Survival, integration, and differentiation of cardiomyocyte grafts - A study in normal and injured rat hearts
Survival, integration, and differentiation of cardiomyocyte grafts - A study in normal and injured rat hearts
复制标题
DOI：
10.1161/01.cir.100.2.193
复制
发表时间：
1999-07-13
期刊：
影响因子：
37.8
通讯作者：
Murry, CE
中科院分区：
文献类型：
--
作者：
Reinecke, H;Zhang, M;Murry, CE
背景：心肌细胞移植增加了心脏中的心肌细胞数量。我们研究了(1)发育阶段对移植物存活的影响；(2)是否急性坏死或正在愈合的心脏病变支持移植物；(3)移植心肌细胞在损伤心脏中的分化与整合。方法与结果：将胚胎大鼠、新生大鼠和成年自交系大鼠的心肌细胞移植到正常心肌、急性冷冻损伤心肌或肉芽组织中（损伤后6 d）。成人心肌细胞在任何条件下都不能存活。相比之下，胎儿和新生儿心肌细胞在所有条件下都能形成存活的移植物。对新生儿心肌细胞的时间过程研究表明，移植物再现了正常发育的许多方面。粘附体连接蛋白n -钙粘蛋白在第1天呈周状分布，到第6天开始组织成插层的盘状结构。相对于n -钙粘蛋白，缝隙连接蛋白connexin43遵循类似但延迟的模式。从2到8周，出现进行性肥大，形成成熟的间插椎间盘。在一些心脏中，移植物细胞与宿主心肌细胞形成粘附和间隙连接，提示机电耦合。然而，更常见的是，移植物被疤痕组织与宿主心肌分离。在共培养中，新生儿和成人心肌细胞之间形成了间隙和粘附连接，这可以通过细胞间连接处的染料转移和钙粘蛋白和连接蛋白43的定位来证明。结论：移植的胎儿和新生儿心肌细胞可形成新的、成熟的心肌，并具有与损伤的宿主心肌偶联的能力。然而，最佳修复可能需要减少移植物与中间疤痕组织的隔离。
Background-Cardiomyocyte grafting augments myocyte numbers in the heart. We investigated (1) how developmental stage influences graft survival; (2) whether acutely necrotic or healing cardiac lesions support grafts; and (3) the differentiation and integration of cardiomyocyte grafts in injured hearts.Methods and Results-Cardiomyocytes from fetal, neonatal, or adult inbred rats were grafted into normal myocardium, acutely cryoinjured myocardium, or granulation tissue (6 days after injury). Adult cardiomyocytes did not survive under any conditions. In contrast, fetal and neonatal cardiomyocytes formed viable grafts under all conditions. Time-course studies with neonatal cardiomyocytes showed that the grafts recapitulated many aspects of normal development. The adherens junction protein N-cadherin was distributed circumferentially at day 1 but began to organize into intercalated disk-like structures by day 6. The gap junction protein connexin43 followed a similar but delayed pattern relative to N-cadherin. From 2 to 8 weeks, there was progressive hypertrophy and the formation of mature intercalated disks. In some hearts, graft cells formed adherens and gap junctions with host cardiomyocytes, suggesting electromechanical coupling. More commonly, however, grafts were separated from the host myocardium by scar tissue. Gap and adherens junctions formed between neonatal and adult cardiomyocytes in coculture, as evidenced by dye transfer and localization of cadherin and connexin43 at intercellular junctions.Conclusions-Grafted fetal and neonatal cardiomyocytes form new, mature myocardium with the capacity to couple with injured host myocardium. Optimal repair, however, may require reducing the isolation of the graft by the intervening scar tissue.