Macrophage-to-Myofibroblast Transition Contributes to Interstitial Fibrosis in Chronic Renal Allograft Injury.
Ying-ying Wang,Ying-ying Wang,Hong Jiang,Jun Pan,Jun Pan,Xiao R. Huang,Yucheng Wang,Yucheng Wang,Hong Feng Huang,Ka Fai To,David J. Nikolic-Paterson,Hui-Yao Lan,Jianghua Chen +12 more
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TLDR
Macrophage-to-myofibroblast transition contributes to interstitial fibrosis in chronic renal allograft injury and the transition of bone marrow-derived M2-type macrophages to my ofibroblasts in the renalAllograft is regulated via a Smad3-dependent mechanism.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) and α-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 of α-SMA+ myofibroblasts in renal allografts originated from recipient bone marrow-derived macrophages. Knockout of Smad3 protected 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 in Smad3-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 regulated via a Smad3-dependent mechanism.read more
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Macrophages: versatile players in renal inflammation and fibrosis
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Decoding myofibroblast origins in human kidney fibrosis
Christoph Kuppe,Mahmoud M. Ibrahim,Mahmoud M. Ibrahim,Jennifer Kranz,Jennifer Kranz,Xiaoting Zhang,Susanne Ziegler,Javier Perales-Patón,Javier Perales-Patón,Jitske Jansen,Jitske Jansen,Jitske Jansen,Katharina C Reimer,James R Smith,Ross Dobie,John R. Wilson-Kanamori,Maurice Halder,Yaoxian Xu,Nazanin Kabgani,Nadine Kaesler,Martin Klaus,Lukas Gernhold,Victor G. Puelles,Victor G. Puelles,Tobias B. Huber,Peter Boor,Sylvia Menzel,Remco Hoogenboezem,Eric Bindels,Joachim Steffens,Jürgen Floege,Rebekka K. Schneider,Rebekka K. Schneider,Julio Saez-Rodriguez,Julio Saez-Rodriguez,Julio Saez-Rodriguez,Neil C. Henderson,Rafael Kramann,Rafael Kramann +38 more
TL;DR: Using single-cell RNA sequencing, the transcriptomes of cells from the proximal and non-proximal tubules of healthy and fibrotic human kidneys are profiled to map the entire human kidney and identify distinct subpopulations of pericytes and fibroblasts as the main cellular sources of scar-forming myofibro Blasts during human kidney fibrosis.
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Central role of dysregulation of TGF-β/Smad in CKD progression and potential targets of its treatment
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TL;DR: TGF-β/Smad signaling is an important pathway that mediates renal fibrosis and inflammation and an effective target of anti-fibrotic therapies for treatment of CKD.
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Macrophage and Fibroblast Interactions in Biomaterial-Mediated Fibrosis.
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Natural Products as a Source for Antifibrosis Therapy
TL;DR: Natural products can target these mediators and inhibit chronic inflammation, myofibroblast activation, epithelial-mesenchymal transition, and extracellular matrix accumulation to alleviate fibrosis and provide new strategies to find antifibrotic drugs.
References
More filters
Journal ArticleDOI
The Banff 97 working classification of renal allograft pathology
Lorraine C. Racusen,Kim Solez,Robert B. Colvin,Stephen M. Bonsib,Maria Castro,Tito Cavallo,Byron P. Croker,A. Jake Demetris,Cynthia B. Drachenberg,Agnes B. Fogo,Peter N. Furness,Lillian W. Gaber,Ian W. Gibson,Dennis Glotz,J. Goldberg,Joseph P. Grande,Philip F. Halloran,H.E. Hansen,Barry Hartley,Pekka Hayry,Claire M. Hill,Ernesto O. Hoffman,Lawrence G. Hunsicker,Anne S. Lindblad,Niels Marcussen,M. J. Mihatsch,Tibor Nadasdy,Peter Nickerson,T. Steen Olsen,John C. Papadimitriou,Parmjeet Randhawa,David C. Rayner,Ian S.D. Roberts,Stephen Rose,D. Rush,Luis Salinas-Madrigal,Daniel R. Salomon,Stale Sund,Eero Taskinen,Kiril Trpkov,Yutaka Yamaguchi +40 more
TL;DR: Major changes include the following: rejection with vasculitis is separated from tubulointerstitial rejection; severe rejection requires transmural changes in arteries; "borderline" rejection can only be interpreted in a clinical context; antibody-mediated rejection is further defined, and lesion scoring focuses on most severely involved structures.
Journal ArticleDOI
Conditional gene targeting in macrophages and granulocytes using LysMcre mice.
TL;DR: The generation of mice that express Cre in myeloid cells due to targeted insertion of the cre cDNA into their endogenous M lysozyme locus is reported, allowing for both specific and highly efficient Cre–mediated deletion of loxP–flanked target genes in myELoid cells.
Journal ArticleDOI
Fate Tracing Reveals the Pericyte and Not Epithelial Origin of Myofibroblasts in Kidney Fibrosis
Benjamin D. Humphreys,Benjamin D. Humphreys,Shuei-Liong Lin,Shuei-Liong Lin,Akio Kobayashi,Thomas E. Hudson,Brian T. Nowlin,Joseph V. Bonventre,Joseph V. Bonventre,M. Todd Valerius,Andrew P. McMahon,Jeremy S. Duffield,Jeremy S. Duffield +12 more
TL;DR: Data indicate that therapeutic strategies directly targeting pericyte differentiation in vivo may productively impact fibrotic kidney disease.
Journal ArticleDOI
Origin and function of myofibroblasts in kidney fibrosis.
Valerie S. LeBleu,Gangadhar Taduri,Joyce T. O’Connell,Yingqi Teng,Vesselina G. Cooke,Craig B. Woda,Hikaru Sugimoto,Hikaru Sugimoto,Raghu Kalluri +8 more
TL;DR: The data suggest that targeting diverse pathways is required to substantially inhibit the composite accumulation of myofibroblasts in kidney fibrosis, and specific deletion of Tgfbr2 in α-smooth muscle actin (αSMA)+ cells revealed the importance of this pathway in the recruitment of my ofibro Blasts through differentiation.
Journal ArticleDOI
Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-β
Xiao Yang,John J. Letterio,Robert J. Lechleider,Lin Chen,Russ Hayman,Hua Gu,Anita B. Roberts,Chu-Xia Deng +7 more
TL;DR: The data suggest that SMAD3 has an important role in TGF‐β‐mediated regulation of T cell activation and mucosal immunity, and that the loss of these functions is responsible for chronic infection and the lethality of Smad3‐null mice.