Congenital heart defects (CHDs) are the most common birth defects. Pregestational maternal diabetes is a noninherited factor associated with a five-fold increase in CHDs and cardiac dysfunction. The underlying mechanism of diabetes-induced CHDs and cardiac dysfunction is unknown but one mechanism may involve inhibition of cardiogenesis by high glucose levels. c-Kit+ cardiac progenitor cells (CPCs) are now being studied as a potential treatment option for adult heart failure patients for stimulating cardiac function. Our preliminary studies have determined that both diabetes and high glucose in vitro induce a spectrum of cellular dysfunction in c-kit+ CPCs, that is implicated in the etiology of diabetes-induced CHDs. Eliminating c- kit+ CPCs during cardiogenesis led to CHDs resembling those in diabetic pregnancy offspring. Equally important is to determine the adverse programming effect caused during maternal diabetic exposure on the postnatal derived c-kit+ CPCs which will be used in our upcoming autologous based c-kit+ CHD trial. Therefore, we hypothesize that high glucose in diabetes induces cellular dysfunction in c-kit+ CPCs, which contributes to cardiac septation defects and limits the remodeling effect of post- natal derived c-kit+ CPCs on damaged hearts. Reducing cellular stress or DNA methylation or histone acetylation in c-kit+ CPCs alleviates maternal diabetes-induced CHDs, and improves the therapeutic value of ex vivo expanded c-kit+ CPCs by restoring their paracrine function. Studies are designed specifically to reveal the diabetes or high glucose on c-kit+ CPC function.
Aim 1 will determine whether cellular stress-induced c-kit+ CPCs dysfunction contributes to the teratogenicity of maternal diabetes. We hypothesize that diabetes triggers apoptosis and reduce cell proliferation of c-kit+ CPCs through cellular stress, which impairs cardiac septation and the function of critical cardiac septation regulators: second heart field progenitors and cardiac neural crest cells.
Aim 2 will determine whether enhanced histone acetylation and DNA methylation in c-kit+ CPCs mediate the adverse effects of maternal diabetes on cardiogenesis and imprinting on these progenitors. We hypothesize that diabetes-reduced sirtuin deacetylase 2 (SIRT2) causes DNA hypermethylation leading to c-kit+ CPCs cellular dysfunction that critically involve in altered cardiac septation and adverse imprinting.
Aim 3 will determine the therapeutic abilities of offspring derived c-kit+ CPCs and their exosomes from nondiabetic and diabetic mothers in a myocardial infarction model and embryonic hearts of diabetic pregnancy. We hypothesize that offspring derived c-kit+ CPCs from maternal diabetics have lower abilities in repairing CHDs and cardiac dysfunction due to miR-34a up-regulation, which alters secretome and exosome profiling compared with nondiabetic mothers, and retain high levels of cellular stress, histone acetylation and DNA methylation during CPC therapies.
Cardiac progenitor cell (CPC) therapy to congenital heart defects (CHDs) patients can further repair and improve cardiac function after surgical repair. Understanding the adverse effect of high glucose of maternal diabetes on offspring c-kit+ CPC biology and regenerative capability will provide importance guidance for optimizing c-kit+ CPC therapy to structural heart defects and offspring cardiac dysfunction in diabetic pregnancies.
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