The origin of interstitial myofibroblasts in chronic kidney disease

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.

Fig. 1

Current concepts of myofibroblast recruitment in CKD. The traditional concept holds that myofibroblasts primarily derive from local stromal cells in the kidney such as resident fibroblasts and pericytes/perivascular fibroblasts. Epithelial-mesenchymal transition (EMT), a process in which epithelial cells are believed to undergo complete phenotypical transformation, acquire mesenchymal properties and traverse the tubular basement membrane (TBM), has been proposed as an important alternative route of recruitment. Recent studies using state-of-the-art fate mapping techniques, however, have cast serious doubt on the significance of EMT as generator of myofibroblasts in renal fibrosis. Other proposed sources of recruitment include endothelial cells (via endothelial-mesenchymal transition, EndMT) and bone-marrow-derived cells. Published data indicates that bone-marrow-derived cells make very little, if any, contribution to collagen-secreting cells in kidney fibrosis

Fig. 2

Genetically labeled pericytes in adult kidney. FoxD1-Cre driver was crossed to R26-tdtomato reporter mice resulting in recombination and permanent labeling (red) of renal stromal cells, including pericytes and perivascular fibroblasts, in bigenic offspring. Note the delicate spindle shape and long processes extending around the tubules that characterize labeled cells in the renal interstitium. Nuclei were counterstained with DAPI and the image was captured by confocal microscopy at 400x magnification

Fig. 3

EM photomicrographs of peritubular capillaries from human kidney. a Micrograph demonstrating the relationship of pericytes to endothelial cells. Of note, the pericyte is sheathed by duplication of the capillary basement membrane (CBM capillary basement membrane; cf collagen fibers; EC endothelial cell; Mϕ resident macrophage; P pericyte; Pp pericyte process; PTC peritubular capillary; RBC red blood cell; Tu tubule). b A pericyte with characteristic projections abutting and within the CBM. c Extensive pericyte process within cortical CBM. Insert shows higher power image of the tip of the process, and arrowhead indicates the reflection of the CBM and junction with the endothelial cell

Fig. 4

Myofibroblasts originating from kidney pericytes and perivascular fibroblasts. The schematic shows the perception of myofibroblast recruitment from local pericytes and perivascular fibroblasts in the setting of chronic kidney injury (↓). Persistent irritation and injury lead to activation and transformation of pericytes and perivascular fibroblasts into myofibroblasts with subsequent migration, proliferation, and deposition of extracellular matrix (ECM) in tubulointerstitial spaces. The consequences are progressive scar tissue formation and loss of functional renal parenchyma