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      Transforming growth factor–β in tissue fibrosis

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      Publication date (Electronic):
      Journal: The Journal of Experimental Medicine
      Publisher: Rockefeller University Press

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          Abstract

          TGF-β is a central mediator in the fibrotic response. This review discusses the role of TGF-β in tissue fibrosis, highlighting the mechanisms of TGF-β activation and signaling, the cellular targets of TGF-β actions, and the challenges of therapeutic translation.

          Abstract

          TGF-β is extensively implicated in the pathogenesis of fibrosis. In fibrotic lesions, spatially restricted generation of bioactive TGF-β from latent stores requires the cooperation of proteases, integrins, and specialized extracellular matrix molecules. Although fibroblasts are major targets of TGF-β, some fibrogenic actions may reflect activation of other cell types, including macrophages, epithelial cells, and vascular cells. TGF-β–driven fibrosis is mediated through Smad-dependent or non-Smad pathways and is modulated by coreceptors and by interacting networks. This review discusses the role of TGF-β in fibrosis, highlighting mechanisms of TGF-β activation and signaling, the cellular targets of TGF-β actions, and the challenges of therapeutic translation.

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          Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition.

          Jason R. Rock, Christina E Barkauskas, Michael J Cronce … (2011)
          There are currently few treatment options for pulmonary fibrosis. Innovations may come from a better understanding of the cellular origin of the characteristic fibrotic lesions. We have analyzed normal and fibrotic mouse and human lungs by confocal microscopy to define stromal cell populations with respect to several commonly used markers. In both species, we observed unexpected heterogeneity of stromal cells. These include numerous cells with molecular and morphological characteristics of pericytes, implicated as a source of myofibroblasts in other fibrotic tissues. We used mouse genetic tools to follow the fates of specific cell types in the bleomcyin-induced model of pulmonary fibrosis. Using inducible transgenic alleles to lineage trace pericyte-like cells in the alveolar interstitium, we show that this population proliferates in fibrotic regions. However, neither these cells nor their descendants express high levels of the myofibroblast marker alpha smooth muscle actin (Acta2, aSMA). We then used a Surfactant protein C-CreER(T2) knock-in allele to follow the fate of Type II alveolar cells (AEC2) in vivo. We find no evidence at the cellular or molecular level for epithelial to mesenchymal transition of labeled cells into myofibroblasts. Rather, bleomycin accelerates the previously reported conversion of AEC2 into AEC1 cells. Similarly, epithelial cells labeled with our Scgb1a1-CreER allele do not give rise to fibroblasts but generate both AEC2 and AEC1 cells in response to bleomycin-induced lung injury. Taken together, our results show a previously unappreciated heterogeneity of cell types proliferating in fibrotic lesions and exclude pericytes and two epithelial cell populations as the origin of myofibroblasts.
          Article 0 comments Cited 348 times – based on 0 reviews     Review now
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            Fibroblast-specific TGF-β-Smad2/3 signaling underlies cardiac fibrosis.

            Vikram Prasad, Robert N. Correll, Onur Kanisicak … (2017)
            The master cytokine TGF-β mediates tissue fibrosis associated with inflammation and tissue injury. TGF-β induces fibroblast activation and differentiation into myofibroblasts that secrete extracellular matrix proteins. Canonical TGF-β signaling mobilizes Smad2 and Smad3 transcription factors that control fibrosis by promoting gene expression. However, the importance of TGF-β-Smad2/3 signaling in fibroblast-mediated cardiac fibrosis has not been directly evaluated in vivo. Here, we examined pressure overload-induced cardiac fibrosis in fibroblast- and myofibroblast-specific inducible Cre-expressing mouse lines with selective deletion of the TGF-β receptors Tgfbr1/2, Smad2, or Smad3. Fibroblast-specific deletion of Tgfbr1/2 or Smad3, but not Smad2, markedly reduced the pressure overload-induced fibrotic response as well as fibrosis mediated by a heart-specific, latency-resistant TGF-β mutant transgene. Interestingly, cardiac fibroblast-specific deletion of Tgfbr1/2, but not Smad2/3, attenuated the cardiac hypertrophic response to pressure overload stimulation. Mechanistically, loss of Smad2/3 from tissue-resident fibroblasts attenuated injury-induced cellular expansion within the heart and the expression of fibrosis-mediating genes. Deletion of Smad2/3 or Tgfbr1/2 from cardiac fibroblasts similarly inhibited the gene program for fibrosis and extracellular matrix remodeling, although deletion of Tgfbr1/2 uniquely altered expression of an array of regulatory genes involved in cardiomyocyte homeostasis and disease compensation. These findings implicate TGF-β-Smad2/3 signaling in activated tissue-resident cardiac fibroblasts as principal mediators of the fibrotic response.
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              How cells read TGF-beta signals.

              J Massagué (2000)
              Cell proliferation, differentiation and death are controlled by a multitude of cell-cell signals, and loss of this control has devastating consequences. Prominent among these regulatory signals is the transforming growth factor-beta (TGF-beta) family of cytokines, which can trigger a bewildering diversity of responses, depending on the genetic makeup and environment of the target cell. What are the networks of cell-specific molecules that mould the TGF-beta response to each cell's needs?
              Article 0 comments Cited 347 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Nikolaos G. Frangogiannis:
                ORCID: https://orcid.org/0000-0002-8186-5131
                Role: Writing – original draftRole: Writing – review & editing
                Journal
                Journal ID (nlm-ta): J Exp Med
                Journal ID (iso-abbrev): J. Exp. Med
                Journal ID (publisher-id): jem
                Title: The Journal of Experimental Medicine
                Publisher: Rockefeller University Press
                ISSN (Print): 0022-1007
                ISSN (Electronic): 1540-9538
                Publication date Collection: 02 March 2020
                Publication date (Electronic): 20 February 2020
                Volume: 217
                Issue: 3
                Electronic Location Identifier: e20190103
                Affiliations
                [1]The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY
                Author notes
                Correspondence to Nikolaos G. Frangogiannis: nikolaos.frangogiannis@ 123456einstein.yu.edu

                Disclosures: The author declares no competing interests exist.

                Author information
                https://orcid.org/0000-0002-8186-5131
                Article
                Publisher ID: jem.20190103
                DOI: 10.1084/jem.20190103
                PMC ID: 7062524
                PubMed ID: 32997468
                SO-VID: 6e9bc4ce-5f5d-47b8-8bb7-3dbe051b11de
                Copyright © © 2020 Frangogiannis
                License:

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

                History
                Date received : 22 May 2019
                Date revision received : 19 September 2019
                Date accepted : 24 December 2019
                Page count
                Pages: 16
                Funding
                Funded by: National Institutes of Health, DOI http://dx.doi.org/10.13039/100000002;
                Award ID: R01 HL76246
                Award ID: R01 HL85440
                Funded by: US Department of Defense, DOI http://dx.doi.org/10.13039/100000005;
                Award ID: PR151134
                Award ID: PR151029
                Award ID: PR181464
                Categories
                Subject: Review
                Subject: Innate immunity and inflammation
                Subject: Cytokines Focus
                Subject: Cytokines Focus

                ScienceOpen disciplines: Medicine
                Data availability:
                ScienceOpen disciplines: Medicine

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