HSC-derived fibroblasts in normal and diseased valves.

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DESCRIPTION (provided by applicant): Using a single hematopoietic stem cell (HSC) transplantation approach employing HSCs derived from mice that ubiquitously express enhanced green fluorescent protein, we have shown that HSCs give rise to fibroblast-like cells that populate adult cardiac valves. We refer to this cell population as HSC-derived valve interstitial cells (HVICs). We know very little as to the function of HVICs other than they synthesize collagen. Experimentation outlined in this application seeks to answer fundamental questions pertaining to the biochemical/biosynthetic and growth characteristics of HVICs under both physiological and pathological conditions. An overarching hypothesis that will be addressed by the proposed experimentation is that transplantation of normal HSCs leading to engraftment of HVICs into diseased valves could ameliorate valvular pathologies. There are two specific Aims: The first Aim seeks to determine: 1) the proportion of total valve cells represented by HVICs, 2) whether their CD antigen, cytokine (ILI-beta) and cytokine receptor expression profile distinguishes HVICs from other resident valvular cells, 3) whether the cells are proliferative or quiescent once they engraft, and 4) whether HVICs are a source of myofibroblasts. In addition, the growth and synthetic responsiveness of HVICs to valvular injury will be studied. In the second Aim the therapeutic potential of HSCs to valvular disease will be assessed. To accomplish this, we will determine the consequence of transplanting HSCs from normal mice into mice having postnatal valve pathologies (i.e., myxomatous valve lesions and valve prolapse) induced by mutation in genes encoding the ECM proteins, periostin and fibrillin-1. These studies will include post-transplantation assessment of valve function (i.e., by echocardiography and measurement of biomechanical properties), histological assessment, and transcriptomic profiling to determine the genetic basis for any observed response.