Cell-free embryonic stem cell extract-mediated derivation of multipotent stem cells from NIH3T3 fibroblasts for functional and anatomical ischemic tissue repair
Cell-free embryonic stem cell extract-mediated derivation of multipotent stem cells from NIH3T3 fibroblasts for functional and anatomical ischemic tissue repair
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DOI：
10.1161/circresaha.108.176115
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发表时间：
2008-06-06
影响因子：
20.1
通讯作者：
Kishore, Raj
中科院分区：
文献类型：
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作者：
Rajasingh, Johnson;Lambers, Erin;Kishore, Raj
多能干细胞的产生的卵母细胞的非依赖性来源是再生医学的最终目标之一。我们报告说，暴露于小鼠胚胎干细胞（mESC）提取物，可逆透化NIH 3 T3细胞经历去分化，然后刺激诱导再分化成多个谱系细胞类型。全基因组表达谱显示，NIH 3 T3对照和ESC提取物处理的NIH 3 T3细胞之间存在显著差异，包括ESC特异性转录物的再活化。表观遗传学上，ESC提取物诱导Oct 4启动子的CpG去甲基化，组蛋白3和4的超乙酰化，并减少组蛋白3的赖氨酸9（K-9）二甲基化。在手术诱导的后肢缺血或急性心肌梗死的小鼠模型中，移植重编程的NIH 3 T3细胞显着改善损伤后的生理功能，并显示出植入和转分化为骨骼肌，内皮细胞和心肌细胞的解剖学证据。这些数据为从终末分化的体细胞产生功能性多能干细胞样细胞而不引入逆转录病毒介导的转基因或ESC融合提供了证据。
The oocyte-independent source for the generation of pluripotent stem cells is among the ultimate goals in regenerative medicine. We report that on exposure to mouse embryonic stem cell (mESC) extracts, reversibly permeabilized NIH3T3 cells undergo dedifferentiation followed by stimulus-induced redifferentiation into multiple lineage cell types. Genome-wide expression profiling revealed significant differences between NIH3T3 control and ESC extract-treated NIH3T3 cells including the reactivation of ESC-specific transcripts. Epigenetically, ESC extracts induced CpG demethylation of Oct4 promoter, hyperacetylation of histones 3 and 4, and decreased lysine 9 (K-9) dimethylation of histone 3. In mouse models of surgically induced hindlimb ischemia or acute myocardial infarction transplantation of reprogrammed NIH3T3 cells significantly improved postinjury physiological functions and showed anatomic evidence of engraftment and transdifferentiation into skeletal muscle, endothelial cell, and cardiomyocytes. These data provide evidence for the generation of functional multipotent stem-like cells from terminally differentiated somatic cells without the introduction of retroviral mediated transgenes or ESC fusion.