Stem cell population of the renal tubule

肾小管干细胞群

• 批准号: 6712559
• 负责人: LLOYD G CANTLEY
• 金额: $ 32.37万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6712559
• 关键词: acute renal failure; bone marrow; cell cell interaction; cell differentiation; cell migration; genetically modified animals; hematopoietic stem cells; hematopoietic tissue transplantation; kidney function; laboratory mouse; mesenchyme; microarray technology; regeneration; renal ischemia /hypoxia; renal tubule; stem cell transplantation; tissue /cell culture

DESCRIPTION (provided by applicant): Despite significant advances in our understanding of the pathogenesis of ischemic renal injury, we have made little headway in therapeutic interventions that can alter the rate or degree of recovery from clinical acute tubular necrosis. The present paradigm for recovery of the renal tubule from ATN is that surviving cells from the areas bordering the injury de-differentiate, migrate into the regions of tubular denudation and proliferate to re-establish the normal tubular epithelium. In this application, we describe an entirely new and unexpected pathway for renal tubule repair, the mobilization and homing of bone marrow stem cells to the injured tubular segment. We have found that mouse adult bone marrow contains Lin-Sca-1+ stem cells that are mobilized into the circulation by transient renal ischemia, and that these cells home specifically to injured regions of the renal tubule where they differentiate into renal tubular epithelial cells. Furthermore, 1 week after the ischemic injury, these bone marrow-derived cells appear to make up the majority of the cells present in the previously necrotic tubule segments. Our hypothesis is that the adult bone marrow contains stem cells (BMSCs) that retain features similar to embryonic metanephric mesenchyme, and that ischemic renal injury can induce the homing of these cells to the kidney, where they fully differentiate and functionally incorporate into the renal tubule. Our goal is to determine how BMSCs differentiate to become renal tubular cells, including what regions of the kidney they can populate and their level of functional differentiation (SA 1), to identify the factors that regulate the mobilization and targeting of these cells to the kidney (SA 2), to culture BMSCs in vitro and determine the mechanism of their differentiation into epithelia (SA 3), and then use BMSCs to functionally repopulate the renal epithelium in models of tubular cell dysfunction. These experiments are designed to provide the functional basis for an entirely novel approach for enhancing renal tubular repair following acute injury, as well as for using stem cell transplant to deliver normal tubular cells precursors as therapy for genetically mediated tubule dysfunction.

描述（由申请人提供）：尽管我们对缺血性肾脏损伤的发病机理的理解取得了重大进展，但我们在治疗干预措施方面几乎没有取得进展，这可以改变临床急性管状坏死的率或程度。目前从ATN恢复肾小管的范例是，与损伤接壤的区域的幸存细胞迁移到管状剥落的区域并增殖到重新建立正常的管状上皮。在此应用中，我们描述了肾小管修复的全新且出乎意料的途径，动员和将骨髓干细胞的归纳为受伤的管状片段。我们发现，小鼠成年骨髓含有LIN-SCA-1+干细胞，这些细胞通过瞬时肾脏缺血动员到循环中，并且这些细胞专门为肾小管的损伤区域，它们分化为肾小管上皮细胞。此外，在缺血性损伤1周后，这些骨髓衍生的细胞似乎构成了先前坏死小管片段中存在的大多数细胞。我们的假设是，成年骨髓含有干细胞（BMSC），保留类似于胚胎元素间充质的特征，而缺血性肾脏损伤可以诱导这些细胞将这些细胞的归为肾脏，在那里它们完全区分并在功能上将其功能融合到肾小管中。我们的目标是确定BMSC如何区分成为肾小管细胞，包括它们可以填充的肾脏区域及其功能差异水平（SA 1），以确定调节这些细胞向肾脏动员和靶向肾脏（SA 2）的因素（SA 2），以在体外培养BMSC，并确定其对Eptheelia的差异（SA 3），然后使用BM的机制（SA 3），以及SA 3），以及SA 3），以及SA 3），并确定了BMSC的机制。管状细胞功能障碍模型中的上皮。这些实验旨在为一种全新的方法提供功能基础，以增强急性损伤后肾小管修复，以及使用干细胞移植以提供正常的管状细胞前体作为遗传介导的小管功能障碍的治疗。