Adult Progenitors in Kidney Tubulointerstitium

 描述(申请人提供)：肾衰竭在美国是一个严重的健康问题，它反映了肾单位修复失败和进行性纤维化的后果。治疗肾衰竭的两种有希望的策略包括体内功能肾单位的再生和体外可移植肾单位的工程。我们已经确定了两个关键的成人肾祖细胞群体，它们具有在每种策略中发挥重要作用的强大潜力。在小管内，我们先前已经证明去分化的近端小管细胞负责通过增殖扩张修复近端小管。我们现在已经创造了一种新的方法来轻松分离这些去分化的上皮祖细胞的纯群体，我们将表征、培养和定义这些关键细胞的功能特性。此外，我们 最近发现了一个肾脏间充质干细胞群体，它由Gli1的表达决定，它代表了纤维化疾病中主要的肌成纤维细胞前体群体。这些细胞具有稳定血管的特性，能够分化为周细胞和血管平滑肌细胞。我们将在体外和体内进一步鉴定这些细胞的功能，并将它们与内皮细胞和上皮细胞共同培养，以建立体外肾小管间质的模型。总之，拟议的实验不仅将定义治疗肾衰竭的新的再生策略，而且还将验证两个关键的成体祖细胞群体，这将对治疗肾衰竭的各种再生方法有用。

 DESCRIPTION (provided by applicant): Kidney failure is a critical health problem in the United States and it reflects the consequences of failed nephron repair and progressive fibrosis. Two promising strategies to treat kidney failure include regeneration of functional nephrons in vivo, and engineering of transplantable nephrons in vitro. We have identified two critical adult kidney progenitor populations with strong potential to play important roles in each strategy. Within the tubule, we have previously shown that dedifferentiated proximal tubule cells are responsible for repairing proximal tubule by proliferative expansion. We have now generated a novel approach to easily isolate a pure population of these dedifferentiated epithelial progenitors, and we will characterize, culture and define the functional properties of these critical cells. In addition, we have recently identified a kidney resident mesenchymal stem cell population defined by expression of Gli1 that represents the major myofibroblast precursor population in fibrotic disease. These cells have vascular stabilizing properties and are capable of differentiating into both pericytes and vascular smooth muscle cells. We will further characterize the function of these cells both in vitro and in vivo, and coculture them with endothelial cells and epithelial cels to model the kidney tubulointerstitium in vitro. Together, the proposed experiments will not only define novel regenerative strategies for kidney failure, but will also validate two critical adult progenitor cell populations that will be useful for a variety of regenerative approaches to treat kidney failure.