STEM CELLS IN THE KIDNEY

肾脏中的干细胞

• 批准号: 6801313
• 负责人: QAIS AL-AWQATI
• 金额: $ 26.31万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 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 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6801313
• 关键词: acute renal failure; cell biology; cell differentiation; cell growth regulation; cell proliferation; cell surface receptors; developmental genetics; gene expression; growth factor; growth factor receptors; hypoxia; kidney; kidney pharmacology; laboratory mouse; laboratory rat; microarray technology; molecular genetics; nephrogenesis; osmotic pressure; renal ischemia /hypoxia; renal medulla; secretory protein; stem cells; tissue /cell culture; ureter obstruction

Kidney development begins when the ureteric bud invades the metanephric mesenchyme and induces it to convert to the epithelium of the nephron. Metanephric mesenchyme eventually gets segmented into glomerulus, proximal, loop and distal epithelia. We had shown previously that the metanephric mesenchyme contains stem cells capable of generating all of the nephron segments. Stem cells are slow cycling cells hence when labeled with a marker that is incorporated during DNA replication they retain the label. They are also pluripotent and exist in regions of a tissue that is protected from the environment, a niche that is often hypoxic. We recently discovered that adult kidneys contain label-retaining cells that when cultured as single cells differentiate into epithelial or smooth muscle cells with an occasional cell acquiring a neuron like phenotype. Remarkably, these adult stem cells are present mostly in the papilla. We will characterize these cells in terms of their requirement for growth in clonal cultures, their proliferative ability, and their capacity to differentiate to epithelial endothelial, smooth muscle and fibroblastic lineages. The role of the papillary environment (hypoxia, hyper-osmolality, ECM proteins growth factors etc) on the potential for growth and differentiation of these cells in clonal cultures will also be studied. In a second Aim, we will study their gene expression using microarrays. The aim here is to identify the membrane protein receptors and the proteins and growth factors that they secrete. These findings will help us in developing strategies to develop appropriate culture conditions for their expansion. We found that induction of ischemic acute tubular necrosis induced a change in abundance and distribution in these papillary stem cells and we will study their pathway and the segment of incorporation of the progeny of these stem cells. Similarly we will study the effect of ureteric obstruction on the survival of these cells located in the papilla. Finally, we will test the effect of certain growth factors whose receptors will be identified in the microarray studies on protection, prevention or improvement of the renal disease. The discovery of adult stem cells in the kidney promises to yield important basic and clinical insight into the pathogenesis and treatment of renal disease.

当输尿管芽侵入后肾间质并诱导其转化为肾元上皮时，肾脏发育开始。后肾间质最终分为肾小球上皮、近端上皮、环状上皮和远端上皮。我们之前已经证明，后肾间质含有能够产生所有肾元节段的干细胞。干细胞是缓慢循环的细胞，因此当在DNA复制过程中被标记时，它们会保留标记。他们也