Coordinated interactions between endothelial cells and macrophages in the islet microenvironment promote beta cell regeneration

Saunders, D. C.; Aamodt, K. I.; Richardson, T. M.; Hopkirk, A.; Khan, Z.; Aramandla, R.; Poffenberger, G.; Jenkins, R.; Flaherty, D. K.; Prasad, N.; Levy, S.; Powers, A.; Brissova, M.

doi:10.1101/2020.08.28.265728

bioRxiv · 10.1101/2020.08.28.265728

Coordinated interactions between endothelial cells and macrophages in the islet microenvironment promote beta cell regeneration

Saunders, D. C.·Aamodt, K. I.·Richardson, T. M.·Hopkirk, A.·Khan, Z.·Aramandla, R.·Poffenberger, G.·Jenkins, R.·Flaherty, D. K.·Prasad, N.·Levy, S.·Powers, A.·Brissova, M.

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Abstract

Endogenous {beta} cell regeneration could alleviate diabetes, but proliferative stimuli within the islet microenvironment are incompletely understood. We previously found that {beta} cell recovery following hypervascularization-induced {beta} cell loss involves interactions with endothelial cells (ECs) and macrophages (M{Phi}s). Here we show that proliferative ECs modulate M{Phi} infiltration and phenotype during {beta} cell loss, and recruited M{Phi}s are essential for {beta} cell recovery. Furthermore, VEGFR2 inactivation in quiescent ECs accelerates islet vascular regression during {beta} cell recovery and leads to increased {beta} cell proliferation without changes in M{Phi} phenotype or number. Transcriptome analysis of {beta} cells, ECs, and M{Phi}s reveals that {beta} cell proliferation coincides with elevated expression of extracellular matrix remodeling molecules and growth factors likely driving activation of proliferative signaling pathways in {beta} cells. Collectively, these findings suggest a new {beta} cell regeneration paradigm whereby coordinated interactions between intra-islet M{Phi}s, ECs, and extracellular matrix mediate {beta} cell self-renewal.

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Saunders, D. C., Aamodt, K. I., Richardson, T. M., Hopkirk, A., Khan, Z., Aramandla, R., Poffenberger, G., Jenkins, R., Flaherty, D. K., Prasad, N., Levy, S., Powers, A., Brissova, M.. 2020-08-30. Coordinated interactions between endothelial cells and macrophages in the islet microenvironment promote beta cell regeneration. https://doi.org/10.1101/2020.08.28.265728

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