San Diego Heart Research Institute, San Diego State University, 5500 Campanile Drive, San Diego, CA, 92182, USA.
Nat Commun. 2020 Aug 7;11(1):3955. doi: 10.1038/s41467-020-17742-z.
Cellular therapy to treat heart failure is an ongoing focus of intense research, but progress toward structural and functional recovery remains modest. Engineered augmentation of established cellular effectors overcomes impediments to enhance reparative activity. Such 'next generation' implementation includes delivery of combinatorial cell populations exerting synergistic effects. Concurrent isolation and expansion of three distinct cardiac-derived interstitial cell types from human heart tissue, previously reported by our group, prompted design of a 3D structure that maximizes cellular interaction, allows for defined cell ratios, controls size, enables injectability, and minimizes cell loss. Herein, mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs) and c-Kit cardiac interstitial cells (cCICs) when cultured together spontaneously form scaffold-free 3D microenvironments termed CardioClusters. scRNA-Seq profiling reveals CardioCluster expression of stem cell-relevant factors, adhesion/extracellular-matrix molecules, and cytokines, while maintaining a more native transcriptome similar to endogenous cardiac cells. CardioCluster intramyocardial delivery improves cell retention and capillary density with preservation of cardiomyocyte size and long-term cardiac function in a murine infarction model followed 20 weeks. CardioCluster utilization in this preclinical setting establish fundamental insights, laying the framework for optimization in cell-based therapeutics intended to mitigate cardiomyopathic damage.
细胞疗法治疗心力衰竭是目前研究的重点，但结构和功能的恢复进展仍然有限。通过工程增强已建立的细胞效应器可以克服增强修复活性的障碍。这种“下一代”的实施方法包括输送协同作用的组合细胞群。我们小组之前曾报道过从人类心脏组织中同时分离和扩增三种不同的心脏衍生间质细胞类型，这促使我们设计了一种 3D 结构，最大限度地增加细胞间的相互作用，允许定义细胞比例，控制大小，实现可注射性，并最大限度地减少细胞损失。在此，间质干细胞（MSCs）、内皮祖细胞（EPCs）和 c-Kit 心脏间充质细胞（cCICs）在培养时会自发形成无支架 3D 微环境，称为 CardioClusters。scRNA-Seq 分析显示，CardioCluster 表达与干细胞相关的因子、黏附/细胞外基质分子和细胞因子，同时保持更类似于内源性心脏细胞的天然转录组。在心肌梗塞模型中，CardioCluster 心肌内给药可提高细胞保留率和毛细血管密度，同时保持心肌细胞大小和长期心脏功能，该模型在 20 周后进行了研究。CardioCluster 在这一临床前环境中的应用为优化旨在减轻心肌病损伤的基于细胞的治疗奠定了基础，为其提供了重要的见解。
