Inhibition of Apoptosis Overcomes Stage-Related Compatibility Barriers to Chimera Formation in Mouse Embryos
Inhibition of Apoptosis Overcomes Stage-Related Compatibility Barriers to Chimera Formation in Mouse Embryos
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DOI：
10.1016/j.stem.2016.10.013
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发表时间：
2016-11-03
期刊：
影响因子：
23.9
通讯作者：
Nakauchi, Hiromitsu
中科院分区：
文献类型：
--
作者：
Masaki, Hideki;Kato-Itoh, Megumi;Nakauchi, Hiromitsu
比胚胎干细胞发育更高级的细胞类型，如EpiSCs，当注射到植入前囊胚中时，不能形成嵌合体，显然是因为注射的细胞经历了凋亡。本研究表明，通过表达抗凋亡基因BCL2可短暂促进细胞存活，使EpiSCs和Sox17（+）内胚层祖细胞能够整合到囊胚中并形成嵌合胚胎。在注入囊胚后，表达bcl2的EpiSCs在嵌合动物的所有身体组织中起作用，而Sox17（+）内胚层祖细胞以特定区域的方式特异性地在内胚层组织中起作用。此外，BCL2的表达使大鼠EpiSCs能够促进小鼠胚胎嵌合体，从而形成可以存活到成年的种间嵌合体。因此，我们的系统提供了一种方法来克服通常限制嵌合体形成的细胞相容性问题。这种方法的应用可以扩大胚胎嵌合体的应用，包括区域特异性嵌合体，用于基础发育生物学研究和再生医学。
Cell types more advanced in development than embryonic stem cells, such as EpiSCs, fail to contribute to chimeras when injected into pre-implantation-stage blastocysts, apparently because the injected cells undergo apoptosis. Here we show that transient promotion of cell survival through expression of the anti-apoptotic gene BCL2 enables EpiSCs and Sox17(+) endoderm progenitors to integrate into blastocysts and contribute to chimeric embryos. Upon injection into blastocyst, BCL2-expressing EpiSCs contributed to all bodily tissues in chimeric animals while Sox17(+) endoderm progenitors specifically contributed in a region-specific fashion to endodermal tissues. In addition, BCL2 expression enabled rat EpiSCs to contribute to mouse embryonic chimeras, thereby forming interspecies chimeras that could survive to adulthood. Our system therefore provides a method to overcome cellular compatibility issues that typically restrict chimera formation. Application of this type of approach could broaden the use of embryonic chimeras, including region-specific chimeras, for basic developmental biology research and regenerative medicine.