Mechanisms Underlying Stem Cell Plasticity

描述(由申请人提供)：我们将建立干细胞(SC)和造血组织定向祖细胞(HSC)修复上皮组织损伤的定性和定量潜力。这些研究旨在研究组织修复和再生的机制。我们认为，为了确定什么是修复/再生的调节因素，我们必须表明：a)诱导造血干细胞转化为肝脏的因素是什么；b)负责修复的靶细胞是什么；c)如何将细胞运送到损伤部位；d)我们如何在移植后跟踪细胞；以及e)随着时间的推移，修复/再生的水平是什么。我们这些研究的长期目标是利用来自造血和非造血组织的干细胞为糖尿病、囊性纤维化以及肝或肾衰竭等疾病提供治疗选择。我们的计划是建立机制，允许成年SC对特定的损伤信号做出反应。因此，我们的具体目标是：1)我们计划确定SC修复/再生的潜力，以修复急性或慢性损伤的肝脏。此外，我们将使用一种新的体外实验来研究损伤信号对HSC转化为损伤组织表型的功能细胞的影响。核聚变是一种可能负责转化的额外机制。因此，我们还将研究渗出的后果，如果它发生以及何时发生，以了解这种细胞修复的机制。我们的体外研究将与体内移植研究相补充，以确定SC治疗的功能潜力。我们的目标是研究哪些靶细胞可以影响受损组织的修复。有没有可能每个组织都有自己的干细胞储存库，可以在特定情况下修复？我们将尝试通过我们已经成功地分离HSC的方法从上皮组织中分离SC，并确定这些细胞修复受损的上皮组织和造血组织的潜力。相关性：我们这些研究的长期目标是利用来自造血和非造血组织的干细胞为糖尿病、囊性纤维化以及肝或肾衰竭等疾病提供治疗选择。我们的计划是建立机制，允许成年SC对特定的损伤信号做出反应。

DESCRIPTION (provided by applicant): We will establish the qualitative and quantitative potential of stem cells (SC) and committed progenitor cells of hematopoietic tissue (HSC) for the repair of damage to epithelial tissues. These studies are designed to examine the mechanisms responsible for tissue repair and regeneration. We believe in order to determine what regulates repair/regeneration we must show: a) What the factors are that induce conversion of hematopoietic stem cells into liver; b) what are the target cells responsible for the repair; c) how the cells can be delivered to the site of injury; d) how we can track the cells after transplantation; and e) what is the level of repair/regeneration over time. Our long term goals of these studies are to utilize SC from hematopoietic and non-hematopoietic tissue to offer treatment options for diseases such as Diabetes, Cystic Fibrosis, as well as liver or kidney failure. Our plan is to establish the mechanisms which allow adult SC to reprogram in response to specific injury signals. Thus our specific aims are: 1) we plan to determine the repair/regeneration potential of SC for repair of acutely or chronically injured liver. Further, we will examine the effect of injury signals on the conversion of HSC into functional cells of the injured tissue phenotype using a novel in vitro assay. Fusion is an additional mechanism which might be responsible for conversion. Therefore we will also study the consequences effusion if and when it occurs to understand this mechanism of cellular repair. Our in vitro studies will be complemented with in vivo transplant studies to determine the functional potential for SC therapy. Our aim 2) is to study which target cells can affect the repair of injured tissue. Is it possible that each tissue has its own reservoir of SC which can repair in particular circumstances? We will attempt to isolate SC from epithelial tissues by methods which we have already used to successfully isolated HSC and determine the potential for these cells to repair injured epithelial and hematopoietic tissue. Relevance: Our long term goals of these studies are to utilize SC from hematopoietic and non-hematopoietic tissue to offer treatment options for diseases such as Diabetes, Cystic Fibrosis, as well as liver or kidney failure. Our plan is to establish the mechanisms which allow adult SC to reprogram in response to specific injury signals.