Pericytes Are Not Merely Accessory Cells in Pancreatic Islets

We would like to thank Drs. Zhang, Wu, and Yao for their comment (1) regarding our recent publication in Diabetes (2) where we examined changes in mural cell coverage and microvascular homeostasis in islets after treating mice with subdiabetogenic doses of streptozotocin. Data from this study and previous work from our laboratory using living pancreas slices from single autoantibody-positive organ donors (from the Network for Pancreatic Organ Donors with Diabetes) show that the islet microvasculature becomes dysfunctional in multiple ways in prediabetic stages in mice and in humans (3). These studies suggest that islet microvascular defects may have pathogenic roles and contribute to endocrine cell dysfunction during the development of diabetes, highlighting the vascular niche as a promising site for therapeutic discovery.

As the authors state in their letter, we framed our most recent study primarily around the context of type 1 diabetes pathogenesis, but we agree that conclusions may be relevant for other fields such as islet transplantation and replacement therapies. Current initiatives for producing islets from stem cells, for instance, are now recognizing that including vascular and stromal cells can significantly improve outcomes. During the 5th International Pancreas & Islet Transplant Association (IPITA) Summit on Stem Cell-Derived Islets meeting in 2024, for instance, we discussed the importance of a functional islet vasculature for the success of stem cell–derived islet transplantation and durable islet graft function (unpublished data).

We also think that the benefits of having islets with “mature microvessels with functional pericyte coverage” are enormous and crucial for proper and long-lasting islet performance. As an endocrine organ, this vascular control provides another layer of regulation of islet function that may go beyond ensuring that active islet regions receive adequate nutritional support and gas exchange: islets may rely on this vascular response for glucose sensing and timely hormone secretion into the circulation. This control is provided by pericytes, excitable mural cells that cover islet capillaries; a subset of them is contractile, and their activity is coupled to changes in capillary diameter and blood flow. Importantly, pericytes are the predominant cellular targets of autonomic nerves in the human islet (4), raising the possibility that autonomic control of islet function occurs partly by altering blood flow (5). Islet pericytes play additional pivotal roles in the regulation of islet function by providing trophic support for β-cells (6) and by modulating the islet immune environment (7).

For these reasons, studies examining when a functional pericyte coverage of islet capillaries is established during development and how it is maintained throughout life are warranted. We are also investigating whether endocrine-vascular coupling mechanisms exist in islets and enable adjusting blood flow to metabolic needs, and whether pericytes control endothelial barrier properties in islets as they do in other tissues. In summary, we thank the authors for appreciating our work and for supporting the idea that “microvascular maturity, rather than vessel density alone” matters and should be preserved.

Funding Statement

This work has been funded by National Institutes of Health grants R01 DK133483 and R01 DK138471 (to J.A.) and by Breakthrough T1D (formerly JDRF) postdoctoral fellowship 3-PDF-2024-1503-A-N (to L.M.G.).