Derivation of Smooth Muscle Lineages from Stem Cells

University Of Virginia Charlottesville, Charlottesville VA

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Abstract

DESCRIPTION (provided by applicant): A large number of major human diseases including coronary artery disease, hypertension, and asthma are associated with abnormal function of the smooth muscle cell (SMC). The long term goal of the studies in this proposal is to develop methods for producing SMC or SMC "progenitor" cells from various human multi-potential stem cell populations with the intent of potentially using these cells for a variety of clinical applications including: a) in vitro production of SMC tissues or cells for surgical repair or augmentation; and b) production of SM tissues or cells that are genetically engineered to express a desired therapeutic gene or agent. Of particular relevance to this grant application, we have developed unique experimental methods, employing SMC specific/selective promoter-enhancers initially characterized in our laboratory, that permit high efficiency induction, identification, and purification of SMC and SMC "progenitor" cells from multi-potential murine P19 stem cell populations. The studies outlined in this proposal will: 1) use representative difference analyses (RDA), and gene array analyses of unique P19 derived mouse SMC "progenitor" cell lines previously developed in our lab to identify markers of SMC progenitor cells, and/or genes that control early commitment/determination events in SMC (Aim 1); 2) test the applicability of our unique SM a-actin/SM MHC promoter-enhancer based screening methods for identifying and purifying SMC or SMC "progenitor" cells from various murine and human stem cell populations (Aim 2-3); and 3) characterize the properties of stem cell derived SMC and SMC "progenitors" upon surgical re-implantation in vivo (Aim 4). Taken together studies will provide novel insights of mechanisms that control specification of SMC during embryonic development, and lead to development of unique methods for producing SMC from stem cell sources for potential therapeutic applications.