Department of Bioengineering, Sanford Consortium for Regenerative Medicine, UC San Diego, USA.
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Emory University, USA.
J Mol Cell Cardiol. 2022 Oct;171:45-55. doi: 10.1016/j.yjmcc.2022.06.007. Epub 2022 Jul 1.
Congenital heart defects are the leading cause of right heart failure in pediatric patients. Implantation of c-kit cardiac-derived progenitor cells (CPCs) is being clinically evaluated to treat the failing right ventricle (RV), but faces limitations due to reduced transplant cell survival, low engraftment rates, and low retention. These limitations have been exacerbated due to the nature of cell delivery (narrow needles) and the non-optimal recipient microenvironment (reactive oxygen species (ROS)). Extracellular matrix (ECM) hydrogels derived from porcine left ventricular (LV) myocardium have emerged as a potential therapy to treat the ischemic LV and have shown promise as a vehicle to deliver cells to injured myocardium. However, no studies have evaluated the combination of an injectable biomaterial, such as an ECM hydrogel, in combination with cell therapy for treating RV failure. In this study we characterized LV and RV myocardial matrix (MM) hydrogels and performed in vitro evaluations of their potential to enhance CPC delivery, including resistance to forces experienced during injection and exposure to ROS, as well as their potential to enhance angiogenic paracrine signaling. While physical properties of the two hydrogels are similar, the decellularized LV and RV have distinct protein signatures. Both materials were equally effective in protecting CPCs against needle forces and ROS. CPCs encapsulated in either the LV MM or RV MM exhibited similar enhanced potential for angiogenic paracrine signaling when compared to CPCs in collagen. The RV MM without cells, however, likewise improved tube formation, suggesting it should also be evaluated as a potential standalone treatment.
先天性心脏缺陷是小儿右心衰竭的主要原因。植入 c-kit 心脏来源的祖细胞（CPCs）正在临床上评估用于治疗衰竭的右心室（RV），但由于移植细胞存活率降低、植入率低和保留率低而面临限制。这些限制因细胞递送的性质（细针）和非最佳受体微环境（活性氧（ROS））而加剧。源自猪左心室（LV）心肌的细胞外基质（ECM）水凝胶已成为治疗缺血性 LV 的潜在疗法，并已显示出作为将细胞递送至损伤心肌的载体的潜力。然而，尚无研究评估可注射生物材料（例如 ECM 水凝胶）与细胞疗法相结合治疗 RV 衰竭。在这项研究中，我们对 LV 和 RV 心肌基质（MM）水凝胶进行了表征，并对它们增强 CPC 递送的潜力进行了体外评估，包括对注射过程中所经历的力和 ROS 暴露的抵抗力，以及它们增强血管生成旁分泌信号的潜力。虽然两种水凝胶的物理性质相似，但去细胞化的 LV 和 RV 具有不同的蛋白质特征。两种材料在保护 CPC 免受针力和 ROS 方面同样有效。与 CPC 在胶原蛋白中的情况相比，包封在 LV MM 或 RV MM 中的 CPC 表现出类似增强的血管生成旁分泌信号的潜力。然而，没有细胞的 RV MM 同样改善了管形成，这表明它也应该作为一种潜在的独立治疗方法进行评估。
