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：
10687826
负责人：
PAUL T SCHUMACKER
金额：
$ 60.76万
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/10687826
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 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 Sequences Rattus Recovery Regression Analysis Reporting Rodent Rodent Model Role Serum Stem cell transplant Surface Systems Biology Techniques Testing Time Tissues Transplantation Treatment Efficacy Ventricular Remodeling Work angiogenesis 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 myocardial injury neonatal human next generation non-invasive monitor novel overexpression 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 RNA 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之前的 R01 资助，我们一致证明新生儿 CPC (nCPC) 在修复受损心脏方面具有卓越功效与任何其他细胞类型相比，由于分泌组更有效，部分受热休克因子 1 控制 (HSF1)。 nCPC 临床成功的关键是确定其心肌恢复机制。最近报告了 aCDC 和 aCPC 之间的头对头比较，结果表明 aCPC 在基于细胞和体内再生测定中优于 aCDC 以无创监测活性。在体内移植的 aCPC 或 aCDC 中，我们纯化并分析了祖细胞特异性外泌体 (EXO) 通过使用我们之前发布的计算模型，从接受者总血浆 EXO 中提取。借助主成分分析（PCA）和偏最小二乘回归分析（PLSR），我们在 aCPC 衍生的循环 EXO 中识别出潜在影响的 miRNA 特征，这些特征驱动受损心肌的修复机制至少涉及两个重要过程：抗纤维化和由于这些原因，我们认为移植祖细胞的 miRNA 分析- 从受体血浆中分离出的 EXO 可以更准确地预测干细胞的临床结果然而，所鉴定的直接作用比培养的祖细胞或其 EXO 的 RNA 谱更重要。移植CPC内的miRNA在体内尚未确定，血浆miRNA如何变化细胞移植后的术后期间，最后该方法的有效性和因此，我们对血浆 EXO 进行了研究。反映了由恢复的亲代移植祖细胞触发的特定分子途径 Aim1 将验证受损心肌是否有血管生成和抗纤维化 mIR 预测。 CPC 的计算模型对于恢复缺血心肌至关重要，目标 2 将确定。通过 Aim3 计算模型，循环 EXO 的 mIR 成分在术后会发生怎样的变化。在大型动物临床前使用移植的 nCPC 扩展我们的计算模型的预测能力猪MI模型的成功完成将证明使用源自新生儿的祖细胞。组织具有最高的再生能力，这可能对临床成功至关重要。确定一种新的范例，用于基于细胞的疗法的更定量方法，以揭示非侵入性总的来说，这些发现将证明移植细胞的条件状态。循环祖细胞特异性外泌体作为液体活检的潜力，提供非侵入性窗口这些数据暗示了移植新生儿 CPC 的监测潜力。用于其他同种异体细胞疗法的细胞特异性外泌体。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Characterization and functionality of cardiac progenitor cells in congenital heart patients.

DOI：
10.1161/circulationaha.110.971622
发表时间：
2011-02-01
期刊：
Circulation
影响因子：
37.8
作者：
Mishra R;Vijayan K;Colletti EJ;Harrington DA;Matthiesen TS;Simpson D;Goh SK;Walker BL;Almeida-Porada G;Wang D;Backer CL;Dudley SC Jr;Wold LE;Kaushal S
通讯作者：
Kaushal S

Engineering patient-specific valves using stem cells generated from skin biopsy specimens.

DOI：
10.1016/j.athoracsur.2014.04.075
发表时间：
2014-09
期刊：
The Annals of thoracic surgery
影响因子：
0
作者：
D. Simpson;B. Wehman;Yekaterina Galat;Sudhish Sharma;Rachana Mishra;V. Galat;S. Kaushal
通讯作者：
D. Simpson;B. Wehman;Yekaterina Galat;Sudhish Sharma;Rachana Mishra;V. Galat;S. Kaushal

Clinical Progress in Cell Therapy for Single Ventricle Congenital Heart Disease.

DOI：
10.1161/circresaha.117.310702
发表时间：
2017-03-31
期刊：
Circulation research
影响因子：
20.1
作者：
Bittle GJ;Wehman B;Karathanasis SK;Kaushal S
通讯作者：
Kaushal S

Cardiosphere-derived cells from pediatric end-stage heart failure patients have enhanced functional activity due to the heat shock response regulating the secretome.

DOI：
10.1002/stem.1937
发表时间：
2015-04
期刊：
Stem cells (Dayton, Ohio)
影响因子：
0
作者：
Sharma S;Mishra R;Simpson D;Wehman B;Colletti EJ;Deshmukh S;Datla SR;Balachandran K;Guo Y;Chen L;Siddiqui OT;Kaushal S;Kaushal S
通讯作者：
Kaushal S

A strong regenerative ability of cardiac stem cells derived from neonatal hearts.