M2 macrophages promote beta-cell proliferation by up-regulation of SMAD7

Abstract

Determination of signaling pathways that regulate beta-cell replication is critical for beta-cell therapy. Here, we show that blocking pancreatic macrophage infiltration after pancreatic duct ligation (PDL) completely inhibits beta-cell proliferation. The TGFβ superfamily signaling inhibitor SMAD7 was significantly up-regulated in beta cells after PDL. Beta cells failed to proliferate in response to PDL in beta-cell-specific SMAD7 mutant mice. Forced expression of SMAD7 in beta cells by itself was sufficient to promote beta-cell proliferation in vivo. M2, rather than M1 macrophages, seem to be the inducers of SMAD7-mediated beta-cell proliferation. M2 macrophages not only release TGFβ1 to directly induce up-regulation of SMAD7 in beta cells but also release EGF to activate EGF receptor signaling that inhibits TGFβ1-activated SMAD2 nuclear translocation, resulting in TGFβ signaling inhibition. SMAD7 promotes beta-cell proliferation by increasing CyclinD1 and CyclinD2, and by inducing nuclear exclusion of p27. Our study thus reveals a molecular pathway to potentially increase beta-cell mass through enhanced SMAD7 activity induced by extracellular stimuli.TGFβ superfamily signaling pathway | epidermal growth factor receptor signaling pathway

End Sequence Analysis Toolkit (ESAT) expands the extractable information from single-cell RNA-seq data

“…6A, B; Shih et al 2002). Cluster C7 is enriched in genes with immune function and likely represents innate cells such as macrophages or dendritic cells (Supplemental Table S3), which have been previously reported to reside in islets and are critical for proper development (Xiao et al 2014;Morris 2015). Our data also revealed an interplay between hormone-producing cells and vascular cells (cluster C9).…”

Islet inflammation in type 2 diabetes and physiology

“…In a study analyzing the streptozotocin model of diabetes, stromal cell-derived factor 1 recruited M2-like macrophages via CXCR4, after which these macrophages activated Wnt signaling in β cells, making M2-like macrophages indispensable for β cell replication (44). In the partial pancreatic ductal ligation (PDL) model, a well-established model of damage-induced islet proliferation, clodronate liposome-mediated macrophage ablation revealed the indispensability of F4/80 + macrophages recruited to islets for β cell proliferation (42). The majority of the recruited macrophages were CD206 + F4/80 + macrophages that exhibited increased Arg1 expression and decreased Nos2 expression, which is indicative of the alternatively activated M2-like phenotype.…”

“…During islet inflammation, overall macrophage polarity shifts toward the proinflammatory classically activated M1-like phenotype, and this shift has been shown to contribute to β cell dysfunction in T2D mouse models (21)(22)(23). Additionally, alternatively activated M2-like macrophages, which include macrophages with antiinflammatory (36), pro-fibrosis (37), and pro-angiogenic (38) phenotypes, were recently found to be the key mediators of β cell proliferation during both development (39,40) and adulthood (41)(42)(43)(44) in mice.…”

Cytokine Regulation of Regenerative Processes in Pancreatic Gland in Alloxan-Induced Diabetic Rats, and It Correction by 1,3,4-Thiadiazine Composition and Lipoic Acid

“…Известно, что IGF-1 является по-средником действия соматотропного гормона и обеспечивает регуляцию анаболических эф-фектов этого гормона и может также, соединя-ясь с рецепторами инсулина, оказывать влияние на утилизацию глюкозы [5,13]. На эксперимен-тальных моделях СД 1 типа было установлено, что IGF-1 предотвращает апоптоз инсулиноци-тов и способствует их пролиферации [43,44].…”