title: Macrophage-to-Myofibroblast Transition Contributes to Interstitial Fibrosis in Chronic Renal Allograft Injury.
abstract: Interstitial fibrosis is an important contributor to graft loss in chronic renal allograft injury. Inflammatory macrophages are associated with fibrosis in renal allografts, but how these cells contribute to this damaging response is not clearly understood. Here, we investigated the role of macrophage-to-myofibroblast transition in interstitial fibrosis in human and experimental chronic renal allograft injury. In biopsy specimens from patients with active chronic allograft rejection, we identified cells undergoing macrophage-to-myofibroblast transition by the coexpression of macrophage (CD68) and myofibroblast (α-smooth muscle actin [α-SMA]) markers. CD68+/α-SMA+cells accounted for approximately 50% of the myofibroblast population, and the number of these cells correlated with allograft function and the severity of interstitial fibrosis. Similarly, in C57BL/6J mice with a BALB/c renal allograft, cells coexpressing macrophage markers (CD68 or F4/80) andα-SMA composed a significant population in the interstitium of allografts undergoing chronic rejection. Fate-mapping in Lyz2-Cre/Rosa26-Tomato mice showed that approximately half ofα-SMA+myofibroblasts in renal allografts originated from recipient bone marrow-derived macrophages. Knockout ofSmad3protected against interstitial fibrosis in renal allografts and substantially reduced the number of macrophage-to-myofibroblast transition cells. Furthermore, the majority of macrophage-to-myofibroblast transition cells in human and experimental renal allograft rejection coexpressed the M2-type macrophage marker CD206, and this expression was considerably reduced inSmad3-knockout recipients. In conclusion, our studies indicate that macrophage-to-myofibroblast transition contributes to interstitial fibrosis in chronic renal allograft injury. Moreover, the transition of bone marrow-derived M2-type macrophages to myofibroblasts in the renal allograft is regulatedviaa Smad3-dependent mechanism.
authors.affiliation: Kidney Disease Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.|Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, and The Chinese University of Hong Kong, Shenzhen Research Institute, and.
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Wang
authors.affiliation: Kidney Disease Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, and The Chinese University of Hong Kong, Shenzhen Research Institute, and.|Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Pan
authors.affiliation: Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, and The Chinese University of Hong Kong, Shenzhen Research Institute, and.
authors.forename: Xiao-Ru
authors.initials: XR
authors.lastname: Huang
authors.affiliation: Kidney Disease Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.|Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, and The Chinese University of Hong Kong, Shenzhen Research Institute, and.
authors.forename: Yu-Cheng
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Kidney Disease Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Hong-Feng
authors.initials: HF
authors.lastname: Huang
authors.affiliation: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China; and.
authors.forename: Ka-Fai
authors.initials: KF
authors.lastname: To
authors.affiliation: Department of Nephrology, Monash Medical Center and Monash University Department of Medicine, Clayton, Melbourne, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Nikolic-Paterson
authors.affiliation: Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, and The Chinese University of Hong Kong, Shenzhen Research Institute, and hylan@cuhk.edu.hk chenjianghua@zju.edu.cn.
authors.forename: Hui-Yao
authors.initials: HY
authors.lastname: Lan
authors.affiliation: Kidney Disease Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China, hylan@cuhk.edu.hk chenjianghua@zju.edu.cn.
authors.forename: Jiang-Hua
authors.initials: JH
authors.lastname: Chen
mesh_terms: D064591:Allografts; D000818:Animals; D054338:Cell Transdifferentiation; D002908:Chronic Disease; D005260:Female; D005355:Fibrosis / Q000209:etiology; D006801:Humans; D007668:Kidney / Q000473:pathology*; D007674:Kidney Diseases / Q000209:etiology*; D016030:Kidney Transplantation; D008264:Macrophages / Q000166:cytology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000166:cytology / Q000502:physiology*; D011183:Postoperative Complications / Q000209:etiology*
keywords: M2 macrophage; Smad3; chronic allograft rejection; interstitial fibrosis; lineage tracing; macrophage myofibroblast transition