Nelson Timothy J, Martinez-Fernandez Almudena, Yamada Satsuki, Perez-Terzic Carmen, Ikeda Yasuhiro, Terzic Andre
Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.
Circulation. 2009 Aug 4;120(5):408-16. doi: 10.1161/CIRCULATIONAHA.109.865154. Epub 2009 Jul 20.
Nuclear reprogramming provides an emerging strategy to produce embryo-independent pluripotent stem cells from somatic tissue. Induced pluripotent stem cells (iPS) demonstrate aptitude for de novo cardiac differentiation, yet their potential for heart disease therapy has not been tested.
In this study, fibroblasts transduced with human stemness factors OCT3/4, SOX2, KLF4, and c-MYC converted into an embryonic stem cell-like phenotype and demonstrated the ability to spontaneously assimilate into preimplantation host morula via diploid aggregation, unique to bona fide pluripotent cells. In utero, iPS-derived chimera executed differentiation programs to construct normal heart parenchyma patterning. Within infarcted hearts in the adult, intramyocardial delivery of iPS yielded progeny that properly engrafted without disrupting cytoarchitecture in immunocompetent recipients. In contrast to parental nonreparative fibroblasts, iPS treatment restored postischemic contractile performance, ventricular wall thickness, and electric stability while achieving in situ regeneration of cardiac, smooth muscle, and endothelial tissue.
Fibroblasts reprogrammed by human stemness factors thus acquire the potential to repair acute myocardial infarction, establishing iPS in the treatment of heart disease.
核重编程为从体细胞组织中产生不依赖胚胎的多能干细胞提供了一种新策略。诱导多能干细胞（iPS）显示出从头进行心脏分化的能力，但其在心脏病治疗中的潜力尚未得到测试。
在本研究中，用人类干性因子OCT3/4、SOX2、KLF4和c-MYC转导的成纤维细胞转变为胚胎干细胞样表型，并通过二倍体聚集显示出自发融入植入前宿主桑椹胚的能力，这是真正多能细胞所特有的。在子宫内，iPS来源的嵌合体执行分化程序以构建正常的心脏实质模式。在成年动物的梗死心脏中，心肌内递送iPS产生的后代能够在免疫活性受体中正常植入而不破坏细胞结构。与亲本的无修复能力的成纤维细胞相比，iPS治疗恢复了缺血后的收缩性能、心室壁厚度和电稳定性，同时实现了心脏、平滑肌和内皮组织的原位再生。
因此，经人类干性因子重编程的成纤维细胞获得了修复急性心肌梗死的潜力，确立了iPS在心脏病治疗中的应用。
