-combined-immunodeficient mice were treated with sphingosine-1-phosphate, its analogs, or vehicle for 1–10 days. We found that sphingosine-1-phosphate treatment increased vascular density in ovarian transplants significantly whereas FTY720 and SEW2871 had the opposite effect. In addition, sphingosine-1-phosphate accelerated the angiogenic process compared to vehicle-treated controls. Furthermore, sphingosine-1-phosphate treatment was associated with a significant proliferation of ovarian stromal cell as well as reduced necrosis and tissue hypoxia compared to the vehicle-treated controls. This resulted in a significantly lower percentage of apoptotic follicles in sphingosine-1-phosphate-treated transplants. We conclude that while sphingosine-1-phosphate promotes neoangiogenesis in ovarian transplants and reduces ischemic reperfusion injury, sphingosine-1-phosphate receptor agonists appear to functionally antagonize this process. Sphingosine-1-phosphate holds great promise to clinically enhance the survival and longevity of human autologous ovarian transplants.

Chemotherapy-Induced Damage to Ovary: Mechanisms and Clinical Impact

“…Validating and confirming in vitro organ culture experiments, doxorubicin treatment also resulted in reduced vascular density in xenografted human ovarian tissues compared with controls. These results are consistent with other studies that have demonstrated that chemotherapy may induce stromal fibrosis and o varian vascular abnormalities [18,21].While it is challenging to demonstrate that vascular damage directly contributes to chemotherapy-induced ovarian damage, in a recent study we showed an inverse correlation between ovarian vascular density and primordial follicles apoptosis [22]. It is normally supposed that primordial follicles do not depend on blood perfusion, but clinical experience from ovarian tissue transplantation do not support this belief [5].…”

“…While it is challenging to demonstrate that vascular damage directly contributes to chemotherapy-induced ovarian damage, in a recent study we showed an inverse correlation between ovarian vascular density and primordial follicles apoptosis [22]. It is normally supposed that primordial follicles do not depend on blood perfusion, but clinical experience from ovarian tissue transplantation do not support this belief [5].…”

VEGF and bFGF increase survival of xenografted human ovarian tissue in an experimental rabbit model

“…Examine the possible presence of malignant cells in ovarian cortex from patients with tumors after xenografting of the ovarian tissue into host [21,22], analyze follicular developmental potential [23], discuss oocyte quality and ovarian histology and function after cryopreservation [24,25], investigate the methods improving ovarian function and reducing apoptosis after transplantation [20,26,27]. In our study, the ovarian xenotransplantation used pharmacological angiogenic factor in a rabbit model to improve angiogenesis after transplantation.…”

Applicability of adult techniques for ovarian preservation to childhood cancer patients

“…In this controlled study, it is noteworthy that untreated xenografted animals showed a normal uterine development, whereas those xenografted and treated with gonadotropins, triptorelin, or both, showed underdevelopment [78]. Other substances such as the anti-apoptotic S1P and angiogenic factors, such as VEGF, are currently under scrutiny to establish if they could improve the immediate post-transplant follicular loss [87][88][89].…”