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Restoration of myocardial reparative function of diabetic progenitor cells by epigenetic modulation

通过表观遗传调节恢复糖尿病祖细胞的心肌修复功能

基本信息

批准号：
10521253
负责人：
Raj Kishore
金额：
$ 56.03万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-10 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10521253
关键词：
American Animals Attenuated Azacitidine Blood Vessels Bone Marrow CD34 gene Cardiac Cardiovascular Diseases Cell Reprogramming Cell Therapy Cell division Cells Clinical Clinical Trials Coupled DNA Modification Methylases DNMT3a Diabetes Mellitus Diabetic mouse Endothelium Enzymes Epigenetic Process Functional disorder G9a histone methyltransferase Gene Expression Genes Goals HDAC1 gene Heart Diseases Heart failure Hematopoietic stem cells Histone Acetylation Histone Deacetylase Histones Human Hyperglycemia Impairment In Vitro Inherited Ischemia Lysine Mediator Memory Methylation Methyltransferase MicroRNAs Modeling Modification Molecular Morbidity - disease rate Mus Myocardial Myocardial Infarction Myocardial Ischemia Natural regeneration Non-Insulin-Dependent Diabetes Mellitus Outcome Patients Pattern Perfusion Pharmaceutical Preparations Phenotype Physiological Process Property Public Health Publishing Research Role Sequential Treatment Testing Tissues Valproic Acid Vascular Diseases adult stem cell angiogenesis critical limb Ischemia daughter cell db/db mouse diabetic diabetic patient differential expression disability endothelial stem cell epigenetic silencing exosome experimental study functional disability functional restoration gene repression genome wide methylation heart disease risk histone modification improved in vivo inhibitor ischemic injury limb ischemia mortality mouse model neovascularization novel strategies novel therapeutic intervention pre-clinical research progenitor programs promoter regenerative cell repair function repaired reparative capacity restoration small molecule small molecule inhibitor stem cell function stem cell survival stem cells targeted agent tissue repair transmission process

项目摘要

In the absence of effective endogenous repair mechanisms after ischemic injury, cell-based therapies have emerged as a potential novel therapeutic approach in ischemic tissue repair. After the initial characterization of putative bone marrow-derived endothelial progenitor cells (EPC) and their potential to promote cardiac and critical limb ischemia neovascularization and to attenuate ischemic injury, more than a decade of intense preclinical research, led to the BM progenitors/EPC-based clinical trials. However, despite early enthusiasm, cell based therapies yielded modest clinical results. Modest clinical outcomes of cell-based therapies may reflect the cellular dysfunction that is known to ensue in EPC/progenitor cells obtained from diabetic animals as well as patients. Compelling evidence indicates that EPCs dysfunction represents a mechanism for impaired vascular repair and angiogenesis in diabetes, subsequently leading to vascular dysfunction. Therefore, understanding the molecular basis of diabetes-induced EPC dysfunction and potentially reversing EPC dysfunction may represent a strategy to enhance cell-based therapeutics for myocardial/ischemic limb repair in diabetic patients. Increasing evidence also indicates that the mechanism underlying hyperglycemic memory and EPC dysfunction may involve epigenetic mechanisms involving enhanced epigenetic repressive marks on vascular genes leading to their epigenetic silencing. Moreover, since hyperglycemic memory is inherited through cell division, and altered epigenetic patterns in diabetic EPCs can be transmitted to daughter cells. Understanding the epigenetic basis of EPC dysfunction in diabetics and epigenetic reprogramming of diabetic EPCs, is therefore, of paramount importance for cell based therapies in diabetic patients. Therefore, our central hypothesis is that epigenetic repressive marks in diabetic EPCs render them dysfunctional and epigenetic modifying agents targeting those repressive marks can reprogram diabetic EPCs to a more functional and reparative phenotype. This project aims to study, in detail, phenotypic, epigenetic and molecular characterization of reprogrammed diabetic EPCs from diabetic mice as well as human CD34+ hematopoietic stem cells from diabetic patients and their exosome derivatives and test the ischemic myocardial repair capacity of these reprogrammed diabetic EPCs in physiologically relevant model of MI and hind limb ischemia. This overall aim will be achieved by conducting experiments organized under the following three specific aims: 1) To evaluate phenotypic stability and reparative potential of epigenetically reprogrammed diabetic EPCs; 2) To determine the specific epigenetic modifications in reprogrammed EPCs and establish a role of HDAC1 and G9a methytransferase in reprogramming process and 3) To establish epigenetic reprogramming rescues functional and reparative deficits in human CD34+ stem cells from patients with Type 2 diabetes.

在缺血损伤后缺乏有效的内源性修复机制的情况下，基于细胞的治疗已经出现