One of the main reasons that attempts to treat type 1 diabetes mellitus with transplanted pancreatic islets have been unsuccessful is that islet grafts undergo deficient vascularization, which leads to graft loss. Now, Ramon Gomis, Rosa Gasa and colleagues show that the protein tyrosine phosphatase 1B (PTP1B) is a potential therapeutic target to improve islet graft vascularization.

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PTP1B is known to inhibit phosphorylation of vascular endothelial growth factor A (VEGFA) and vascular endothelial cadherin, which are important factors in angiogenesis. To investigate PTP1B importance in islet grafts, the researchers used a PTP1B-deficient mouse model (PTP1B–/–). Notably, islets isolated from PTP1B–/– mice showed a decreased rate of endothelial cell loss in vitro, as compared with islets from wild-type animals.

In vivo experiments showed that PTP1B–/– mouse islets could be successfully transplanted into a diabetic mouse model. Transplantation resulted in normalized plasma glucose and insulin levels. Of note, the eye was used as the site of islet engraftment, as it represents an immune privileged and highly vascular location and it is easily and non-invasively imaged in living animals.

Further analysis of transplanted PTP1B–/– islets showed that compared with islets derived from wild-type animals, the PTP1B–/– islets grafted into diabetic mice had improved revascularization and survival rates. Moreover, islets from PTP1B–/– mice that were cultured in vitro in nutrient-deprived conditions or were transplanted into diabetic mice had increased VEGFA production.

Importantly, in vitro interfering RNA experiments in islets obtained from human donors showed that silencing PTP1B can increase expression of VEGFA and improve islet graft revascularization.

silencing PTP1B can increase expression of VEGFA and improve islet graft revascularization

“From a translational point of view, it will be exciting to test non-genetic approaches to inhibit PTP1B in islets,” explains Gasa. “It will also be interesting to investigate whether stem cell-derived β-cells respond similarly to PTP1B inhibition, as improved vascularization together with the use of patient-derived inducible pluripotent stem cells as a cell source might greatly improve the chances of successful and long-term maintenance of the transplant.”