β-Cells rely on the islet microenvironment for their functionality and mass. Pericytes, along with endothelial cells, make up the dense islet capillary network. However, although the role of endothelial cells in supporting β-cell homeostasis has been vastly investigated, the role of pericytes remains largely unknown. Here, we focus on contribution of pericytes to β-cell function. To this end, we used a transgenic mouse system that allows diphtheria toxin-based depletion of pericytes. Our results indicate that islets depleted of their pericytes have reduced insulin content and expression. Additionally, isolated islets displayed impaired glucose-stimulated insulin secretion, accompanied by a reduced expression of genes associated with β-cell function. Importantly, reduced levels of the transcription factors MafA and Pdx1 point to β-cell dedifferentiation in the absence of pericytes. Ex vivo depletion of pericytes in isolated islets resulted in a similar impairment of gene expression, implicating their direct, blood flow-independent role in maintaining β-cell maturity. To conclude, our findings suggest that pericytes are pivotal components of the islet niche, which are required for β-cell maturity and functionality. Abnormalities of islet pericytes, as implicated in type 2 diabetes, may therefore contribute to β-cell dysfunction and disease progression.

Polymorphism in , a component of the canonical Wnt signaling pathway, has a strong association with β-cell dysfunction and type 2 diabetes through a mechanism that has yet to be defined. β-Cells rely on cells in their microenvironment, including pericytes, for their proper function. Here, we show that Tcf7l2 activity in pancreatic pericytes is required for β-cell function. Transgenic mice in which Tcf7l2 was selectively inactivated in their pancreatic pericytes exhibited impaired glucose tolerance due to compromised β-cell function and glucose-stimulated insulin secretion. Inactivation of pericytic Tcf7l2 was associated with impaired expression of genes required for β-cell function and maturity in isolated islets. In addition, we identified Tcf7l2-dependent pericytic expression of secreted factors shown to promote β-cell function, including bone morphogenetic protein 4 (BMP4). Finally, we show that exogenous BMP4 is sufficient to rescue the impaired glucose-stimulated insulin secretion of transgenic mice, pointing to a potential mechanism through which pericytic Tcf7l2 activity affects β-cells. To conclude, we suggest that pancreatic pericytes produce secreted factors, including BMP4, in a Tcf7l2-dependent manner to support β-cell function. Our findings thus propose a potential cellular mechanism through which abnormal TCF7L2 activity predisposes individuals to diabetes and implicates abnormalities in the islet microenvironment in this disease.

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ObjectiveThe maintenance and expansion of β-cell mass rely on their proliferation, which reaches its peak in the neonatal stage. β-cell proliferation was found to rely on cells of the islet microenvironment. We hypothesized that pericytes, which are components of the islet vasculature, support neonatal β-cell proliferation.MethodsTo test our hypothesis, we combined in vivo and in vitro approaches. Briefly, we used a Diphtheria toxin-based transgenic mouse system to specifically deplete neonatal pancreatic pericytes in vivo. We further cultured neonatal pericytes isolated from the neonatal pancreas and combined the use of a β-cell line and primary cultured mouse β-cells.ResultsOur findings indicate that neonatal pancreatic pericytes are required and sufficient for β-cell proliferation. We observed impaired proliferation of neonatal β-cells upon in vivo depletion of pancreatic pericytes. Furthermore, exposure to pericyte-conditioned medium stimulated proliferation in cultured β-cells.ConclusionsThis study introduces pancreatic pericytes as regulators of neonatal β-cell proliferation. In addition to advancing current understanding of the physiological β-cell replication process, these findings could facilitate the development of protocols aimed at expending these cells as a potential cure for diabetes.