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Diverse origins of the myofibroblast—implications for kidney fibrosis

Key Points

  • Myofibroblasts involved in kidney fibrosis might originate from diverse origins, including bone marrow-derived fibroblasts, tubular epithelial cells, endothelial cells, pericytes and interstitial fibroblasts

  • Independent studies have shown that myofibroblasts can be derived from either one or more sources, irrespective of the nature of the initial damage responsible for the induction of kidney fibrosis

  • The diversity of myofibroblast progenitors in kidney fibrosis might be relevant for the development of novel therapies

  • Systemic therapies have been developed that can inhibit myofibroblast accumulation and fibrotic development; however, the efficacy and safety of these therapies in chronic kidney disease is not clear

  • Targeting strategies to support resident and circulating cells in maintaining or regaining their original functional differentiation state and resisting transition to a myofibroblast phenotype might prevent or reverse fibrosis

Abstract

Fibrosis is the common end point of chronic kidney disease. The persistent production of inflammatory cytokines and growth factors leads to an ongoing process of extracellular matrix production that eventually disrupts the normal functioning of the organ. During fibrosis, the myofibroblast is commonly regarded as the predominant effector cell. Accumulating evidence has demonstrated a diverse origin of myofibroblasts in kidney fibrosis. Proposed major contributors of myofibroblasts include bone marrow-derived fibroblasts, tubular epithelial cells, endothelial cells, pericytes and interstitial fibroblasts; the published data, however, have not yet clearly defined the relative contribution of these different cellular sources. Myofibroblasts have been reported to originate from various sources, irrespective of the nature of the initial damage responsible for the induction of kidney fibrosis. Here, we review the possible relevance of the diversity of myofibroblast progenitors in kidney fibrosis and the implications for the development of novel therapeutic approaches. Specifically, we discuss the current status of preclinical and clinical antifibrotic therapy and describe targeting strategies that might help support resident and circulating cells to maintain or regain their original functional differentiation state. Such strategies might help these cells resist their transition to a myofibroblast phenotype to prevent, or even reverse, the fibrotic state.

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Figure 1: Differentiation steps of fibroblasts towards myofibroblast subtypes.
Figure 2: Expression of fibroblast markers only partially overlap in kidney fibrosis.
Figure 3: Schematic of the Cre–lox system used to trace FOXD1-positive pericytes.
Figure 4: Potential origins of myofibroblast progenitors.

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L.L.F., S.G., R.G., R.J.K. and T.Q.N. researched data for the article. All authors provided substantial contributions to discussions of its content and wrote the article. L.L.F., R.G., R.J.K. and T.Q.N. undertook review and/or editing of the manuscript before submission. L.L.F. and S.G. contributed equally. R.J.K. and T.Q.N. contributed equally.

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Correspondence to Roel Goldschmeding.

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Falke, L., Gholizadeh, S., Goldschmeding, R. et al. Diverse origins of the myofibroblast—implications for kidney fibrosis. Nat Rev Nephrol 11, 233–244 (2015). https://doi.org/10.1038/nrneph.2014.246

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