Hoffman Jessica R, Park Hyun-Ji, Bheri Sruti, Platt Manu O, Hare Joshua M, Kaushal Sunjay, Bettencourt Judith L, Lai Dejian, Slesnick Timothy C, Mahle William T, Davis Michael E
Wallace H. Coulter Department of Biomedical Engineering, Emory University School of Medicine & Georgia Institute of Technology, Atlanta, GA 30322, USA.
Molecular & Systems Pharmacology Graduate Training Program, Laney Graduate School, Emory University, Atlanta, GA 30322, USA.
iScience. 2023 Sep 21;26(10):107980. doi: 10.1016/j.isci.2023.107980. eCollection 2023 Oct 20.
Cardiac-derived c-kit+ progenitor cells (CPCs) are under investigation in the CHILD phase I clinical trial (NCT03406884) for the treatment of hypoplastic left heart syndrome (HLHS). The therapeutic efficacy of CPCs can be attributed to the release of extracellular vesicles (EVs). To understand sources of cell therapy variability we took a machine learning approach: combining bulk CPC-derived EV (CPC-EV) RNA sequencing and cardiac-relevant experiments to build a predictive model. We isolated CPCs from cardiac biopsies of patients with congenital heart disease (n = 29) and the lead-in patients with HLHS in the CHILD trial (n = 5). We sequenced CPC-EVs, and measured EV inflammatory, fibrotic, angiogeneic, and migratory responses. Overall, CPC-EV RNAs involved in pro-reparative outcomes had a significant fit to cardiac development and signaling pathways. Using a model trained on previously collected CPC-EVs, we predicted outcomes for the CHILD clinical samples. Finally, CPC-EV angiogenic performance correlated to clinical improvements in right ventricle performance.
心脏来源的c-kit+祖细胞（CPCs）正在儿童I期临床试验（NCT03406884）中接受研究，用于治疗左心发育不全综合征（HLHS）。CPCs的治疗效果可归因于细胞外囊泡（EVs）的释放。为了了解细胞治疗变异性的来源，我们采用了机器学习方法：结合大量CPC来源的EV（CPC-EV）RNA测序和心脏相关实验来建立预测模型。我们从先天性心脏病患者（n = 29）的心脏活检组织以及儿童试验中HLHS的导入患者（n = 5）中分离出CPCs。我们对CPC-EVs进行了测序，并测量了EV的炎症、纤维化、血管生成和迁移反应。总体而言，参与促修复结果的CPC-EV RNAs与心脏发育和信号通路有显著的契合度。使用基于先前收集的CPC-EVs训练的模型，我们预测了儿童临床样本的结果。最后，CPC-EV血管生成性能与右心室性能的临床改善相关。
