Understanding connective tissue development and disease with PDGFR-driven.....

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Fibrosis is an aberrant wound-healing response where cells proliferate and secrete collagen that forms scar tissue and disrupts organ functions. This occurs in many chronic diseases including liver cirrhosis and atherosclerosis, as well as autoimmune diseases like scleroderma where skin and other organ fibrosis is the principal feature. There are currently no effective treatments for most types of fibrosis. Despite the prevalence of fibrosis in many diseases, the driving mechanisms at the cell and tissue level are largely unknown. Our research is focused on the ability of platelet-derived growth factor receptor (PDGFR) signaling to cause fibrosis in the skin, and we have devised new mouse models to identify the underlying cellular and molecular mechanisms. In Specific Aim 1, we will use skin-injury assays in mice with induced PDGFR signaling to identify specific wound-repair processes that are altered by PDGFR pathway activation. We will activate PDGFR signaling specifically in pericytes because our preliminary data indicate that this cell type has a key role in fibrosis following skin injury. In Specific Aim 2 we will use fate mapping to determine the lineage contribution of pericytes to the myofibroblast population that is directly responsible for fibrosis. We hypothesize that nestin+ pericytes in the skin are mesenchymal stem cells (MSCs) and that PDGF pathway activity alters their differentiation towards a myofibroblast fate. In Specific Aim 3 we will isolate nestin+ MSCs from the skin and determine which MSC processes are regulated by PDGF signaling using stem cell assays. We will also use microarrays and bioinformatics to characterize this cell type and identify the gene programs regulated by the PDGFR pathway. Finally, we will test the fibrotic potential of nestin+ MSCs using transplantation assays. Together, these experiments will explore poorly understood fibrotic mechanisms in the skin and identify cellular and molecular mechanisms that are regulated by a major pro-fibrotic growth factor. An understanding of the mechanisms of fibrosis can be expected to lead to rational therapeutic approaches to limit or reverse disease.