Cytokines and BMP-4 promote hematopoietic differentiation of human embryonic stem cells
Cytokines and BMP-4 promote hematopoietic differentiation of human embryonic stem cells
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DOI：
10.1182/blood-2003-03-0832
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发表时间：
2003-08-01
期刊：
影响因子：
20.3
通讯作者：
Bhatia, M
中科院分区：
文献类型：
--
作者：
Chadwick, K;Wang, LS;Bhatia, M
人胚胎干细胞(HESCs)在类胚体(EB)发育过程中随机分化为多种细胞类型。到目前为止，能够影响人类胚胎干细胞造血细胞命运的特定因素的特征仍然难以捉摸。在这里，我们报告了在EB发育过程中用细胞因子和骨形态发生蛋白-4(BMP-4)的组合治疗胚胎干细胞，BMP-4是一种腹侧中胚层诱导剂，强烈促进造血分化。多个谱系的造血祖细胞由EBS产生，并被发现仅限于表达细胞表面CD45的后代群体。添加BMP-4对造血细胞分化无统计学意义，但可显著增强祖细胞的自我更新，不依赖于细胞因子的治疗。造血承诺的特征是单个CD45(+)细胞在培养10天后首次出现，并伴随着造血转录因子的表达。尽管在第10天去除了细胞因子，但hESCs的造血细胞分化仍在继续，这表明细胞因子作用于造血祖细胞，而不是分化的造血细胞。我们的研究首次证明了细胞因子和BMP-4在促进人胚胎干细胞系向造血细胞分化中的作用，并提供了一个前所未有的系统来研究控制人类造血启动的早期发育事件。
Human embryonic stem cells (hESCS) randomly differentiate into multiple cell types during embryoid body (EB) development. To date, characterization of specific factors capable of influencing hematopoietic cell fate from hESCs remains elusive. Here, we report that the treatment of hESCs during EB development with a combination of cytokines and bone morphogenetic protein-4 (BMP-4), a ventral mesoderm inducer, strongly promotes hematopoietic differentiation. Hematopoietic progenitors of multiple lineages were generated from EBs and were found to be restricted to the population of progeny expressing cell surface CD45. Addition of BMP-4 had no statistically significant effect on hematopoietic differentiation but enabled significant enhancement in progenitor self-renewal, independent of cytokine treatment. Hematopoietic commitment was characterized as the temporal emergence of single CD45(+) cells first detectable after day 10 of culture and was accompanied by expression of hematopoietic transcription factors. Despite the removal of cytokines at day 10, hematopoietic differentiation of hESCs continued, suggesting that cytokines act on hematopoietic precursors as opposed to differentiated hematopoietic cells. Our study establishes the first evidence for the role of cytokines and BMP-4 in promoting hematopoietic differentiation of hESC lines and provides an unprecedented system to study early developmental events that govern the initiation of hematopoiesis in the human.