Institute for Regenerative Medicine (IREM), University of Zurich, Zurich, Switzerland; Clinic for Cardiac Surgery, University Hospital of Zurich, Zurich, Switzerland; Wyss Translational Center Zurich, ETH and University of Zurich, Zurich, Switzerland; Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, USA.
Clinic for Cardiac Surgery, University Hospital of Zurich, Zurich, Switzerland.
Biomaterials. 2017 Apr;122:48-62. doi: 10.1016/j.biomaterials.2016.11.029. Epub 2016 Nov 23.
To date, clinical success of cardiac cell-therapies remains limited. To enhance the cardioreparative properties of stem cells, the concept of lineage-specification through cardiopoietic-guidance has been recently suggested. However, so far, only results from murine studies and from a clinical pilot-trial in chronic heart-failure (CHF) are available, while systematic evidence of its therapeutic-efficacy is still lacking. Importantly, also no data from large animals or for other indications are available. Therefore, we here investigate the therapeutic-efficacy of human cardiopoietic stem cells in the treatment of post-infarction LV-dysfunction using a translational pig-model. Using growth-factor priming, lineage-specification of human bone-marrow derived MSCs was achieved to generate cardiopoietic stem cells according to GMP-compliant protocols. Thereafter, pigs with post-infarction LV-dysfunction (sub-acute phase;1-month) were randomized to either receive transcatheter NOGA 3D electromechanical-mapping guided intramyocardial transplantation of cardiopoietic cells or saline (control). After 30days, cardiac MRI (cMRI) was performed for functional evaluation and in-vivo cell-tracking. This approach was coupled with a comprehensive post-mortem cell-fate and mode-of-repair analysis. Cardiopoietic cell therapy was safe and ejection-fraction was significantly higher when compared to controls (p = 0.012). It further prevented maladaptive LV-remodeling and revealed a significantly lower relative and total infarct-size (p = 0.043 and p = 0.012). As in-vivo tracking and post-mortem analysis displayed only limited intramyocardial cardiopoietic cell-integration, the significant induction of neo-angiogenesis (∼40% higher; p = 0.003) and recruitment of endogenous progenitors (∼2.5x higher; p = 0.008) to the infarct border-zone appeared to be the major modes-of-repair. This is the first report using a pre-clinical large animal-model to demonstrate the safety and efficacy of cardiopoietic stem cells for the treatment of post-infarction LV-dysfunction to prevent negative LV-remodeling and subsequent CHF. It further provides insight into post-delivery cardiopoietic cell-fate and suggests the mechanisms of cardiopoietic cell-induced cardiac-repair. The adoption of GMP-/GLP-compliant methodologies may accelerate the translation into a phase-I clinical-trial in patients with post-ischemic LV-dysfunction broadening the current indication of this interesting cell-type.
迄今为止，心脏细胞疗法的临床疗效仍然有限。为了增强干细胞的心脏修复特性，最近提出了通过心脏发生指导来指定谱系的概念。然而，到目前为止，只有来自鼠类研究和慢性心力衰竭（CHF）的临床初步试验的结果可用，而其治疗效果的系统证据仍然缺乏。重要的是，也没有来自大型动物或其他适应症的数据。因此，我们在此使用转化猪模型研究人心肌发生干细胞治疗心肌梗死后左心室功能障碍的治疗效果。使用生长因子启动，根据 GMP 合规性方案对人骨髓来源的 MSC 进行谱系指定，以生成心肌发生干细胞。此后，将左心室功能障碍（亚急性期；1 个月）的猪随机分为接受经导管 NOGA 3D 机电映射指导的心肌内移植心肌发生细胞或生理盐水（对照组）。30 天后，进行心脏 MRI（cMRI）以进行功能评估和体内细胞追踪。这种方法与全面的死后细胞命运和修复模式分析相结合。与对照组相比，心肌发生细胞治疗是安全的，射血分数显著更高（p=0.012）。它进一步防止了适应性不良的左心室重塑，并显示出明显更低的相对和总梗死面积（p=0.043 和 p=0.012）。由于体内追踪和死后分析仅显示有限的心肌内心肌发生细胞整合，因此诱导的新生血管生成（高约 40%；p=0.003）和内源性祖细胞的募集（高约 2.5 倍；p=0.008）到梗塞边界区似乎是主要的修复模式。这是使用临床前大型动物模型首次报道证明心肌发生干细胞治疗心肌梗死后左心室功能障碍的安全性和有效性，以防止左心室重塑和随后的 CHF。它进一步提供了对心肌发生细胞后命运的深入了解，并提示了心肌发生细胞诱导的心脏修复的机制。采用 GMP-/GLP 合规性方法可能会加速向缺血性左心室功能障碍患者的 I 期临床试验的转化，从而扩大这种有趣的细胞类型的现有适应症。
