Inefficient reprogramming of the hematopoietic stem cell genome following nuclear transfer
Inefficient reprogramming of the hematopoietic stem cell genome following nuclear transfer
复制标题
DOI：
10.1242/jcs.02913
复制
发表时间：
2006-05-15
影响因子：
4
通讯作者：
Ogura, Atsuo
中科院分区：
文献类型：
--
作者：
Inoue, Kimiko;Ogonuki, Narumi;Ogura, Atsuo
一般来说，克隆未分化的植入前胚胎（卵裂球）或胚胎干细胞比克隆分化的体细胞更有效。因此，有一种假设，即组织特异性干细胞可能作为核移植的有效供体，因为它们的基因组的未分化状态。在这里，我们表明，这不是与成人造血干细胞（HSC）的情况。尽管我们首次证明了小鼠HSC可以被克隆以产生后代，但在测试的克隆（卵丘、未成熟的支持细胞和成纤维细胞）中，出生率（0-0.7%）最低。只有6%的重构胚胎在体外达到桑椹胚或囊胚期（卵丘克隆为46%; P < 5 × 10 - 10）。HSC克隆胚胎的转录和基因表达分析显示，它们在适当的时间启动合子基因激活（ZGA），但未能激活六个重要胚胎基因中的五个，包括Hdac 1（编码组蛋白去乙酰化酶1），随后ZGA的关键调节因子。这些结果表明，HSC基因组的可塑性比我们想象的要小，至少在核移植后卵质中的可重编程性方面。
In general, cloning undifferentiated preimplantation embryos (blastomeres) or embryonic stem cells is more efficient than cloning differentiated somatic cells. Therefore, there has been an assumption that tissue-specific stem cells might serve as efficient donors for nuclear transfer because of the undifferentiated state of their genome. Here, we show that this is not the case with adult hematopoietic stem cells (HSCs). Although we have demonstrated for the first time that mouse HSCs can be cloned to generate offspring, the birth rates (0-0.7%) were lowest among the clones tested ( cumulus, immature Sertoli and fibroblast cells). Only 6% of reconstructed embryos reached the morula or blastocyst stage in vitro (versus 46% for cumulus clones; P < 5 x 10(-10)). Transcription and gene expression analyses of HSC clone embryos revealed that they initiated zygotic gene activation (ZGA) at the appropriate timing, but failed to activate five out of six important embryonic genes examined, including Hdac1 ( encoding histone deacetylase 1), a key regulator of subsequent ZGA. These results suggest that the HSC genome has less plasticity than we imagined, at least in terms of reprogrammability in the ooplasm after nuclear transfer.