Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University School of Medicine, Atlanta, Georgia, USA.
Division of Pediatric Cardiology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.
Stem Cells Transl Med. 2019 Nov;8(11):1212-1221. doi: 10.1002/sctm.19-0059. Epub 2019 Aug 6.
Congenital heart disease can lead to severe right ventricular heart failure (RVHF). We have shown that aggregated c-kit progenitor cells (CPCs) can improve RVHF repair, likely due to exosome-mediated effects. Here, we demonstrate that miRNA content from monolayer (2D) and aggregated (3D) CPC exosomes can be related to in vitro angiogenesis and antifibrosis responses using partial least squares regression (PLSR). PLSR reduced the dimensionality of the data set to the top 40 miRNAs with the highest weighted coefficients for the in vitro biological responses. Target pathway analysis of these top 40 miRNAs demonstrated significant fit to cardiac angiogenesis and fibrosis pathways. Although the model was trained on in vitro data, we demonstrate that the model can predict angiogenesis and fibrosis responses to exosome treatment in vivo with a strong correlation with published in vivo responses. These studies demonstrate that PLSR modeling of exosome miRNA content has the potential to inform preclinical trials and predict new promising CPC therapies. Stem Cells Translational Medicine 2019;8:1212-1221.
先天性心脏病可导致严重的右心室心力衰竭（RVHF）。我们已经表明，聚集的 c-kit 祖细胞（CPCs）可以改善 RVHF 修复，这可能是由于外泌体介导的作用。在这里，我们证明使用偏最小二乘回归（PLSR），来自单层（2D）和聚集（3D）CPC 外泌体的 miRNA 含量可以与体外血管生成和抗纤维化反应相关。PLSR 将数据集的维数降低到具有体外生物学反应的最高加权系数的前 40 个 miRNA。对这前 40 个 miRNA 的靶通路分析表明，它们与心脏血管生成和纤维化通路具有显著的吻合度。尽管该模型是基于体外数据进行训练的，但我们证明该模型可以预测外泌体治疗体内血管生成和纤维化反应，与已发表的体内反应具有很强的相关性。这些研究表明，外泌体 miRNA 含量的 PLSR 建模有可能为临床前试验提供信息，并预测新的有前途的 CPC 治疗方法。《干细胞转化医学》2019；8:1212-1221.
