Ravens Ursula
Institut für Pharmakologie und Toxikologie, Medizinische Fakultät der TU Dresden, Dresden.
Herz. 2006 Apr;31(2):123-6. doi: 10.1007/s00059-006-2793-y.
New concepts for treatment of myocardial infarction include the implantation of adult stem cells for regeneration of damaged muscle tissue. Several clinical trials have demonstrated a small, but significant improvement of ventricular function. Transdifferentiation of stem cells into cardiomyocytes, formation of new vessels and paracrine factors have been discussed as putative mechanisms for the therapeutic effect. Several types of stem cells have been used clinically including myoblasts derived from skeletal muscle satellite cells, bone marrow-derived stem cells or blood-derived mononuclear progenitor cells. In addition, multiple organs were shown to contain a small number of stem cells that could differentiate into cardiomyocytes. Embryonic stem cells differentiate into spontaneously beating cells that have varying electrophysiological properties. Their action potentials resemble those of cardiac pacemaker cell, atrial or ventricular myocytes (Figure 1) suggesting true differentiation into cardiomyocytes. Beating cells derived from a newly described population of skeletal muscle-derived cells ("skeletal precursors of cardiomyocytes" [SPOCs]) also exhibit spontaneous action potentials, however, unlike cardiac pacemaker cells, their electrical activity is suppressed with the sodium channel blocker tetrodotoxin (Figure 2). Undifferentiated bone marrow-derived mesenchymal stem cells are not electrically excitable. Nevertheless, they express functional ion channels like L-type Ca(2+) channels, albeit not in every cell. Co-culturing stem cells with neonatal rat ventricular myocytes induces good electrical contacts between cells via gap junction formation. Excitatory wave fronts spread evenly in the co-culture. By contrast, gap junctions fail to form when myoblasts are co-cultured with neonatal cardiomyocytes and reentry arrhythmias develop. This pathomechanism could serve as an explanation for the enhanced clinical risk of arrhythmia after transplantation of myoblasts into the infarcted hearts.
心肌梗死治疗的新概念包括植入成体干细胞以再生受损的肌肉组织。多项临床试验已证明心室功能有微小但显著的改善。干细胞向心肌细胞的转分化、新血管的形成以及旁分泌因子已被讨论为治疗效果的可能机制。临床上已使用多种类型的干细胞,包括源自骨骼肌卫星细胞的成肌细胞、骨髓来源的干细胞或血液来源的单核祖细胞。此外,多个器官被证明含有少量可分化为心肌细胞的干细胞。胚胎干细胞可分化为具有不同电生理特性的自发搏动细胞。它们的动作电位类似于心脏起搏细胞、心房或心室肌细胞的动作电位(图1),表明真正分化为心肌细胞。源自新描述的骨骼肌来源细胞群体(“心肌细胞的骨骼肌前体”[SPOCs])的搏动细胞也表现出自发动作电位,然而,与心脏起搏细胞不同,它们的电活动会被钠通道阻滞剂河豚毒素抑制(图2)。未分化的骨髓间充质干细胞不具有电兴奋性。尽管如此,它们表达功能性离子通道,如L型Ca(2+)通道,尽管并非每个细胞都表达。将干细胞与新生大鼠心室肌细胞共培养可通过形成缝隙连接诱导细胞间良好的电接触。兴奋性波阵面在共培养物中均匀传播。相比之下,当成肌细胞与新生心肌细胞共培养时,缝隙连接无法形成,并且会发生折返性心律失常。这种发病机制可以解释将成肌细胞移植到梗死心脏后心律失常临床风险增加的原因。