BMP10 as a potent inducer of trophoblast differentiation in human embryonic and induced pluripotent stem cells
BMP10 as a potent inducer of trophoblast differentiation in human embryonic and induced pluripotent stem cells
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DOI：
10.1016/j.biomaterials.2013.08.084
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发表时间：
2013-12-01
期刊：
影响因子：
14
通讯作者：
Adjaye, James
中科院分区：
文献类型：
--
作者：
Lichtner, Bjoern;Knaus, Petra;Adjaye, James
骨形态发生蛋白（BMPs）在人胚胎干细胞（hESCs）中具有诱导分化的作用。在本研究中，我们比较了BMP 5、BMP 10和BMP 13诱导hESC和人诱导多能干细胞（hiPSC）分化的效力，BMP 5、BMP 10和BMP 13由于序列和结构同源性的差异而属于不同的BMP亚组。我们观察到，在协议与以前的BMP 4模型研究，所有配体诱导分化的滋养层细胞谱系中没有bFGF。然而，不同的骨形态发生蛋白诱导分化的动力学表现出差异，与骨形态发生蛋白10是最有效的。hiPSC和hESC共享BMP I型和II型受体亚型的可比较的表达模式，这可以解释关于配体效力和SMAD依赖性（通过SMAD 1/5/8）和非依赖性（通过MAPK p38）信号转导途径的激活的保守性质。所测试的BMP具有独特且保守的靶基因，如CDX 2、DLX 3、DIX 5、GATA 2、GATA 3、HAND 1、ID 2、MSX 2和TFAP 2A，已知这些靶基因与滋养层细胞的出现相关。hESC诱导BMP拮抗剂NOGGIN的表达，作为限制广泛的BMP作用的保护机制。与BMP 4不同，BMP 10已显示对NOGGIN诱导的抑制具有抗性，这可以部分解释其效力。BMP，特别是BMP 4，是分化方案中常用的细胞因子，以从人多能干细胞产生多种中胚层和内胚层衍生物。我们的研究已经确定了BMP 10，一种心脏特异性蛋白，作为BMP 4的上级替代品，用于诱导人类多能干细胞的滋养层分化。(C)2013爱思唯尔有限公司保留所有权利。
Bone morphogenetic proteins (BMPs) are known to induce diverse differentiation fates in human embryonic stem cells (hESCs). In the present study, we compared the potency at which BMP5, BMP10 and BMP13, which are members of distinct BMP subgroups due to differences in sequential and structural homology, induce differentiation in hESCs and human induced pluripotent stem cells (hiPSCs). We observed, in agreement with previous BMP4 model studies, that all ligands induced differentiation to the trophoblast lineage in the absence of bFGF. However, distinct BMPs exerted differences in the kinetics of induced differentiation, with BMP10 being the most potent. hiPSCs and hESCs shared comparable expression patterns of BMP type-I and -II receptor subtypes, which might explain conserved properties with respect to ligand potency and activation of SMAD-dependent (via SMAD1/5/8) and -independent (via MAPK p38) signal transduction pathways. The tested BMPs had distinct and also conserved target genes such as CDX2, DLX3, DIX5, GATA2, GATA3, HAND1, ID2, MSX2 and TFAP2A, known to be associated with the emergence of trophoblast cells. hESCs induced expression of the BMP antagonist NOGGIN as a protection mechanism to constrict extensive BMP action. Unlike BMP4, BMP10 has been shown to be resistant to NOGGIN-induced inhibition which in part might explain its potency. BMPs, in particular BMP4, are commonly used cytokines in differentiation protocols to generate diverse mesoderm- and endoderm-derivates from human pluripotent stem cells. Our study has identified BMP10, a cardiac-specific protein, as a superior alternative to BMP4 for inducing trophoblast differentiation in human pluripotent stem cells. (C) 2013 Elsevier Ltd. All rights reserved.