间充质干细胞与多能干细胞来源的心肌细胞在治疗心力衰竭中的免疫调节和血管生成作用比较。
Potent immunomodulation and angiogenic effects of mesenchymal stem cells versus cardiomyocytes derived from pluripotent stem cells for treatment of heart failure.
机构信息
Cardiology Division, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Rm 1928, Block K, Hong Kong SAR, China.
Shenzhen Institutes of Research and Innovation, The University of Hong Kong, Shenzhen, China.
出版信息
Stem Cell Res Ther. 2019 Mar 7;10(1):78. doi: 10.1186/s13287-019-1183-3.
BACKGROUND
Optimal cell type as cell-based therapies for heart failure (HF) remains unclear. We sought to compare the safety and efficacy of direct intramyocardial transplantation of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and human induced pluripotent stem cell-derived mesenchymal stem cells (hiPSC-MSCs) in a porcine model of HF.
METHODS
Eight weeks after induction of HF with myocardial infarction (MI) and rapid pacing, animals with impaired left ventricular ejection fraction (LVEF) were randomly assigned to receive direct intramyocardial injection of saline (MI group), 2 × 10 hESC-CMs (hESC-CM group), or 2 × 10 hiPSC-MSCs (hiPSC-MSC group). The hearts were harvested for immunohistochemical evaluation after serial echocardiography and hemodynamic evaluation and ventricular tachyarrhythmia (VT) induction by in vivo programmed electrical stimulation.
RESULTS
At 8 weeks post-transplantation, LVEF, left ventricular maximal positive pressure derivative, and end systolic pressure-volume relationship were significantly higher in the hiPSC-MSC group but not in the hESC-CM group compared with the MI group. The incidence of early spontaneous ventricular tachyarrhythmia (VT) episodes was higher in the hESC-CM group but the incidence of inducible VT was similar among the different groups. Histological examination showed no tumor formation but hiPSC-MSCs exhibited a stronger survival capacity by activating regulatory T cells and reducing the inflammatory cells. In vitro study showed that hiPSC-MSCs were insensitive to pro-inflammatory interferon-gamma-induced human leukocyte antigen class II expression compared with hESC-CMs. Moreover, hiPSC-MSCs also significantly enhanced angiogenesis compared with other groups via increasing expression of distinct angiogenic factors.
CONCLUSIONS
Our results demonstrate that transplantation of hiPSC-MSCs is safe and does not increase proarrhythmia or tumor formation and superior to hESC-CMs for the improvement of cardiac function in HF. This is due to their immunomodulation that improves in vivo survival and enhanced angiogenesis via paracrine effects.
背景
用于心力衰竭（HF）的基于细胞的治疗的最佳细胞类型仍不清楚。我们试图在 HF 的猪模型中比较直接心肌内移植人胚胎干细胞衍生的心肌细胞（hESC-CM）和人诱导多能干细胞衍生的间充质干细胞（hiPSC-MSC）的安全性和疗效。
方法
在心肌梗死（MI）和快速起搏诱导 HF 8 周后，左心室射血分数（LVEF）受损的动物被随机分配接受生理盐水（MI 组）、2×10 hESC-CM（hESC-CM 组）或 2×10 hiPSC-MSC（hiPSC-MSC 组）的直接心肌内注射。在连续超声心动图和血流动力学评估以及体内程控电刺激诱导室性心动过速（VT）后，收获心脏进行免疫组织化学评估。
结果
移植后 8 周，与 MI 组相比，hiPSC-MSC 组的 LVEF、左心室最大正压力导数和收缩末期压力-容积关系显著升高，但 hESC-CM 组则不然。hESC-CM 组的早期自发性室性心动过速（VT）发作发生率较高，但不同组之间可诱导 VT 的发生率相似。组织学检查未发现肿瘤形成，但 hiPSC-MSC 通过激活调节性 T 细胞和减少炎症细胞而显示出更强的存活能力。体外研究表明，与 hESC-CM 相比，hiPSC-MSC 对促炎干扰素-γ诱导的人类白细胞抗原 II 类表达不敏感。此外，与其他组相比，hiPSC-MSC 还通过增加特定血管生成因子的表达，显著增强了血管生成。
结论
我们的结果表明，hiPSC-MSC 的移植是安全的，不会增加致心律失常或肿瘤形成，并且在改善 HF 中的心脏功能方面优于 hESC-CM。这是由于其免疫调节作用，通过旁分泌作用改善了体内存活和增强了血管生成。
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