Direct reprogramming of terminally differentiated mature B lymphocytes to pluripotency
Direct reprogramming of terminally differentiated mature B lymphocytes to pluripotency
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DOI：
10.1016/j.cell.2008.03.028
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发表时间：
2008-04-18
期刊：
影响因子：
64.5
通讯作者：
Jaenisch, Rudolf
中科院分区：
文献类型：
--
作者：
Hanna, Jacob;Markoulaki, Styliani;Jaenisch, Rudolf
多能细胞可以通过特定转录因子的异位表达从成纤维细胞衍生。一个基本的未解决的问题是终末分化的细胞是否可以重编程为多能性。我们利用四种转录因子（Oct 4，Sox 2，Klf 4和c-Myc）的转基因和诱导表达来重编程小鼠B淋巴细胞。这些因子足以将非终末分化的B细胞转化为多能状态。然而，成熟B细胞的重编程需要额外的中断，通过髓样转录因子CCAAT/增强子结合蛋白-α（C/EBP α）的异位表达或B细胞转录因子Pax 5的特异性敲低，维持B细胞身份的转录状态。多个iPS系克隆来源于未完全分化和完全分化的B淋巴细胞，其产生具有种系贡献的成年嵌合体，并且当注射到四倍体胚泡中时产生晚期胚胎。我们的研究为终末分化的成体细胞直接核重编程为多能性提供了明确的证据。
Pluripotent cells can be derived from fibroblasts by ectopic expression of defined transcription factors. A fundamental unresolved question is whether terminally differentiated cells can be reprogrammed to pluripotency. We utilized transgenic and inducible expression of four transcription factors (Oct4, Sox2, Klf4, and c-Myc) to reprogram mouse B lymphocytes. These factors were sufficient to convert nonterminally differentiated B cells to a pluripotent state. However, reprogramming of mature B cells required additional interruption with the transcriptional state maintaining B cell identity by either ectopic expression of the myeloid transcription factor CCAAT/enhancer-binding-protein-alpha (C/EBP alpha) or specific knockdown of the B cell transcription factor Pax5. Multiple iPS lines were clonally derived from both nonfully and fully differentiated B lymphocytes, which gave rise to adult chimeras with germline contribution, and to late-term embryos when injected into tetraploid blastocysts. Our study provides definite proof for the direct nuclear reprogramming of terminally differentiated adult cells to pluripotency.