Understanding the role of adult perivascular progenitors in vascular homeostasis, sclerosis and calcification in chronic kidney disease.

• Applicant: Professor Dr. Rafael Kramann
• Subject Area: Nephrology
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 278107546

Vascular sclerosis and arterial calcification contribute centrally to increased cardiovascular morbidity and mortality in chronic and end-stage renal disease (CKD/ESRD). Recent data including our own suggest the involvement of resident vascular mesenchymal stem cells (MSC).We have identified that Gli1, a transcriptional activator of the Hedgehog (Hh) pathway is specifically expressed in a perivascular MSC population. We have demonstrated that these Gli1+ cells are key myofibroblast progenitors after injury of solid organs and our preliminary data point towards an involvement of these cells in vascular sclerosis. We are hypothesizing that Gli1+ cells are important in homeostasis of the vascular wall and might serve as progenitors in repair after acute injury, but trigger vascular sclerosis and calcification in chronic injury as in CKD by differentiation in myofibroblasts and osteoblasts-type cells . Thus, we will utilize genetic fate tracing techniques to elucidate the role of this progenitor population in homeostasis, acute injury and CKD vascular disease. Furthermore, we will study whether cell-specific ablation of Gli1 progenitors alters the vascular phenotype and ameliorates or even reverses the vascular sclerosis and calcification process in mice. Our data point towards a similar cell-population in humans. We will characterize this cell-population in homeostasis and vascular disease and we will utilize whole human artery ring culture models to understand the role of these progenitors during vascular calcification. Furthermore, we will develop a fate tracing technique in human tissue using CRISPR/Cas9 mediated genome engineering to perform clonal analysis and answer the question whether the Progenitor population expands and differentiates during disease modelling and calcification.We hypothesize that canonical and non-canonical Hh signaling is involved in self-renewal, recruitment and expansion during vascular calcification. We will utilize CRISPR/Cas9 mediated genome editing and pharmacologic modulation to comprehensively assess the role of the Hh pathway in adventitial progenitors of mice and humans during homeostasis and disease.

• DFG Programme: Research Grants