Editors' ChoiceInflammation

Promoting Pancreatic Cell Proliferation

Sci. Signal.  08 Apr 2014:
Vol. 7, Issue 320, pp. ec94
DOI: 10.1126/scisignal.2005340

The loss of insulin production due to the autoimmune destruction of pancreatic β cells causes type 1 diabetes mellitus. Some preclinical therapeutic strategies have focused on β cell replacement through differentiation of progenitor cells; however, in rodents, adult β cells derive primarily from dividing, self-renewing mature cells. Partial ligation of the pancreatic duct (PDL) in mice is an injury model that stimulates proliferation without directly ablating β cells. Xiao et al. found that in response to PDL, M2-type (proproliferative) macrophages signal to mature β cells to promote expansion. Treating mice with clodronate, a drug that kills macrophages, reduced pancreatic infiltration of macrophages and proliferation of β cells induced by PDL. Isolated β cells of control but not clodronate-treated mice subjected to PDL had greater expression of Smad7, which is both a transcriptional target of transforming growth factor β (TGFβ) signaling and encodes an inhibitor of this pathway, as well as greater expression of CyclinD1 and CyclinD2, which encode cell cycle activating proteins. In mice subjected to PDL, β cell–specific deficiency of Smad7 did not affect macrophage infiltration but reduced β cell proliferation and expression of CyclinD1 and CyclinD2, whereas β cell–specific overexpression of Smad7 enhanced proliferation of β cells and expression of CyclinD1 and CyclinD2. M2 macrophages isolated from the pancreas of mice subjected to PDL showed greater expression of TGFβ1, which encodes a ligand for TGFβ receptors, and chemical inhibition of type I TGFβ receptors inhibited proliferation of β cells cocultured with M2 macrophages. The nuclear abundance of the cyclin-dependent kinase inhibitor 1β (also known as p27) was decreased in β cells from mice subjected to PDL, those overexpressing Smad7, or those cocultured with M2 macrophages. Thus, during pancreatic injury, macrophages release TGFβ1 to stimulate Smad7 expression in β cells, which in turn inhibits an inhibitor of cell cycle progression and promotes β cell expansion.

X. Xiao, I. Gaffar, P. Guo, J. Wiersch, S. Fischbach, L. Peirish, Z. Song, Y. El-Gohary, K. Prasadan, C. Shiota, G. K. Gittes, M2 macrophages promote beta-cell proliferation by up-regulation of SMAD7. Proc. Natl. Acad. Sci. U.S.A. 111, E1211–E1220 (2014). [Abstract] [Full Text]