Research Papers:

TGF-β/Smad3 signalling regulates the transition of bone marrowderived macrophages into myofibroblasts during tissue fibrosis

Shuang Wang, Xiao-Ming Meng, Yee-Yung Ng, Frank Y. Ma, Shuang Zhou, Yang Zhang, Chen Yang, Xiao-Ru Huang, Jun Xiao, Ying-Ying Wang, Shuk-Man Ka, Yong-Jiang Tang, Arthur C.K. Chung, Ka-Fai To, David J. Nikolic-Paterson and Hui-Yao Lan _

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Oncotarget. 2016; 7:8809-8822. https://doi.org/10.18632/oncotarget.6604

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Shuang Wang1,*, Xiao-Ming Meng1,*, Yee-Yung Ng2,*, Frank Y. Ma3, Shuang Zhou1, Yang Zhang1, Chen Yang1, Xiao-Ru Huang1, Jun Xiao1, Ying-Ying Wang1, Shuk-Man Ka1, Yong-Jiang Tang1, Arthur C.K. Chung1, Ka-Fai To1, David J. Nikolic-Paterson3, Hui-Yao Lan1

1Li Ka Shing Institute of Health Sciences, Departments of Medicine and Therapeutics, Chemical Pathology, and Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China

2Division of Nephrology, Department of Medicine, Institute of Clinical Medicine, Taipei Veterans General Hospital, National Yang Ming University, Taipei, Taiwan

3Department of Nephrology and Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia

*These authors contributed equally to this work

Correspondence to:

Hui-Yao Lan, e-mail: [email protected]

Keywords: TGF-beta, Smad3, macrophage-myofibroblast transition (MMT), lineage tracing, renal fibrosis

Received: July 08, 2015     Accepted: November 25, 2015     Published: December 14, 2015


Myofibroblasts are a main cell-type of collagen-producing cells during tissue fibrosis, but their origins remains controversial. While bone marrow-derived myofibroblasts in renal fibrosis has been reported, the cell origin and mechanisms regulating their transition into myofibroblasts remain undefined. In the present study, cell lineage tracing studies by adoptive transfer of GFP+ or dye-labelled macrophages identified that monocyte/macrophages from bone marrow can give rise to myofibroblasts via the process of macrophage-myofibroblast transition (MMT) in a mouse model of unilateral ureteric obstruction. The MMT cells were a major source of collagen-producing fibroblasts in the fibrosing kidney, accounting for more than 60% of α-SMA+ myofibroblasts. The MMT process occurred predominantly within M2-type macrophages and was regulated by TGF-β/Smad3 signalling as deletion of Smad3 in the bone marrow compartment of GFP+ chimeric mice prevented the M2 macrophage transition into the MMT cells and progressive renal fibrosis. In vitro studies in Smad3 null bone marrow macrophages also showed that Smad3 was required for TGF-β1-induced MMT and collagen production. In conclusion, we have demonstrated that bone marrow-derived fibroblasts originate from the monocyte/macrophage population via a process of MMT. This process contributes to progressive renal tissue fibrosis and is regulated by TGF-β/Smad3 signalling.

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