Origin of fibroblasts during kidney fibrosis. (a) Fibrotic kidney which displays accumulation of numerous fibroblasts (blue arrow), damaged kidney tubules (yellow arrow), and blood vessels (green arrow). (b) Normal kidney with proper tubular structures and very few fibroblasts. (c) Schematic illustration of three possible mechanisms via which fibroblasts can originate during kidney injury. Recent experiments suggest that approximately 14–15% of fibroblasts are from bone marrow, 36% can arise via local EMT involving tubular epithelial cells under inflammatory stress, and the rest are likely contributed by proliferation of fibroblasts from all sources. (d) Systemic treatment of mice with renal fibrosis using recombinant human BMP-7 results in reversal of renal disease due to severe decrease in EMT-derived fibroblasts and potentially bone marrow–derived fibroblasts. Such events likely have a cascade of beneficial effects that decreasing the overall number of fibroblasts in the kidney, and attenuating fibrosis.