# The Role of C-Kit Positive Cardiac Progenitors in Maternal Diabetes-Induced Heart Defects and the Therapeutic Values of These Cells > **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $602,408 ## Abstract Project Summary 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 th... ## Key facts - **NIH application ID:** 9930125 - **Project number:** 5R01HL139060-04 - **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE - **Principal Investigator:** Sunjay Kaushal - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2020 - **Award amount:** $602,408 - **Award type:** 5 - **Project period:** 2017-08-01 → 2023-05-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/9930125 ## Citation > US National Institutes of Health, RePORTER application 9930125, The Role of C-Kit Positive Cardiac Progenitors in Maternal Diabetes-Induced Heart Defects and the Therapeutic Values of These Cells (5R01HL139060-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9930125. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*