Department of Medicine, Division of Cardiovascular Diseases, Marriott Heart Disease Research Program, Mayo Clinic, Rochester, Minnesota 55905, USA.
J Am Coll Cardiol. 2010 Aug 24;56(9):721-34. doi: 10.1016/j.jacc.2010.03.066.
The goal of this study was to guide bone marrow-derived human mesenchymal stem cells (hMSCs) into a cardiac progenitor phenotype and assess therapeutic benefit in chronic myocardial infarction.
Adult stem cells, delivered in their naïve state, demonstrate a limited benefit in patients with ischemic heart disease. Pre-emptive lineage pre-specification may optimize therapeutic outcome.
hMSC were harvested from a coronary artery disease patient cohort. A recombinant cocktail consisting of transforming growth factor-beta(1), bone morphogenetic protein-4, activin A, retinoic acid, insulin-like growth factor-1, fibroblast growth factor-2, alpha-thrombin, and interleukin-6 was formulated to engage hMSC into cardiopoiesis. Derived hMSC were injected into the myocardium of a nude infarcted murine model and followed over 1 year for functional and structural end points.
Although the majority of patient-derived hMSC in their native state demonstrated limited effect on ejection fraction, stem cells from rare individuals harbored a spontaneous capacity to improve contractile performance. This reparative cytotype was characterized by high expression of homeobox transcription factor Nkx-2.5, T-box transcription factor TBX5, helix-loop-helix transcription factor MESP1, and myocyte enhancer factor MEF2C, markers of cardiopoiesis. Recombinant cardiogenic cocktail guidance secured the cardiopoietic phenotype across the patient cohort. Compared with unguided counterparts, cardiopoietic hMSC delivered into infarcted myocardium achieved superior functional and structural benefit without adverse side effects. Engraftment into murine hearts was associated with increased human-specific nuclear, sarcomeric, and gap junction content along with induction of myocardial cell cycle activity.
Guided cardiopoiesis thus enhances the therapeutic benefit of bone marrow-derived hMSC in chronic ischemic cardiomyopathy.
本研究旨在指导骨髓源性人间质干细胞（hMSC）向心脏祖细胞表型分化，并评估其在慢性心肌梗死中的治疗效果。
在缺血性心脏病患者中，以原始状态递送的成体干细胞疗效有限。预先指定谱系可能会优化治疗效果。
从冠状动脉疾病患者队列中采集 hMSC。设计了一种由转化生长因子-β（1）、骨形态发生蛋白-4、激活素 A、维甲酸、胰岛素样生长因子-1、成纤维细胞生长因子-2、α-凝血酶和白细胞介素-6 组成的重组鸡尾酒，用于诱导 hMSC 向心肌发生。将衍生的 hMSC 注射到裸鼠梗死模型的心肌中，并进行了 1 年以上的功能和结构终点随访。
尽管大多数源自患者的 hMSC 在其天然状态下对射血分数的影响有限，但少数个体的干细胞具有改善收缩性能的自发能力。这种修复性细胞表型的特征是高表达同源盒转录因子 Nkx-2.5、T 盒转录因子 TBX5、螺旋-环-螺旋转录因子 MESP1 和肌细胞增强因子 MEF2C，这些都是心肌发生的标志物。重组心脏发生指导确保了整个患者队列的心脏发生表型。与未指导的对照组相比，将心脏发生的 hMSC 递送到梗死的心肌中可获得更好的功能和结构获益，而没有不良反应。移植到鼠心中与增加人类特异性核、肌节和缝隙连接含量以及诱导心肌细胞周期活性有关。
因此，指导心脏发生增强了骨髓源性 hMSC 在慢性缺血性心肌病中的治疗效果。
