The Role of C-Kit Positive Cardiac Progenitors in Maternal Diabetes-Induced Heart Defects and the Therapeutic Values of These Cells

C-Kit 阳性心脏祖细胞在母亲糖尿病引起的心脏缺陷中的作用以及这些细胞的治疗价值

• 批准号: 9403962
• 负责人: Sunjay Kaushal
• 金额: $ 60.24万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9403962
• 关键词: Adult; Adverse effects; Affect; Antioxidants; Apoptosis; Autologous; Biological; Birth; Cardiac; Cell Cycle; Cell Proliferation; Cell Therapy; Cell physiology; Cells; Cellular Stress; Cellular biology; Congenital Abnormality; Congenital Heart Defects; Cyclin D1; DNA; DNA Methylation; DNA Modification Methylases; DNMT3a; Data; Deacetylase; Defect; Diabetes Mellitus; Diabetic mother; Embryonic Development; Embryonic Heart; Enzymes; Etiology; Fetal Therapies; Functional disorder; Glucose; Heart; Heart Abnormalities; Heart failure; Histone Acetylation; Hypermethylation; Impairment; In Vitro; Inositol; Mediating; Methylation; Modeling; Morphogenesis; Mothers; Myocardial; Myocardial Infarction; Myocardial dysfunction; Neonatal; Neural Crest Cell; Operative Surgical Procedures; Oxidative Stress; Patients; Phenylbutyrates; Pregnancy; Pregnancy in Diabetics; Proto-Oncogene Protein c-kit; Role; Sirtuins; Stem cells; Stress; Teratogens; Therapeutic; Transplantation; Up-Regulation; base; cardiogenesis; cyclin D3; design; diabetic; exosome; imprint; improved; in vivo; inhibitor/antagonist; maternal diabetes; mouse model; non-diabetic; offspring; overexpression; paracrine; phase 1 study; postnatal; progenitor; promoter; regenerative; repaired; structural heart disease; superoxide dismutase 1

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 therapies.

项目摘要 先天性心脏病是最常见的出生缺陷。妊娠期糖尿病是 一种与冠心病和心脏功能障碍增加五倍相关的非遗传因素。潜在的 糖尿病引起的冠心病和心功能不全的机制尚不清楚，但有一种机制可能 包括通过高糖水平抑制心脏生成。C-Kit+心脏祖细胞(CPC)现在 正在研究作为成人心力衰竭患者刺激心功能的潜在治疗选择。 我们的初步研究已经确定，糖尿病和高血糖在体外都会诱导一系列 C-kit+CPC中的细胞功能障碍，这与糖尿病诱导的冠心病的病因有关。消除c- 在心脏发生过程中，KIT+CPC导致类似于糖尿病妊娠后代的CHDS。同样 重要的是要确定在母亲糖尿病暴露期间对 出生后衍生的c-Kit+CPC将用于我们即将进行的基于自体的c-Kit+CHD试验。 因此，我们假设糖尿病患者的高血糖导致c-kit+细胞功能障碍。 它导致心脏间隔缺陷，限制了心脏重构的作用。 Natal在受损心脏上衍生c-kit+CPC。减少细胞压力或DNA甲基化或 C-kit+CPC中组蛋白乙酰化可缓解母体糖尿病引起的冠心病，并改善 体外扩增的c-kit+CPC恢复旁分泌功能的治疗价值。研究 都是专为揭示糖尿病或高血糖对c-kit+CPC的作用而设计的。目标1将 确定细胞应激诱导的c-kit+CPC功能障碍是否与致畸有关 产妇糖尿病的症状。我们假设糖尿病触发细胞凋亡并减少c-kit+的细胞增殖 通过细胞应激，损害心脏间隔和临界心脏间隔的功能 调节因子：第二心域前体细胞和心脏神经脊细胞。目标2将决定是否 C-kit+CPC中组蛋白乙酰化和DNA甲基化增强介导的不良反应 母体糖尿病对心脏生成和这些祖细胞的印记。我们假设 糖尿病降低的sirtuin脱乙酰酶2(SIRT2)导致DNA高甲基化导致c-kit+CPC 严重涉及心脏间隔改变和不良印迹的细胞功能障碍。目标3将 检测子代c-kit+CPC及其外切体的治疗能力 非糖尿病和糖尿病母亲的心肌梗死模型和糖尿病患者胚胎心脏 怀孕了。我们假设母体糖尿病患者的后代c-kit+cpc的能力较低。 在修复由miR-34a上调引起的CHDS和心功能障碍方面，miR-34a上调改变了分泌组和 外切体谱与非糖尿病母亲相比，并保持高水平的细胞应激，组蛋白 CPC治疗中的乙酰化和DNA甲基化。