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Cardiac progenitor cells support optimal heart function and repair
Bailey, Brandi Lynn
Heart disease remains a serious and intractable disease resulting in decreased productivity and increased mortality throughout the world. Cardiac Progenitor Cells (CPCs) have been shown to be a potential cellular therapeutic approach to blunt tissue damage and facilitate reparative and regenerative processes after myocardial infarction (MI). Cardiac progenitor cells are important for maintenance of myocardial structure and function, but molecular mechanisms governing CPCs remain obscure and require elucidation to enhance regenerative therapeutic approaches. Normal CPCs engineered with fluorescent reporter protein constructs under control of the _MHC promoter show transgene protein expression, confirming activity of the promoter in CPCs. Cultured CPCs from both non-transgenic and cardiac-specific transgenic mice expressing survival kinases driven by the _-MHC promoter were analyzed to characterize transgene expression following treatments to promote differentiation in culture. Green fluorescent protein under regulatory control of the endogenous Sca-1 promoter is present in vascular structures in mature mice. However, lack of Sca-1 does not result in a primary vascular defect. Instead, genetic deletion of Sca-1 results in early-onset cardiac contractile deficiency as determined by echocardiography and hemodynamics. ScaKI mice show compromised capacity to survive myocardial infarction relative to normal control subjects. Resident cardiac progenitor cells in ScaKI mice do not respond to pathological damage in vivo, consistent with observations of impaired growth and survival of ScaKI cardiac progenitor cells in vitro. Genetic deletion of Sca-1 causes primary cardiac defects in myocardial contractility and repair. These defects are likely due to impairment of resident cardiac progenitor cell proliferative capacity, possibly through altered Lef1 transcription factor expression. Thus, disruption of cardiac progenitor cells results in a heart that is slightly impaired in normal function with greatly reduced capacity to repair itself after injury. CPCs have also been shown to respond to aging or general cardiomyopathy as damage. CPCs can be isolated and cultured from middle-aged hearts but they exhibit slightly impaired growth kinetics. The CPCs used for autologous cardiac progenitor cell therapy purposes would most likely benefit more from genetic engineering to increase proliferation and survival but they are still capable of supporting cardiac function in the context of aging and disease.
Doctor of Philosophy (Ph.D.) University of California, San Diego and San Diego State University, 2011
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