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The origin of interstitial myofibroblasts in chronic kidney disease

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Abstract

Chronic kidney diseases (CKD), independent of their primary cause, lead to progressive, irreversible loss of functional renal parenchyma. Renal pathology in CKD is characterized by tubulointerstitial fibrosis with excessive matrix deposition produced by myofibroblasts. Because blocking the formation of these scar-forming cells represents a logical therapeutic target for patients with progressive fibrotic kidney disease, the origin of renal myofibroblasts is a subject of intense investigation. Although the traditional view holds that resident fibroblasts are the myofibroblast precursor, for the last 10 years, injured epithelial cells have been thought to directly contribute to the myofibroblast pool by the process of epithelial-to-mesenchymal transition (EMT). The recent application of genetic fate mapping techniques in mouse fibrosis models has provided new insights into the cell hierarchies in fibrotic kidney disease and results cast doubt on the concept that EMT is a source of myofibroblast recruitment in vivo, but rather point to the resident pericyte/perivascular fibroblast as the myofibroblast progenitor pool. This review will highlight recent findings arguing against EMT as a direct contributor to the kidney myofibroblast population and review the use of genetic fate mapping to elucidate the cellular mechanisms of kidney homeostasis and disease.

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Acknowledgements

The authors wish to thank Dr. Vanesa Bijol and Colleen Ford (Renal Pathology, Brigham and Women’s Hospital) for generous contribution of EM micrographs and helpful discussions. I.G. is supported by a fellowship from the Deutsche Forschungsgemeinschaft (GR 3301/4-1) and grants from the German Kidney Foundation, German Society of Hypertension, and University Medical Center Giessen and Marburg. Laboratory of Inflammation Research is supported by DK73299, DK84077, DK87389, and the Institute for Stem Cell & Regenerative Medicine, Seattle, WA. Work in the Humphreys Laboratory is supported by NIH grants DK88923, DK84316, and DK73628 and funds from the Harvard Stem Cell Institute.

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Authors and Affiliations

  1. Renal Division, Brigham and Women’s Hospital, Harvard Institutes of Medicine Rm 550, 4 Blackfan Circle, Boston, MA, 02115, USA

    Ivica Grgic & Benjamin D. Humphreys

  2. Department of Internal Medicine and Nephrology, Philipps-University, Marburg, Germany

    Ivica Grgic

  3. Division of Nephrology & Institute for Stem Cell and Regenerative Medicine, Laboratory of Inflammation Research, University of Washington, Seattle, WA, USA

    Jeremy S. Duffield

  4. Harvard Stem Cell Institute, Cambridge, MA, USA

    Benjamin D. Humphreys

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  1. Ivica Grgic
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Correspondence to Benjamin D. Humphreys.

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Grgic, I., Duffield, J.S. & Humphreys, B.D. The origin of interstitial myofibroblasts in chronic kidney disease. Pediatr Nephrol 27, 183–193 (2012). https://doi.org/10.1007/s00467-011-1772-6

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