Pericytes and perivascular fibroblasts are the primary source of collagen-producing cells in obstructive fibrosis of the kidney.
Understanding the origin of scar-producing myofibroblasts is vital in discerning the mechanisms by which fibrosis develops in response to inflammatory injury. Using a transgenic reporter mouse model expressing enhanced green fluorescent protein (GFP) under the regulation of the collagen type I, alpha 1 (coll1a1) promoter and enhancers, we examined the origins of coll1a1-producing cells in the kidney. Here we show that in normal kidney, both podocytes and pericytes generate coll1a1 transcripts as detected by enhanced GFP, and that in fibrotic kidney, coll1a1-GFP expression accurately identifies myofibroblasts. To determine the contribution of circulating immune cells directly to scar production, wild-type mice, chimeric with bone marrow from coll-GFP mice, underwent ureteral obstruction to induce fibrosis. Histological examination of kidneys from these mice showed recruitment of small numbers of fibrocytes to the fibrotic kidney, but these fibrocytes made no significant contribution to interstitial fibrosis. Instead, using kinetic modeling and time course microscopy, we identified coll1a1-GFP-expressing pericytes as the major source of interstitial myofibroblasts in the fibrotic kidney. Our studies suggest that either vascular injury or vascular factors are the most likely triggers for pericyte migration and differentiation into myofibroblasts. Therefore, our results serve to refocus fibrosis research to injury of the vasculature rather than injury to the epithelium.
Lin
Shuei-Liong
SL
Laboratory of Inflammation Research, Renal Division, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Kisseleva
Tatiana
T
Brenner
David A
DA
Duffield
Jeremy S
JS
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002678:Chimera; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005355:Fibrosis / Q000473:pathology*; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020286:Pericytes / Q000166:cytology / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism
D015415:Biomarkers; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D011993:Recombinant Fusion Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors