Adult stem cells demonstrate significant plasticity of their multipotent capabilities in response to cellular environment, and this is crucial for their functions in organ development and tissue homeostasis. In mammals, understanding how adult stem cell plasticity is regulated has been hampered by the complex cell organization and inadequate tools to dissect cellular interactions in vivo. Here, we propose to address this question in the mouse prostate epithelium, an excellent system for investigating the mechanism of stem cell regulations due to its well-defined cell lineage hierarchy and novel genetic tools available. Our discovery of the distinct multipotent capabilities of prostate basal cells in differnt developmental stages and physiological contexts has led us to focus on the roles of extracellular signaling and luminal-basal cell interactions in regulating basal cell plasticity. In three specific aims, we will dissect the developmental stage-dependent interplay of signaling pathways in basal cells; identify the mechanisms by which luminal cells regulate basal cell behaviors; and determine how basal cell proliferation affects its luminal differentiation. To achieve our goals, we will take an integrated approach of ex vivo tissue reconstitution, high-throughput molecular profiling, and genetic lineage tracing, in which genetic manipulation and cell behavior analysis can be simultaneously performed at individual cell level in native tissue environment in vivo. Given that basal and luminal cells together shape the organization of many epithelial tissues and that their dysregulation often precedes cancer initiation, our studies will provide significant insights into the development and maintenance of epithelial tissues, and will have important implications for understanding disease etiology.
Interactions of luminal and basal cells play critical roles in maintaining the normal organization of epitheliums in many tissues. By studying how prostate basal cell multipotency is regulated in the native cellular environment in mice, this proposal will impact understanding of tissue stem cell behaviors in both organ development and cancer initiation.
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