Macrophages are essential for CTGF-mediated adult β-cell proliferation after injury

Abstract

ObjectivePromotion of endogenous β-cell mass expansion could facilitate regeneration in patients with diabetes. We discovered that the secreted protein CTGF (aka CCN2) promotes adult β-cell replication and mass regeneration after injury via increasing β-cell immaturity and shortening the replicative refractory period. However, the mechanism of CTGF-mediated β-cell proliferation is unknown. Here we focused on whether CTGF alters cells of the immune system to enhance β-cell replication.MethodsUsing mouse models for 50% β-cell ablation and conditional, β-cell-specific CTGF induction, we assessed changes in immune cell populations by performing immunolabeling and gene expression analyses. We tested the requirement for macrophages in CTGF-mediated β-cell proliferation via clodronate-based macrophage depletion.ResultsCTGF induction after 50% β-cell ablation increased both macrophages and T-cells in islets. An upregulation in the expression of several macrophage and T-cell chemoattractant genes was also observed in islets. Gene expression analyses suggest an increase in M1 and a decrease in M2 macrophage markers. Depletion of macrophages (without changes in T cell number) blocked CTGF-mediated β-cell proliferation and prevented the increase in β-cell immaturity.ConclusionsOur data show that macrophages are critical for CTGF-mediated adult β-cell proliferation in the setting of partial β-cell ablation. This is the first study to link a specific β-cell proliferative factor with immune-mediated β-cell proliferation in a β-cell injury model.

When beta cells talk back

“…Islet macrophages continuously sample antigen from beta cells [17] and, through surveying the blood vessels and islet milieu for danger signals and invading pathogens, also act as an important first line of immunological defence. Mice lacking tissue resident macrophages have reduced beta cell mass [18] and, more recently, macrophages have been found to play an important role in beta cell proliferation and regeneration in models of acute beta cell loss [19][20][21]. Many proliferative factors are released by macrophages, among them transforming growth factor β (TGFβ1) and EGF, which were reported to mediate beta cell regeneration following pancreatic duct ligation [21].…”

“…Many proliferative factors are released by macrophages, among them transforming growth factor β (TGFβ1) and EGF, which were reported to mediate beta cell regeneration following pancreatic duct ligation [21]. Moreover, macrophages were shown to be crucial for beta cell proliferation following vascular endothelial growth factor-A mediated beta cell reduction [19], and for beta cell regeneration mediated by connective tissue growth factor following pancreatic ductal ligation [20].…”

Stem Cells and Regeneration in the Digestive System: Keystone Meeting

“…Maureen Gannon’s laboratory has reported that the secreted protein CTGF promotes adult beta cell replication and mass regeneration after injury. 12 In this session, Gannon provided new insights into beta-cell compensation mechanisms and specifically the role of CTGF together with inflammation signals in promoting expansion of functional pancreatic beta-cell mass. Tsutomu Chiba shared data on doublecortin-like kinase 1 as a marker for pancreatic intraepithelial neoplasia-initiating cells in acinar-to-ductal metaplasia.…”

Islet macrophages shift to a reparative state following pancreatic beta-cell death and are a major source of islet IGF-1

“…In the presence of aggregates of islet amyloid polypeptide (IAPP), the pro-inflammatory state of these macrophages is enhanced, leading to IL-1 secretion that causes beta-cell dysfunction . During extreme beta-cell injury or pancreatic damage in the absence of IAPP, however, islet macrophages can produce factors that support beta-cell replication and regeneration (Criscimanna et al, 2014, Riley et al, 2015, Xiao et al, 2014, Brissova et al, 2014.…”

“…Various macrophage-derived growth factors are implicated in beta-cell regeneration in models of extreme beta-cell injury or during development, including TGFβ, CTGF, and IGF-2 (Riley et al, 2015, Xiao et al, 2014, Mussar et al, 2017. Here we focused on the role of macrophages in rodent models of type 2 diabetes and in response to moderate beta-cell death more representative of human disease pathology.…”