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.
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