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Published on: November 10, 2021
The origin of interstitial myofibroblasts in chronic kidney disease
Ivica Grgic1, Jeremy S Duffield, Benjamin D Humphreys
1Renal Division, Brigham and Women's Hospital, Harvard Institutes of Medicine Rm 550, Boston, MA 02115, USA.
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.
Insights
New research challenges the epithelial-to-mesenchymal transition (EMT) theory in kidney fibrosis. Findings suggest pericytes, not injured epithelial cells, are the primary source of myofibroblasts in chronic kidney disease (CKD).
Area of Science:
- Nephrology
- Cell Biology
- Fibrosis Research
Background:
- Chronic kidney diseases (CKD) cause irreversible renal parenchyma loss, characterized by tubulointerstitial fibrosis.
- Myofibroblasts drive excessive matrix deposition in renal pathology.
- Identifying myofibroblast origins is crucial for therapeutic strategies in fibrotic kidney disease.
Purpose of the Study:
- To investigate the cellular origins of myofibroblasts in kidney fibrosis.
- To critically evaluate the role of epithelial-to-mesenchymal transition (EMT) in myofibroblast recruitment in vivo.
- To review recent findings from genetic fate mapping studies in kidney fibrosis models.
Main Methods:
- Review of recent scientific literature.
- Analysis of genetic fate mapping techniques in mouse models of kidney fibrosis.
- Comparative analysis of cellular origins of myofibroblasts.
Main Results:
- Recent genetic fate mapping studies cast doubt on EMT as a significant source of myofibroblasts in vivo.
- Evidence points towards resident pericytes/perivascular fibroblasts as the primary myofibroblast progenitor pool.
- The traditional view of resident fibroblasts as the sole precursor is also challenged.
Conclusions:
- EMT is unlikely to be a direct contributor to the kidney myofibroblast population in vivo.
- Pericytes and perivascular fibroblasts are identified as key progenitors of myofibroblasts in fibrotic kidney disease.
- Genetic fate mapping is a powerful tool for understanding kidney homeostasis and disease mechanisms.
Related Concept Videos
Chronic Kidney Disease I: Introduction
Chronic Inflammation: Introduction
Acute Kidney Injury II: Pathophysiology
Chronic Kidney Disease II: Clinical Manifestations
Nephrons
Introduction to Fibroblasts

