title: TGF-β/Smad3 signalling regulates the transition of bone marrow-derived macrophages into myofibroblasts during tissue fibrosis.
abstract: 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.
authors.affiliation: Li 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.
authors.forename: Shuang
authors.initials: S
authors.lastname: Wang
authors.affiliation: Li 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.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Meng
authors.affiliation: Division of Nephrology, Department of Medicine, Institute of Clinical Medicine, Taipei Veterans General Hospital, National Yang Ming University, Taipei, Taiwan.
authors.forename: Yee-Yung
authors.initials: YY
authors.lastname: Ng
authors.affiliation: Department of Nephrology and Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
authors.forename: Frank Y
authors.initials: FY
authors.lastname: Ma
authors.affiliation: Li 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.
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Li 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.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Li 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.
authors.forename: Chen
authors.initials: C
authors.lastname: Yang
authors.affiliation: Li 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.
authors.forename: Xiao-Ru
authors.initials: XR
authors.lastname: Huang
authors.affiliation: Li 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.
authors.forename: Jun
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Li 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.
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Wang
authors.affiliation: Li 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.
authors.forename: Shuk-Man
authors.initials: SM
authors.lastname: Ka
authors.affiliation: Li 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.
authors.forename: Yong-Jiang
authors.initials: YJ
authors.lastname: Tang
authors.affiliation: Li 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.
authors.forename: Arthur C K
authors.initials: AC
authors.lastname: Chung
authors.affiliation: Li 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.
authors.forename: Ka-Fai
authors.initials: KF
authors.lastname: To
authors.affiliation: Department of Nephrology and Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Nikolic-Paterson
authors.affiliation: Li 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.
authors.forename: Hui-Yao
authors.initials: HY
authors.lastname: Lan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D005260:Female; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007124:Immunoenzyme Techniques; D007674:Kidney Diseases / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051900:Smad3 Protein / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D049452:Green Fluorescent Proteins
keywords: Smad3; TGF-beta; lineage tracing; macrophage-myofibroblast transition (MMT); renal fibrosis