Pericytes, mesenchymal stem cells and vascular calcification in chronic kidney disease (CKD). Is hedgehog signaling the missing link between endothelial injury and vascular sclerosis?
Final Report Abstract
Our data indicates that Gli1 marks resident perivascular mesenchymal stem cells that are key progenitors of fibrosis driving myofibroblasts in kidney, lung, heart and liver. Genetic ablation of these cells dramatically reduced fibrosis after kidney and heart injury and rescued left ventricular function following ascending aortic construction. Therefore Gli1+ MSC are a promising therapeutic target in fibrosis. This study was elected as the top story in nephrology of 2014 by the the Renal Fellow Network of the USA, featured by National Kidney Foundation and American Society of Nephrology and highlighted by several news outlets including sciencedaily.com, Kidney International, medicalxpress.com, ddmag.com, Faculty of 1000. Importantly, we demonstrate in a second study that targeting Gli proteins pharmacologically is a novel therapeutic strategy in kidney fibrosis and chronic kidney disease.
Publications
- Fluorescence Microangiography for Quantitative Assessment of Peritubular Capillary Changes after Acute Kidney Injury. - J Am Soc Nephrol – 2014; 25(9):1924-31
Kramann R, Tanaka M, Humphreys BD
(See online at https://doi.org/10.1681/ASN.2013101121) - Perivascular Gli1+ Progenitors Are Key Contributors to Injury-Induced Organ Fibrosis - Cell Stem Cell 2015 Jan 8;16(1):51-66
Kramann R, Schneider RK, DiRocco DP, Machado F, Fleig S, Bondzie FP, Henderson JM, Ebert BL, Humphreys BD
(See online at https://doi.org/10.1016/j.stem.2014.11.004) - Pharmacological Gli2 Inhibition prevents myofibroblast cell-cycle progression and reduces kidney fibrosis - J Clin Invest 2015 Aug 3;125(8):2935-51
Kramann R, Fleig SV, Schneider RK, Fabian SL, DiRocco DP, Maarouf M, Wongboonsin J, Ikeda Y, Heckl D, Chang SL, Rennke HG, Waikar SS, Humphreys BD
(See online at https://doi.org/10.1172/JCI74929) - Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8/S100A9 - Nat Med. 2016 Mar; 22(3): 288–297
Schneider RK, Schenone M, Ventura Ferreira M, Kramann R, Joyce CE, Hartigan C, Beier F, Brümmendorf TH, Germing U, Platzbecker U, Buesche G, Knuechel R, Chen MC, Waters CS, Chen E, Chu LP, Novina C, Lindsley RC, Carr SA, Ebert BL
(See online at https://doi.org/10.1038/nm.4047)
