Cedars-Sinai Heart Institute, 8700 Beverly Blvd, Los Angeles, CA 90048, USA.
Circ Res. 2010 Mar 19;106(5):971-80. doi: 10.1161/CIRCRESAHA.109.210682. Epub 2010 Jan 28.
Multiple biological mechanisms contribute to the efficacy of cardiac cell therapy. Most prominent among these are direct heart muscle and blood vessel regeneration from transplanted cells, as opposed to paracrine enhancement of tissue preservation and/or recruitment of endogenous repair.
Human cardiac progenitor cells, cultured as cardiospheres (CSps) or as CSp-derived cells (CDCs), have been shown to be capable of direct cardiac regeneration in vivo. Here we characterized paracrine effects in CDC transplantation and investigated their relative importance versus direct differentiation of surviving transplanted cells.
In vitro, many growth factors were found in media conditioned by human adult CSps and CDCs; CDC-conditioned media exerted antiapoptotic effects on neonatal rat ventricular myocytes, and proangiogenic effects on human umbilical vein endothelial cells. In vivo, human CDCs secreted vascular endothelial growth factor, hepatocyte growth factor, and insulin-like growth factor 1 when transplanted into the same SCID mouse model of acute myocardial infarction where they were previously shown to improve function and to produce tissue regeneration. Injection of CDCs in the peri-infarct zone increased the expression of Akt, decreased apoptotic rate and caspase 3 level, and increased capillary density, indicating overall higher tissue resilience. Based on the number of human-specific cells relative to overall increases in capillary density and myocardial viability, direct differentiation quantitatively accounted for 20% to 50% of the observed effects.
Together with their spontaneous commitment to cardiac and angiogenic differentiation, transplanted CDCs serve as "role models," recruiting endogenous regeneration and improving tissue resistance to ischemic stress. The contribution of the role model effect rivals or exceeds that of direct regeneration.
多种生物学机制有助于心脏细胞治疗的疗效。其中最主要的是移植细胞的直接心肌和血管再生，而不是旁分泌增强组织保存和/或募集内源性修复。
已证明培养的人心肌祖细胞（CSps）或 CSps 衍生细胞（CDCs）能够在体内直接进行心脏再生。在这里，我们对 CDC 移植中的旁分泌作用进行了特征描述，并研究了其与存活移植细胞的直接分化相比的相对重要性。
在体外，从人成体 CSps 和 CDC 中发现许多生长因子存在于条件培养基中；CDC 条件培养基对新生大鼠心室肌细胞具有抗凋亡作用，对人脐静脉内皮细胞具有促血管生成作用。在体内，当将人 CDC 移植到先前显示可改善功能和产生组织再生的同种 SCID 小鼠急性心肌梗死模型中时，其分泌血管内皮生长因子、肝细胞生长因子和胰岛素样生长因子 1。在心梗周边区注射 CDC 可增加 Akt 的表达，降低细胞凋亡率和 caspase 3 水平，并增加毛细血管密度，表明整体组织弹性更高。基于相对于毛细血管密度和心肌活力的总体增加的人特异性细胞数量，直接分化定量解释了观察到的作用的 20%至 50%。
与它们自发的心脏和血管生成分化承诺一起，移植的 CDC 充当“角色模型”，招募内源性再生并提高组织对缺血应激的抵抗力。角色模型效应的贡献可与直接再生相媲美或超过直接再生。
