National Medical Research Center of Cardiology, Russian Ministry of Health, Moscow 121552, Russia.
Federal Center of Brain Research and Neurotechnologies, Federal Medical Biological Agency, Moscow 117997, Russia.
Int J Mol Sci. 2020 Dec 16;21(24):9603. doi: 10.3390/ijms21249603.
Cell therapy of the post-infarcted myocardium is still far from clinical use. Poor survival of transplanted cells, insufficient regeneration, and replacement of the damaged tissue limit the potential of currently available cell-based techniques. In this study, we generated a multilayered construct from adipose-derived mesenchymal stromal cells (MSCs) modified to secrete stem cell factor, SCF. In a rat model of myocardium infarction, we show that transplantation of SCF producing cell sheet induced activation of the epicardium and promoted the accumulation of c-kit positive cells in ischemic muscle. Morphometry showed the reduction of infarct size (16%) and a left ventricle expansion index (0.12) in the treatment group compared to controls (24-28%; 0.17-0.32). The ratio of viable myocardium was more than 1.5-fold higher, reaching 49% compared to the control (28%) or unmodified cell sheet group (30%). Finally, by day 30 after myocardium infarction, SCF-producing cell sheet transplantation increased left ventricle ejection fraction from 37% in the control sham-operated group to 53%. Our results suggest that, combining the genetic modification of MSCs and their assembly into a multilayered construct, we can provide prolonged pleiotropic effects to the damaged heart, induce endogenous regenerative processes, and improve cardiac function.
心肌梗死后的细胞治疗仍远未临床应用。移植细胞存活率低、再生不足、损伤组织替代有限，限制了现有基于细胞技术的潜力。在这项研究中，我们从脂肪来源的间充质基质细胞（MSCs）构建了一个多层结构，这些细胞被修饰为分泌干细胞因子（SCF）。在大鼠心肌梗死模型中，我们发现 SCF 产生细胞片的移植激活了心外膜，并促进了 c-kit 阳性细胞在缺血肌肉中的积累。形态计量学显示，与对照组（24-28%；0.17-0.32）相比，治疗组的梗死面积减少（16%）和左心室扩张指数（0.12）。存活心肌的比例增加了 1.5 倍以上，达到 49%，而对照组（28%）或未修饰的细胞片组（30%）。最后，在心肌梗死后 30 天，SCF 产生的细胞片移植将对照组假手术组的左心室射血分数从 37%提高到 53%。我们的结果表明，通过对 MSCs 进行基因修饰并将其组装成多层结构，我们可以为受损心脏提供长期的多效性作用，诱导内源性再生过程，并改善心功能。
