Concise Review: New Insights Into the Role of Macrophages in β-Cell Proliferation

Abstract

Diabetes mellitus can potentially be treated with islet transplantation, but additional sources of β cells are necessary to overcome the short supply of donor pancreases. Although controversy still exists, it is generally believed that the postnatal expansion of the β-cell mass is mainly through pre-existing β-cell replication. Thus, understanding the molecular mechanisms underlying the regulation of β-cell proliferation might lead to clinical strategies for increasing β-cell numbers, both in vitro and in vivo. Macrophages have a well-recognized role in the development of insulitis as part of the pathogenesis of type 1 diabetes. However, a potential role for macrophage polarization, triggered by specific environmental stimuli, in promoting β-cell proliferation has only recently been appreciated. In the present review, we discuss several independent studies, using different regeneration models, that demonstrate a substantial inductive role for macrophages in β-cell proliferation. Additional dissection of the involved cell-cell crosstalk through specific signal transduction pathways is expected to improve our understanding of β-cell proliferation and might facilitate the current β-cell replacement therapy.

Significance: New independent findings from different β-cell regeneration models, contributed by different research groups, have provided compelling evidence to highlight a previously unappreciated role for macrophages in β-cell proliferation. Additional dissection of the underlying mechanisms and cell-cell crosstalk might shed new light on strategies to increase the functional β-cell mass in vivo and on β-cell replacement therapies.

Keywords: Diabetes; Macrophage polarization; Macrophages; β-Cell proliferation; β-Cell regeneration.

Figure 1.

Signaling pathways through which macrophages regulate β-cell replication. M2 macrophages, not only release TGF-β1 to directly induce upregulation of SMAD7 in β cells, but also release EGF to activate EGFR signaling that inhibits TGF-β1-activated SMAD2 nuclear translocation, resulting in inhibition of TGF-β receptor signaling. SMAD7 promotes β-cell proliferation by increasing CyclinD1 and CyclinD2 and by inducing nuclear exclusion of p27. M2 macrophages also secrete Wnt ligands to activate the Wnt signaling pathway, which induces nuclear translocation and retention of β-catenin to promote β-cell replication. Abbreviations: EGF, epidermal growth factor; EGFR, EGF receptor; TGF-β1, transforming growth factor-β1.

Figure 2.

M2 macrophages play an essential role in creating a proliferation niche for β-cell proliferation. β-Cell proliferation could involve the coordination of multiple processes, such as detachment of cell-cell contacts, modulation of extracellular matrix, and release of growth factors, both locally and systemically. Macrophages, with their high plasticity and phenotypic diversity, appear to be play a critical role in β-cell proliferation by creating crosstalk among different cell types, including β cells, non-β endocrine cells, endothelial cells, mesenchymal cells, and other circulation-derived blood cells.