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

• 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
• 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

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，并通过我们以前的R 01资助，我们 已经一致证明新生儿CPC（nCPC）在修复受损心脏方面具有上级功效 与任何其他细胞类型相比，由于部分由热休克因子1控制的更有效的分泌组， （HSF 1）。nCPC临床成功的关键是确定其心肌恢复机制。我们 最近报道了aCDC和aCPC之间的头对头比较，表明aCPC 在基于细胞的和体内再生测定中优于aCDC。非侵入性地监测 在体内移植的aCPC或aCDC，我们纯化并询问祖细胞特异性外泌体（EXO）， 从受体的全部血浆EXO中分离出来通过使用我们以前发表的计算模型， 利用主成分分析（PCA）和偏最小二乘回归分析（PLSR）的优点， 在aCPC来源的循环EXO中鉴定出潜在影响力的miRNA特征， 损伤心肌的修复机制涉及至少两个重要过程：抗纤维化和 增加血管生成。基于这些原因，我们认为移植祖细胞的miRNA谱- 从受体血浆中分离的衍生EXO更准确地预测干细胞治疗的临床结果 与培养的祖细胞或它们的EXO的RNA谱相比，然而，确定的直接作用 移植的CPC内的miRNAs尚未在体内确定，血浆miRNAs如何变化， 在细胞移植后的手术后阶段，最后，这种方法的有效性， 在大型临床前动物模型中的计算建模。因此，我们假设等离子体EXO 反映了由恢复的亲本移植祖细胞触发的特定分子途径， 受损的心肌Aim 1将验证是否血管生成和抗纤维化的miR预测 CPC的计算建模对于恢复缺血心肌是必不可少的。目标2将决定 通过计算建模，循环EXO mIR组成在手术后如何变化。AIM 3将 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。成功完成将证明使用来自新生儿的祖细胞 组织具有最高的再生能力，这可能是临床成功的关键。此外，我们将 确定一个新的范例，为基于细胞的治疗提供更定量的方法，以揭示一种非侵入性的 观察移植细胞的条件状态总的来说，这些发现将证明 循环祖细胞特异性外泌体作为液体活检提供非侵入性窗口的潜力 移植的新生儿CPC的条件状态。这些数据表明， 用于其他基于同种异体细胞的疗法的细胞特异性外泌体。

项目成果

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

• DOI: 10.1161/circulationaha.111.084699
• 发表时间: 2012-09-11
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Simpson DL;Mishra R;Sharma S;Goh SK;Deshmukh S;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)
• 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

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
• 作者: D. Simpson;B. Wehman;Yekaterina Galat;Sudhish Sharma;Rachana Mishra;V. Galat;S. Kaushal

A Deep Proteome Analysis Identifies the Complete Secretome as the Functional Unit of Human Cardiac Progenitor Cells.

• DOI: 10.1161/circresaha.116.309782
• 发表时间: 2017-03-03
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Sharma S;Mishra R;Bigham GE;Wehman B;Khan MM;Xu H;Saha P;Goo YA;Datla SR;Chen L;Tulapurkar ME;Taylor BS;Yang P;Karathanasis S;Goodlett DR;Kaushal S
• 通讯作者: Kaushal S