This study investigates the origin and function of myofibroblasts in kidney fibrosis using genetically engineered mouse models. Key findings include: 1. **Origin of Myofibroblasts**: - 50% of myofibroblasts arise from local resident fibroblasts via proliferation. - 35% derive from bone marrow, either through differentiation or recruitment. - 10% result from endothelial-to-mesenchymal transition (EndMT). - 5% come from epithelial-to-mesenchymal transition (EMT). 2. **Function of Myofibroblasts**: - Myofibroblasts are functionally important for renal fibrosis, contributing to type I collagen production. - Ablation of proliferating myofibroblasts reduces fibrosis by about 50%. - Bone marrow-derived myofibroblasts are recruited without proliferation, suggesting a role in fibrosis. 3. **Pericytes and Myofibroblasts**: - NG2+ and PDGFRβ+ pericytes do not contribute to the myofibroblast population in kidney fibrosis. - Depletion of these cells does not significantly reduce fibrosis. 4. **EMT and EndMT**: - EMT contributes to about 5% of interstitial myofibroblasts. - EndMT contributes to about 10% of myofibroblasts, both processes likely involving TGFβ1-dependent differentiation. 5. **Clinical Implications**: - Anti-proliferative drugs may only partially impact myofibroblast accumulation in fibrotic kidneys. - Targeting diverse pathways is necessary to inhibit myofibroblast accumulation in kidney fibrosis. This comprehensive study provides new insights into the origin and function of myofibroblasts in kidney fibrosis, suggesting potential therapeutic targets for managing fibrosis.This study investigates the origin and function of myofibroblasts in kidney fibrosis using genetically engineered mouse models. Key findings include: 1. **Origin of Myofibroblasts**: - 50% of myofibroblasts arise from local resident fibroblasts via proliferation. - 35% derive from bone marrow, either through differentiation or recruitment. - 10% result from endothelial-to-mesenchymal transition (EndMT). - 5% come from epithelial-to-mesenchymal transition (EMT). 2. **Function of Myofibroblasts**: - Myofibroblasts are functionally important for renal fibrosis, contributing to type I collagen production. - Ablation of proliferating myofibroblasts reduces fibrosis by about 50%. - Bone marrow-derived myofibroblasts are recruited without proliferation, suggesting a role in fibrosis. 3. **Pericytes and Myofibroblasts**: - NG2+ and PDGFRβ+ pericytes do not contribute to the myofibroblast population in kidney fibrosis. - Depletion of these cells does not significantly reduce fibrosis. 4. **EMT and EndMT**: - EMT contributes to about 5% of interstitial myofibroblasts. - EndMT contributes to about 10% of myofibroblasts, both processes likely involving TGFβ1-dependent differentiation. 5. **Clinical Implications**: - Anti-proliferative drugs may only partially impact myofibroblast accumulation in fibrotic kidneys. - Targeting diverse pathways is necessary to inhibit myofibroblast accumulation in kidney fibrosis. This comprehensive study provides new insights into the origin and function of myofibroblasts in kidney fibrosis, suggesting potential therapeutic targets for managing fibrosis.