Enhancement of neoangiogenesis and follicle survival by sphingosine-1-phosphate in human ovarian tissue xenotransplants

Reza Soleimani, Elke Heytens, Kutluk Oktay, Reza Soleimani, Elke Heytens, Kutluk Oktay

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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. The effect of S1P, SEW2871…
Figure 1. The effect of S1P, SEW2871 and FTY720 on ovarian transplant revascularization and stromal cell population.
S1P induces ovarian angiogenesis (Left axis) and increases stromal cell population (Right axis) while its analogs, SEW2871 and FTY720 have the opposite effect, 10 days after grafting of ovarian transplantation. * Significantly different from control. # Significantly different from baseline ovarian tissue.
Figure 2. Impact of S1P and its…
Figure 2. Impact of S1P and its analogues on neo-angiogenesis, stromal cell proliferation and tissue hypoxia.
(A–F) Evaluation of angogenic effect of S1P and its analogs in ovarian transplants by anti-CD31 IHC. S1P induces angiogenesis of ovarian transplants (D) while FTY720 (E) or SEW2871 (F) treatment reduces it. Arrows show newly formed blood vessels positively stained for anti-CD31. (G–L) Evaluation of cell proliferation by anti-PCNA expression. S1P induces (J) where as FTY720 (K) reduces stromal cell proliferation. SEW2871 (L) treatment does not affect stromal cell proliferation compared to vehicle-treated control grafts. Arrows show proliferating stromal cell positively stained for PCNA. (M–R) Evaluation of ovarian tissue hypoxia by HIF1α.While S1P (P) treatment reduces tissue hypoxia compared to vehicle-treatment. FTY720 (Q) and SEW2871 (R) treatment is associated with massive tissue hypoxia 10 days post-grafting. (Q) Arrow shows hypoxic ovarian follicles in a FTY720-treated graft. (S) There is an inverse correlation between vascular density and hypoxic ovarian tissue surface area in the grafts, as determined by HIF1α staining. This indicates that enhanced vascular density reduces hypoxia in ovarian transplants.
Figure 3. Impact of S1P on early…
Figure 3. Impact of S1P on early angiogenesis after ovarian transplantation.
S1P-treated ovarian transplants show significantly higher density of microvasculature by as early as two days after transplantation. * Significantly different from matching vehicle-treated control. # Significantly different from baseline.
Figure 4. Impact of S1P on follicle…
Figure 4. Impact of S1P on follicle survival in frozen-thawed ovarian transplants.
Frozen-thawed ovarian tissue was transplanted to SCID mice and percentage of apoptotic follicles were compared between S1P-treated and vehicle-treated control grafts. (A–D) Histomorphological evaluation of apoptosis induced by cryopreservation and/or transplantation. The percentage of apoptotic follicles was significantly lower in fresh baseline ovarian tissue (A) compared to cryopreserved-untransplanted ovarian tissue (B) indicating that cryopreservation process itself induces apoptotic ovarian follicle death. S1P treatment results in significantly decrease in the density of apoptotic follicles (D) compared to the vehicle-treated group (C). Arrows indicate apoptotic ovarian follicles. (E) Inverse correlation of apoptotic follicle death with vascular density indicating that improved vascularization by S1P enhances follicle survival.

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