Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University School of Medicine, Atlanta, GA, USA; Molecular & Systems Pharmacology Graduate Training Program, Graduate Division of Biological & Biomedical Sciences, Laney Graduate School, Emory University, Atlanta, GA 30322, USA.
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University School of Medicine, Atlanta, GA, USA.
Genomics. 2022 May;114(3):110349. doi: 10.1016/j.ygeno.2022.110349. Epub 2022 Mar 26.
Stem/progenitor cells, including cardiac-derived c-kit+ progenitor cells (CPCs), are under clinical evaluation for treatment of cardiac disease. Therapeutic efficacy of cardiac cell therapy can be attributed to paracrine signaling and the release of extracellular vesicles (EVs) carrying diverse cargo molecules. Despite some successes and demonstrated safety, large variation in cell populations and preclinical/clinical outcomes remains a problem. Here, we investigated this variability by sequencing coding and non-coding RNAs of CPCs and CPC-EVs from 30 congenital heart disease patients and used machine learning methods to determine potential mechanistic insights. CPCs retained RNAs related to extracellular matrix organization and exported RNAs related to various signaling pathways to CPC-EVs. CPC-EVs are enriched in miRNA clusters related to cell proliferation and angiogenesis. With network analyses, we identified differences in non-coding RNAs which give insight into age-dependent functionality of CPCs. By taking a quantitative computational approach, we aimed to uncover sources of CPC cell therapy variability.
干细胞/祖细胞，包括心脏来源的 c-kit+祖细胞（CPCs），正在临床评估用于治疗心脏疾病。心脏细胞疗法的治疗效果可归因于旁分泌信号和携带各种货物分子的细胞外囊泡（EVs）的释放。尽管取得了一些成功并证明了安全性，但细胞群体和临床前/临床结果的巨大差异仍然是一个问题。在这里，我们通过对 30 例先天性心脏病患者的 CPCs 和 CPC-EVs 的编码和非编码 RNA 进行测序，并使用机器学习方法来确定潜在的机制见解，研究了这种可变性。CPCs 保留了与细胞外基质组织相关的 RNA，并将与各种信号通路相关的 RNA 输出到 CPC-EVs 中。CPC-EVs 富含与细胞增殖和血管生成相关的 miRNA 簇。通过网络分析，我们发现了非编码 RNA 的差异，这些差异深入了解了 CPC 随年龄变化的功能。通过采用定量计算方法，我们旨在揭示 CPC 细胞治疗变异性的来源。
