Urologic Epithelial Stem Cells

University Of Washington, Seattle WA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): A population of epithelial progenitor cells with self-renewal capability resides in the adult human prostate and urinary bladder. Induced by diffusible signals, and cell-cell interaction with the proper stromal mesenchyme cells; the progenitor cells undergo differentiation to produce functionally mature cells. Thus, progenitor cells from either the prostate or the bladder will develop into prostatic structures when triggered by prostate-inducing stromal cells. For cell type analysis we will use the expression of cluster designation (CD) cell surface molecules to identify cell types in lineages. CD molecules are differentially expressed among the component cell types of organs, and are therefore ideally suited to such analysis. We propose to study the process of prostatic epithelial cell differentiation and to demonstrate possible genetic disorder that leads to abnormal cell proliferation characteristic of the common prostatic diseases of benign hyperplasia and cancer. Our objectives are: (1) to use fluorescent CD antibodies and confocal laser scanning microscopy to show that the progenitor cells found in diverse organs are phenotypically alike whereas the differentiated cells are phenotypically dissimilar with respect to their CD expression, and that distinct intermediate cell types can be identified; (2) to use flow cytometry to characterize and sort by CD expression (in particular, CD49b; CD49f, and CD71) progenitor cells, which are postulated to comprise a similar proportion in these and other organs; (3) to show by in vitro 3-D cell cultures that prostate morphogenesis (formation of ducts and glands) can be modeled with progenitor cells and stromal cell derived factors to give rise to the differentiated cell type of secretory luminal cells (one of the principal stromal factors is hepatocyte growth factor (HGF), which activates the morphogenetic program through its binding to tyrosine kinase receptor c-met on responsive epithelial cells); (4) to show that functional differentiation (as indicated by the synthesis of the abundant secretory protein, prostate-specific antigen (PSA), by luminal cells) requires epithelial/stromal cell-cell interaction; (5) to show that the differentially expressed CD10 and CD13 ectopeptidases play a role in luminal cell differentiation, since cancer cells, which are luminal-like, lack CD10 and CD13 expression; (6) to determine the transcriptome of progenitor cells, to identify differentially expressed genes between progenitor and differentiated cells, to screen for genes expressed by stromal cells that induce prostate epithelial differentiation; and (7) to build a public database of the experimental results obtained.