Inflammatory macrophages can transdifferentiate into myofibroblasts during renal fibrosis

Xiao-Ming Meng, Shuang Wang, Xiao Ru Huang, Chen Yang, Jun Xiao, Yang Zhang, Ka Fai To, David J. Nikolic-Paterson, Hui Yao Lan

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Abstract

Myofibroblasts play a central role in renal fibrosis although the origin of these cells remains controversial. We recently reported that bone marrow-derived macrophages can give rise to myofibroblasts through macrophage to myofibroblast transition (MMT). However, several important issues remain to be addressed, including whether MMT occurs in human kidney disease and verification of the MMT process through lineage tracing. Biopsies from a cohort of 58 patients with various forms of kidney disease were examined for MMT cells that co-express macrophage (CD68) and myofibroblast (smooth muscle actin, -SMA) markers. MMT cells were evident in active fibrotic lesions, but were largely absent in acute inflammatory or sclerotic lesions, suggesting that MMT cells contribute to progressive renal fibrosis. Fate-mapping studies in LysM Cre Tomato mice identified substantial numbers of Tomato + myeloid cells with F4/80 + macrophage phenotype expressing -SMA and collagen I in the unilateral ureteral obstructive model of renal fibrosis, providing direct evidence for the MMT process during the development of renal fibrosis. In addition, MMT cells had a predominant M2 phenotype in both human and mouse renal fibrosis. Finally, selective depletion of myeloid cells via diphtheria toxin in LysM Cre iDTR mice largely abolished macrophage infiltration and MMT cells in the obstructed kidney and substantially reduced accumulation of -SMA + myofibroblasts and collagen deposition, revealing a pathogenic role for inflammatory macrophages in MMT and tissue fibrosis. In conclusion, these findings provide substantial new data to support the postulate that macrophages can directly transdifferentiate into collagen-producing myofibroblasts in human and experimental kidney disease.

Original languageEnglish
Article numbere2495
Number of pages9
JournalCell Death and Disease
Volume7
Issue number12
DOIs
Publication statusPublished - 1 Dec 2016

Cite this

Meng, X-M., Wang, S., Huang, X. R., Yang, C., Xiao, J., Zhang, Y., To, K. F., Nikolic-Paterson, D. J., & Lan, H. Y. (2016). Inflammatory macrophages can transdifferentiate into myofibroblasts during renal fibrosis. Cell Death and Disease, 7(12), [e2495]. https://doi.org/10.1038/cddis.2016.402