HSC-derived fibroblasts in normal and diseased valves.

描述（由申请人提供）：使用单一造血干细胞（HSC）移植方法，使用来自普遍表达增强绿色荧光蛋白的小鼠的HSC，我们已经证明HSC产生成纤维细胞样细胞，填充成人心脏瓣膜。我们将这种细胞群称为造血干细胞衍生的瓣膜间质细胞（hvic）。除了它们能合成胶原蛋白外，我们对hvic的功能知之甚少。本应用程序中概述的实验旨在回答有关hvic在生理和病理条件下的生化/生物合成和生长特性的基本问题。提出的实验将解决的一个总体假设是，将正常造血干细胞移植导致hvic植入病变瓣膜可以改善瓣膜病变。有两个特定的目的：第一个目的旨在确定：1)以hvic为代表的瓣膜细胞总数的比例，2)它们的CD抗原、细胞因子（il - β）和细胞因子受体的表达是否将hvic与其他常驻瓣膜细胞区分开来，3)细胞在移植后是增殖还是静止，4)hvic是否是肌成纤维细胞的来源。此外，还将研究hvic的生长和对瓣膜损伤的合成反应。在第二个目标中，将评估造血干细胞对瓣膜疾病的治疗潜力。为了实现这一目标，我们将确定将正常小鼠的造血干细胞移植到由编码ECM蛋白、骨膜蛋白和纤原蛋白-1的基因突变引起的产后瓣膜病变（即粘液瘤性瓣膜病变和瓣膜脱垂）的小鼠身上的结果。这些研究将包括移植后瓣膜功能评估（即通过超声心动图和生物力学特性测量）、组织学评估和转录组分析，以确定任何观察到的反应的遗传基础。

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.