NANOG and CDX2 Pattern Distinct Subtypes of Human Mesoderm during Exit from Pluripotency
NANOG and CDX2 Pattern Distinct Subtypes of Human Mesoderm during Exit from Pluripotency
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DOI：
10.1016/j.stem.2014.06.006
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发表时间：
2014-09-04
期刊：
影响因子：
23.9
通讯作者：
Pedersen, Roger A.
中科院分区：
文献类型：
--
作者：
Mendjan, Sasha;Mascetti, Victoria L.;Pedersen, Roger A.
中胚层在原条（PS）处被诱导，并随后形成中胚层亚型和器官前体。目前尚不清楚中胚层诱导是否产生多能PS祖细胞或几个不同的限制亚型潜力。我们用ACTIVIN和BMP或用GSK 3-β抑制剂在人多能干细胞中诱导中胚层。两种方法都诱导了具有不同PS样身份的Brachyury（+）中胚层，其具有不同的图案化潜力。ACTIVIN和BMP诱导的中胚层形成心脏亚型，但不形成体节亚型。相反，由GSK 3-β抑制诱导的PS前体不产生侧板和心脏中胚层，而是有利于体节分化。这些细胞命运决定的机制涉及NANOG和CDX 2的相互抑制。虽然NANOG是心脏特化所必需的，但阻断了体细胞亚型，CDX 2是体细胞中胚层所必需的，但阻断了心脏分化。总之，不是形成共同的PS祖细胞，而是不同的诱导机制区分人类中胚层亚型。
Mesoderm is induced at the primitive streak (PS) and patterns subsequently into mesodermal subtypes and organ precursors. It is unclear whether mesoderm induction generates a multipotent PS progenitor or several distinct ones with restricted subtype potentials. We induced mesoderm in human pluripotent stem cells with ACTIVIN and BMP or with GSK3-beta inhibition. Both approaches induced BRACHYURY(+) mesoderm of distinct PS-like identities, which had differing patterning potential. ACTIVIN and BMP-induced mesoderm patterned into cardiac but not somitic subtypes. Conversely, PS precursors induced by GSK3-beta inhibition did not generate lateral plate and cardiac mesoderm and favored instead somitic differentiation. The mechanism of these cell fate decisions involved mutual repression of NANOGand CDX2. Although NANOG was required for cardiac specification but blocked somitic subtypes, CDX2 was required for somitic mesoderm but blocked cardiac differentiation. In sum, rather than forming a common PS progenitor, separate induction mechanisms distinguish human mesoderm subtypes.