Nature2014-06-18 4:44 PM

早期胚胎的重新编程 Nuclear reprogramming by interphase cytoplasm of two-cell mouse embryos

论文摘要 

在进行不育症治疗和其他手术过程中,在“体细胞核转移”(SCNT)之后发生的重新编程被认为取决于接受方的细胞质是否能被严格滞留在“中期”(metaphase) 阶段。现在,Shoukhrat Mitalipov及同事发现,“间期”(interphase) 二细胞小鼠胚胎支持移植的体细胞核的重新编程及胚胎干细胞或克隆小鼠的生成。这表明,能够诱导多能性的因素存在于“间期”细胞的细胞质中,这种细胞的细胞核的去除不会像过去所认为的那样将接受方卵子的必要重新编程因素耗尽。如果这些发现能够延伸到人类,那么它们就有可能推动为再生应用而生成人胚胎干细胞的相关工作,因为“间期”所捐助的细胞(受精的胚胎)比“中期”所捐助的细胞(不成熟的卵细胞)更容易进入。

Abstract 

Successful mammalian cloning using somatic cell nuclear transfer (SCNT) into unfertilized, metaphase II (MII)-arrested oocytes attests to the cytoplasmic presence of reprogramming factors capable of inducing totipotency in somatic cell nuclei. However, these poorly defined maternal factors presumably decline sharply after fertilization, as the cytoplasm of pronuclear-stage zygotes is reportedly inactive. Recent evidence suggests that zygotic cytoplasm, if maintained at metaphase, can also support derivation of embryonic stem (ES) cells after SCNT, albeit at low efficiency. This led to the conclusion that critical oocyte reprogramming factors present in the metaphase but not in the interphase cytoplasm are ‘trapped’ inside the nucleus during interphase and effectively removed during enucleation9. Here we investigated the presence of reprogramming activity in the cytoplasm of interphase two-cell mouse embryos (I2C). First, the presence of candidate reprogramming factors was documented in both intact and enucleated metaphase and interphase zygotes and two-cell embryos. Consequently, enucleation did not provide a likely explanation for the inability of interphase cytoplasm to induce reprogramming. Second, when we carefully synchronized the cell cycle stage between the transplanted nucleus (ES cell, fetal fibroblast or terminally differentiated cumulus cell) and the recipient I2C cytoplasm, the reconstructed SCNT embryos developed into blastocysts and ES cells capable of contributing to traditional germline and tetraploid chimaeras. Last, direct transfer of cloned embryos, reconstructed with ES cell nuclei, into recipients resulted in live offspring. Thus, the cytoplasm of I2C supports efficient reprogramming, with cell cycle synchronization between the donor nucleus and recipient cytoplasm as the most critical parameter determining success. The ability to use interphase cytoplasm in SCNT could aid efforts to generate autologous human ES cells for regenerative applications, as donated or discarded embryos are more accessible than unfertilized MII oocytes.

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