Garcia-Alaman, A.; Fontcuberta-PiSunyer, M.; Saarimaki-Vire, J. M.; Asumaa, N.; Perea-Atienzar, M.; Fernandez-Ruiz, R.; Alves-Figueiredo, H.; Broca, C.; Servitja, J.-M.; Gomis, R.; Balboa, D.; Vidal, J.; Gasa, R.

Insufficient vascularization remains a major obstacle to the success of cell-based therapies for diabetes. Building on prior findings that loss of the phosphatase PTP1B enhances VEGFA production and improves graft vascularization, we investigated sodium tungstate (NaW), a pharmacological phosphatase inhibitor, as a strategy to improve transplantation outcomes. Using human fibroblast-derived insulin-producing cells and human stem cell-derived islets transplanted into the anterior chamber of the eye in immunodeficient mice, we show that NaW treatment significantly increases both vascularized area and insulin-positive tissue area, while reducing apoptosis within transplanted cells. Mechanistically, NaW upregulates VEGFA expression in transplanted cells and amplifies VEGFA-induced endothelial cell proliferation, migration, and tubulogenesis via MAPK/ERK signalling. These dual effects, which encompass stimulating both endocrine and endothelial compartments, lead to enhanced integration and function of transplanted cells. Importantly, the pro-angiogenic effects of NaW occur independently of exogenous endothelial cell supplementation, relying solely on the host endogenous endothelial cells. These findings position NaW, and potentially other phosphatase inhibitors, as promising adjuncts to improve vascularization, survival, and therapeutic efficacy in clinical cell-based transplantation protocols for diabetes.