Mesenchymal 'stem cell rescue' for myocardial disease.
Mesenchymal 'stem cell rescue' for myocardial disease.
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间充质“干细胞拯救”治疗心肌疾病。
DOI：
10.1080/146532402761624683
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发表时间：
2002
期刊：
影响因子：
4.5
通讯作者：
Lederman,RJ
中科院分区：
文献类型：
--
作者：
Hill,JM;Lederman,RJ
由动脉粥样硬化相关的心肌梗死（MI）、瓣膜疾病或其他损伤引起的心肌功能障碍是成年人发病率和死亡率的一个广泛而重要的原因。临床表现包括充血性心力衰竭，泵功能障碍综合征和神经体液反应不良，以及由疤痕和缺血相关的电传导异质性引起的致死性室性心律失常。受损左心室经历进行性“重塑”和心室扩张，伴有肌细胞滑移和成纤维细胞增殖。这反映了心肌修复和再生明显缺乏有效的内在机制。根据目前的范例，没有足够的器官特异性干细胞能够沿着心肌生成谱系增殖。Orlic等人报道了小哺乳动物局部注射脑梗死前体细胞治疗梗死心肌后心室功能接近正常化后不久，学术心脏病专家开始传播“干细胞拯救”的概念。细胞疗法，就像之前的基因疗法一样，可以通过简单的操作，比如局部细胞注射，带来心肌再生的神奇希望。然而，恢复同步跳动的心肌细胞的正常功能合胞体的目标可能不会那么简单。间充质干细胞（MSC）治疗确实可能应用于心肌梗死（MI）的治疗。间充质干细胞具有沿多种不同细胞系分化的能力。“MSC”的多能性似乎在不断扩大，尤其是在Verfaillie的[3]小组最近的工作显示出与胚胎干细胞相当的能力之后。在大鼠、猪和羊的腹腔注射后，功能性心肌表型的再现已得到证实。此外，最近使用间充质干细胞的猪研究表明，心肌梗死后左心室功能得到改善，没有检测到免疫或其他毒性bb0。在最近的造血移植研究中，人类受试者接受了自体或异体培养扩增的人间充质干细胞的静脉输注，输注毒性很小。同种异体间充质干细胞已被用于无免疫抑制的成骨不完全性b[6]患儿，同样具有最小的输注毒性。这在考虑使用MSCs进行临床心血管试验时提供了安慰。鉴于骨髓间充质干细胞明显缺乏免疫原性，一些人现在主张应该提供一种“通用”细胞产品，一些生物技术公司现在正准备生产大量供体骨髓间充质干细胞，以进行非造血再生试验。在加入“干细胞潮流”之前，临床心脏病专家必须权衡几个因素。首先是道德问题。是否应该给预计存活数年甚至数十年的患者提供不完全了解的具有增殖甚至恶性潜能的细胞制剂？答案并不简单。显然，明显充血性心力衰竭患者的5年死亡率超过许多恶性肿瘤。此外，世界范围内心肌功能障碍的负担是如此之大，任何有效的治疗方法的快速临床开发都应得到鼓励。从非亲属献血者输血（包括白细胞人群）的长期安全经验中可以得到一些保证。这些问题并不新鲜，并且已经在将研究性基因转移到临床中进行了访问。没有替代品，
Myocardial dysfunction resulting from atherosclerosisrelated myocardial infarction (MI), valvular disease, or other insults is a widespread and important cause of morbidity and mortality amongst adults. Clinical manifestations include congestive heart failure, a syndrome of pump dysfunction and a maladaptive neurohumoral response, and lethal ventricular arrhythmias due to scar-and ischemia-related heterogeneity of electrical conduction. The damaged left ventricle undergoes progressive ‘remodeling’and chamber dilation, with myocyte slippage and fibroblast proliferation. These reflect an apparent lack of effective intrinsic mechanisms for myocardial repair and regeneration. According to current paradigms there are inadequate organ-specific stem cells able to proliferate along a cardiomyogenic lineage. Soon after Orlic et al.[1] reported near-normalization of ventricular function after treatment of infarcted myocardium with locally-injected BM-derived precursor cells in small mammals, academic cardiologists began promulgating the concept of ‘stem cell rescue’. Cell therapy, like gene therapy before it, could hold the magical promise of myocardial regeneration from simple maneuvers, like local cell injection. However, the goal of restoring a normal functional syncytium of synchronously-beating cardiomyocytes will probably not prove so simple. Mesenchymal stem cell (MSC) therapy might indeed be applied to the treatment of myocardial infarction (MI). MSCs have the capacity to differentiate along a wide variety of different cell lineages [2]. The pluripotentiality of the ‘MSC’seems ever-expanding, especially after recent work from Verfaillie’s group [3] showed capabilities comparable to embryonic stem cells. The reproduction of a functional cardiac muscle phenotype has been demonstrated following injection in rats, pigs, and sheep [4]. Furthermore, recent pig studies using MSCs have shown improvements of left ventricular function following MI, with no detectable immune or other toxicity [5]. In recent studies of hematopoietic transplantation, human subjects have received iv infusions of autologous or allogeneic culture-expanded human MSCs, with minimal infusional toxicity. Allogeneic MSCs have been administered to non-immunosuppressed pediatric patients with osteogenesis imperfecta [6], again with minimal infusional toxicity. This provides comfort when considering clinical cardiovascular trials with MSCs. Given the apparent lack of immunogenicity of MSCs, some would now advocate that a ‘universal’cell product should be made available, and several biotechnology companies are now gearing up to manufacture large stocks of donor MSCs in anticipation of non-hematopoeitic regeneration trials. Before jumping on the ‘stem cell bandwagon’clinical cardiologists must weigh several considerations. The first is ethical. Should incompletely-understood cellular agents with proliferative or even malignant potential be offered to patients who have projected survival times of years or even decades? The answer is not straightforward. Clearly patients with overt congestive heart failure have a 5-year mortality exceeding that of many malignancies. Moreover, the worldwide burden of myocardial dysfunction is so great that rapid clinical development of any effective therapy should be encouraged. Some reassurance is derived from the long safety experience with blood transfusion, including WBC populations, from unrelated donors. These issues are not new, and have been visited in bringing investigational gene transfer to clinic. There is no substitute,