Biological Characterization of Cardiac Stem Cells

心脏干细胞的生物学特性

• 批准号: 9249960
• 负责人: Sunjay Kaushal
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 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 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9249960
• 关键词: Affect; Age; Anatomy; Attenuated; Biological; Biology; Cardiac; Cardiac Myocytes; Cell Therapy; Cells; Characteristics; Child; Clinical; Clinical Research; Data; Disease; Frequencies; Future; Goals; Harvest; Heart; Heart Transplantation; Heart failure; Human; Hypoxia; In Vitro; Infarction; Left; Left Ventricular Function; Left atrial structure; Left ventricular structure; Location; Measures; Modeling; Molecular; Mus; Myocardial; Myocardium; Patients; Performance; Phase; Physiological; Population; Population Control; Proto-Oncogene Protein c-kit; Protocols documentation; Recovery; Recovery of Function; Research Design; Right atrial structure; Rodent Model; Role; Side; Signal Transduction; Site; Stem cells; Testing; Therapeutic; Therapeutic Intervention; Transplantation; United States; angiogenesis; base; cell type; clinically relevant; cytokine; improved; knock-down; public health relevance; stem cell biology; stem cell population; stem cell therapy; therapeutic target

DESCRIPTION (provided by applicant): We have demonstrated that human cardiac stem cells (hCSC) derived from end-stage heart failure (ESHF) hearts are markedly superior in improving post-infarct LV function in comparison to age-match control hCSC. The goal of this application is to characterize the molecular mechanisms underlying this improved performance of ESHF-derived hCSC and to optimize their harvest, molecular characterization and application in a clinically-relevant model of post-MI cardiac failure. Improvement of LV function in ESHF patients, particularly children with end- stage heart failure, via stem cell therapy is of enormous importance since heart transplantation is the only other viable option and in limited supply. Despite their encouraging clinical Phase I results, cardiosphere derived cells (CDCs), comprised of heterogeneous cell types, including c- kit+ cells, are still not well characterized1. Our preliminary data shows that ESHF-derived hCDCs isolated from the left atrium improve ischemic left ventricular function better than ESHF-derived hCDCs from the right atrium, but whether different functional activity is present in all other heart chamber-derived hCDCs is still unknown. Furthermore, since we document significantly higher numbers of c-kit+ cells within ESHF-derived CDCs, the frequency of the c-kit+ cells within CDCs may be critical to recovery of function. Finally, ESHF-derived CDCs secrete higher levels of angiogenic cytokines that correlates with increased angiogenesis in the infarcted myocardium and higher levels of HIF-1a, but the mechanism for the increased cytokine secretion is unclear. Our hypothesis is that the effect of ESHF-derived hCDCs in improving myocardial function is dependent on the anatomic site of hCDC origin and molecular mechanisms by c-kit+ and HIF- 1a. These studies will clarify the biology and function of hCDCs by determining: 1) chamber specific differences amongst hCDCs with the potential need to modify for a more powerful myocardial functional activity, 2) the effect of the frequency of c-kit+ cells on LV recovery, and lastly, 3) the role of HIF-1a as a master cytokine regulator of the myocardial function of ESHF- derived hCDCs. ESHF patients, particularly children, are potentially the most to benefit from hCDC based therapies. This application is the first study designed to determine critical characteristics of ESHF-derived hCDCs and to uncover new mechanisms of their functional activity in a manner that may eventually influence future therapeutic interventions.

描述（由申请人提供）：我们已经证明，与年龄匹配的对照 hCSC 相比，源自终末期心力衰竭 (ESHF) 心脏的人心脏干细胞 (hCSC) 在改善梗死后左心室功能方面明显优于。该应用的目标是表征 ESHF 衍生的 hCSC 性能改善的分子机制，并优化其收获、分子表征和在 MI 后心力衰竭临床相关模型中的应用。通过干细胞治疗改善 ESHF 患者（尤其是终末期心力衰竭儿童）的左心室功能具有巨大意义 重要性，因为心脏移植是唯一可行的选择，而且供应有限。尽管 I 期临床结果令人鼓舞，但由异质细胞类型（包括 c-kit+ 细胞）组成的心脏球衍生细胞 (CDC) 仍然没有得到很好的表征1。我们的初步数据表明，从左心房分离的 ESHF 衍生的 hCDC 比从右心房分离的 ESHF 衍生的 hCDC 更好地改善缺血性左心室功能，但在所有其他心室衍生的 hCDC 中是否存在不同的功能活性仍不清楚。此外，由于我们记录了 ESHF 衍生的 CDC 中 c-kit+ 细胞的数量显着增加，因此 CDC 中 c-kit+ 细胞的频率可能对功能恢复至关重要。最后，ESHF 衍生的 CDC 会分泌更高水平的血管生成细胞因子，这与梗塞心肌中血管生成的增加和 HIF-1a 水平的升高相关，但细胞因子分泌增加的机制尚不清楚。我们的假设是，ESHF 衍生的 hCDC 在改善心肌功能方面的作用取决于 hCDC 起源的解剖位点以及 c-kit+ 和 HIF-1a 的分子机制。这些研究将通过确定以下因素来阐明 hCDC 的生物学和功能：1) hCDC 之间的腔室特异性差异，可能需要进行修改以获得更强大的心肌功能活动，2) c-kit+ 细胞的频率对 LV 恢复的影响，最后，3) HIF-1a 作为 ESHF 衍生的 hCDC 心肌功能的主要细胞因子调节剂的作用。 ESHF 患者，尤其是儿童，可能最能从基于 hCDC 的治疗中受益。该应用是第一项旨在确定 ESHF 衍生的 hCDC 关键特征并揭示其功能活性新机制的研究，其方式可能最终影响未来的治疗干预。