Research ArticleISLET TRANSPLANTATION

Targeting pancreatic islet PTP1B improves islet graft revascularization and transplant outcomes

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Science Translational Medicine  19 Jun 2019:
Vol. 11, Issue 497, eaar6294
DOI: 10.1126/scitranslmed.aar6294

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Revascularizing eye-lets

Pancreatic islet transplantation is a potentially promising therapy for type 1 diabetes, but poor revascularization hinders islet long-term viability. Figueiredo et al. studied the role of protein tyrosine phosphatase 1B (PTP1B) in regulating islet vascularization. Islets from PTP1B−/− mice retained more endothelial cells during in vitro culture and restored normoglycemia when transplanted into the anterior chamber of the eye in diabetic mice. Short hairpin RNA knockdown of PTP1B in human islets yielded similar effects. Deletion of PTP1B increased vascular endothelial growth factor A secretion by activating peroxisome proliferator–activated receptor γ coactivator 1α and estrogen-related receptor α signaling. Targeting PTP1B may improve islet transplantation.

Abstract

Deficient vascularization is a major driver of early islet graft loss and one of the primary reasons for the failure of islet transplantation as a viable treatment for type 1 diabetes. This study identifies the protein tyrosine phosphatase 1B (PTP1B) as a potential modulator of islet graft revascularization. We demonstrate that grafts of pancreatic islets lacking PTP1B exhibit increased revascularization, which is accompanied by improved graft survival and function, and recovery of normoglycemia and glucose tolerance in diabetic mice transplanted with PTP1B-deficient islets. Mechanistically, we show that the absence of PTP1B leads to activation of hypoxia-inducible factor 1α–independent peroxisome proliferator–activated receptor γ coactivator 1α/estrogen-related receptor α signaling and enhanced expression and production of vascular endothelial growth factor A (VEGF-A) by β cells. These observations were reproduced in human islets. Together, these findings reveal that PTP1B regulates islet VEGF-A production and suggest that this phosphatase could be targeted to improve islet transplantation outcomes.

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