Treatment for heart failure with combination of stem cell sheet technology and sustained release of growth factors

本研究利用缺血性心肌病动物模型，建立了基于多能干细胞（ES/iPS细胞）的终末期心力衰竭治疗方法。首先，我们注射小鼠ES细胞来源的和FACS纯化的心肌细胞（CMs）用于大鼠亚急性心肌梗死（MI）模型。然而，由于植入效率低，治疗效果受到限制。接下来，我们使用温度响应性培养皿（UpCell，CellSeed Inc.）以提高效率，并进行ESC衍生的心脏细胞片移植。我们发现，移植的细胞片改善心肌梗死后的心功能障碍，由于通过各种旁分泌效应，主要是新血管形成减弱左心室重构。我们还表明，旁分泌效应主要由分化的CM介导（Masumoto H，Ikeda T等人，Stem Cells，2012）。此外，我们发现，人iPSC衍生的心脏细胞片移植到大鼠亚急性MI模型中也显示出通过新血管形成的功能改善（AHA 2012摘要#11848）。我们清楚地表明，细胞片移植是提高基于多能干细胞的心脏再生的治疗效果的有前途的方法之一。我们还显示了人iPSC衍生的心脏细胞片的优异治疗潜力。这一结果有助于实现基于iPSC的心脏再生治疗。

We performed a pre-clinical research to establish pluripotent stem cell (ES/iPS cell)-based therapy for terminal heart failure using ischemic cardiomyopathy animal model. First we injected mouse ES cell-derived and FACS-purified cardiomyocytes (CMs) for rat subacute myocardial infarction (MI) model. However, the therapeutic effect was limited because of low efficiency of engraftment. Next we employed cell sheet technology using temperature-responsive culture dishes (UpCell, CellSeed Inc.) to improve the efficiency, and performed ESC-derived cardiac cell sheet transplantation. We showed that transplantation of the cell sheets ameliorates cardiac dysfunction after MI due to attenuated left ventricular remodeling through various paracrine effects, mainly neovascularization. We also indicated that the paracrine effects are mainly mediated by differentiated CMs (Masumoto H, Ikeda T et al, Stem Cells, 2012). Furthermore, we showed that human iPSC-derived cardiac cell sheet transplantation to rat subacute MI model also showed functional improvement through neovascularization (AHA 2012 abstract #11848). We clearly showed that cell sheet transplantation is one of the promising methods to improve therapeutic effects on pluripotent stem cell-based cardiac regeneration. We also showed excellent therapeutic potential of human iPSC-derived cardiac cell sheets. This result helps to realize iPSC-based cardiac regenerative therapy.