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Mechanism of transplanted neonatal cardiac progenitor cells to repair ischemic myocardium

移植新生儿心脏祖细胞修复缺血心肌的机制

基本信息

批准号：
10117849
负责人：
Sunjay Kaushal
金额：
$ 64.32万
依托单位：
LURIE CHILDREN'S HOSPITAL OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-20 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10117849
关键词：
Activities of Daily Living Acute Adult Affect Age Allogenic Animal Model Animals Apoptosis Biological Assay Biological Markers Cardiac Cardiac Myocytes Cell Therapy Cell Transplantation Cells Centers for Disease Control and Prevention (U.S.)Characteristics Chronic Clinical Clinical Trials Computer Analysis Computer Models Congenital Heart Defects Coupled Data Detection Diagnosis Europe Family suidae Fibrosis Funding Gender Genes HLA-A gene Head Heart Injuries Heart Transplantation Human Human Resources Hypertrophy In Vitro Infarction Inflammation Inflammatory Least-Squares Analysis Left Ventricular Remodeling Measures Methodology MicroRNAs Microarray Analysis Modeling Molecular Monitor Myocardial Myocardial Infarction Myocardial Ischemia Myocardium Neonatal PTK2 gene Parents Pathway interactions Patients Phase Plasma Postoperative Period Preparation Principal Component Analysis Process Publishing RNA RNA Sequences Rattus Recovery Regression Analysis Reporting Rodent Rodent Model Role Serum Stem cell transplant Surface Systems Biology Techniques Testing Time Tissues Transplantation Treatment Efficacy Variant Ventricular Remodeling Work angiogenesis base cell type effective therapy exosome head-to-head comparison heart function heat-shock factor 1 immunoregulation improved in vivo injured injury and repair liquid biopsy neonatal human next generation non-invasive monitor novel phase III trial pre-clinical predict clinical outcome prevent progenitor regenerative repaired response stem cell differentiation stem cell exosomes stem cell therapy stem cells success therapeutic miRNA transcriptome sequencing wound response

项目摘要

Using our unique resource of human neonatal cardiac tissue and funded through our previous R01, we have consistently demonstrated that neonatal CPCs (nCPCs) have superior efficacy in repairing the injured heart compared to any other cell type due to a more potent secretome controlled partly by the heat shock factor 1 (HSF1). Critical to the nCPC’s clinical success will be determining their mechanism of myocardial recovery. We have recently reported a head to head comparison between aCDCs and aCPCs that demonstrated that aCPCs outperformed the aCDCs in cell-based and in vivo regenerative assays. To noninvasively monitor the activity of the transplanted aCPCs or aCDCs in vivo, we purified and interrogated progenitor-specific exosomes (EXOs) from the recipient total plasma EXOs. By using our previously published computational modeling which takes advantage of principal component analysis (PCA) and partial least squares regression analysis (PLSR), we identified potentially impactful miRNA signatures within aCPCs–derived circulating EXOs that drives mechanisms of repair in the injured myocardium involving at least two important processes: antifibrosis and increased angiogenesis. For these reasons, we believe that miRNA profiling of transplanted progenitor cell– derived EXOs isolated from recipient plasma more accurately predicts the clinical outcomes seen with stem cell therapy than the RNA profiles of cultured progenitor cells or their EXOs. However, the direct role of the identified miRNAs within transplanted CPCs have not yet been determined in vivo, how the plasma miRNAs change during the post-operative period after cell transplantation, and finally the validity of this methodology and computational modeling in a large preclinical animal model. Thus, we hypothesize that the plasma EXOs reflects specific molecular pathways triggered by the parent transplanted progenitor cells that recovers the injured myocardium. Aim1 will validate whether angiogenesis and antifibrosis mIRs predicted by computational modeling for CPCs are essential for recovering the ischemic myocardium. Aim 2 will determine how the circulating EXOs mIR composition changes post-operatively by computational modeling. Aim3 will expand the predictive capacity of our computational model using transplanted nCPCs in a large animal preclinical porcine MI model. Successful completion will demonstrate that the use of progenitor cells derived from neonatal tissue has the highest regenerative abilities which maybe critical for the clinical success. In addition, we will determine a new paradigm for a more quantitative methodology for cell based therapies to reveal a noninvasive window into the conditional state of the transplanted cells. Collectively, these findings will demonstrate the potential of circulating progenitor cell–specific exosomes as a liquid biopsy that provides a noninvasive window into the conditional state of the transplanted neonatal CPCs. These data implicate the surveillance potential of cell-specific exosomes for other allogeneic cell based therapies.

利用我们独特的人类新生儿心脏组织资源并通过我们之前的R01资助，我们