Islet microenvironment, modulated by vascular endothelial growth factor-A signaling, promotes ß cell regeneration.

ABSTRACT

Pancreatic islet endocrine cell and endothelial cell (EC) interactions mediated by vascular endothelial growth factor-A (VEGF-A) signaling are important for islet differentiation and the formation of highly vascularized islets. To dissect how VEGF-A signaling modulates intra-islet vasculature, islet microenvironment, and ß cell mass, we transiently increased VEGF-A production by ß cells. VEGF-A induction dramatically increased the number of intra-islet ECs but led to ß cell loss. After withdrawal of the VEGF-A stimulus, ß cell mass, function, and islet structure normalized as a result of a robust, but transient, burst in proliferation of pre-existing ß cells. Bone marrow-derived macrophages (MΦs) recruited to the site of ß cell injury were crucial for the ß cell proliferation, which was independent of pancreatic location and circulating factors such as glucose. Identification of the signals responsible for the proliferation of adult, terminally differentiated ß cells will improve strategies aimed at ß cell regeneration and expansion.