*Purpose: The current clinical practice of islet transplantation into the portal vein is suboptimal, with reduced vascularization limiting successful engraftment and the inability for monitoring and retrieval of grafts. The subcutaneous site, however, has posed a challenge for transplantation as it is an inhospitable environment for islets to acquire rapid, nurturing blood supply. Endothelial cells (ECs) can provide an instructive tissue-specific vascular niche that fosters islet homeostasis and survival. Adult ECs, however, lack the plasticity and ability to interact with islets; thus, we have engineered adaptable endothelium.

*Methods: By transient transduction of ETS variant transcription factor 2 we have reprogrammed adult human ECs to an adaptable tubulogenic state (R-VECs). These R-VECs form perfusable vascular plexi and avidly arborize islets within microfluidic devices.

*Results: In microfluidic devices, human islets arborized by R-VECs respond to glucose stimulation delivered through the inlet chamber and secrete insulin detected in the outlet chamber. Due to the rich, expedited vascularization from R-VECs, subcutaneously transplanted human islets achieve euglycemia for >12 weeks in streptozotocin-induced diabetic SCID-Beige mice, while transplantation with islets alone or islets with generic ECs do not. Furthermore, diabetic mice transplanted with R-VEC/islets demonstrate body weight stabilization and improved glucose tolerance. Grafts that were retrieved one month after transplantation showed vascularized engraftment only with R-VEC/islets and not with islets alone or islets with generic ECs. Single cell RNA-sequencing of R-VECs after co-culture with human islets reveals gene expression changes suggesting R-VECs adapt to islets and may acquire an islet-specific endothelial phenotype.

*Conclusions: Pre-vascularization of islets with R-VECs provides a specialized vascular niche that supports the engraftment and survival of transplanted islets in the subcutaneous space, avoiding complications associated with intraportal infusion.

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