HOXA9 promotes hematopoietic commitment of human embryonic stem cells
HOXA9 promotes hematopoietic commitment of human embryonic stem cells
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DOI：
10.1182/blood-2014-03-558825
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发表时间：
2014-11-13
期刊：
影响因子：
20.3
通讯作者：
Menendez, Pablo
中科院分区：
文献类型：
--
作者：
Ramos-Mejia, Veronica;Navarro-Montero, Oscar;Menendez, Pablo
调节人类胚胎干细胞(HESCs)分化为造血细胞的分子决定因素仍然难以捉摸。HOXA9在白血病发生和造血中发挥相关作用。它在造血干细胞和祖细胞(HSPC)中高表达，在分化过程中下调。Hoxa9基因缺陷的小鼠表现出造血发育受损，HOXA9表达的解除调控经常与急性白血病有关。对脐血HSPC和hESC来源的HSPC差异表达基因的分析表明，HOXA9是hESC来源的HSPC中下调最多的基因，提示HOXA9的表达水平可能在hESC的造血分化中起关键作用。在此，我们发现在hESCs向造血细胞分化的过程中，HOXA9的表达与造血细胞的发育相平行，但仅限于造血祖细胞(CD31(+)CD34(+)CD45(-))，随着Hep分化为血细胞(CD45(+))，HOXA9的表达减弱。不同的功能获得和功能丧失研究表明，HOXA9通过特异性促进HEPs向原始和总CD45(+)血细胞的承诺来促进hESCs的造血细胞分化。基因表达分析表明，核因子-kappa B信号可能与HOXA9协同增加造血承诺。然而，HOXA9本身并不足以赋予hESC-造血衍生物在体内的长期植入潜力，这强化了这样的观点，即需要额外的分子调控因子才能从hESC产生明确的体内功能性HSPC。
The molecular determinants regulating the specification of human embryonic stem cells (hESCs) into hematopoietic cells remain elusive. HOXA9 plays a relevant role in leukemogenesis and hematopoiesis. It is highly expressed in hematopoietic stem and progenitor cells (HSPCs) and is downregulated upon differentiation. Hoxa9-deficient mice display impaired hematopoietic development, and deregulation of HOXA9 expression is frequently associated with acute leukemia. Analysis of the genes differentially expressed in cord blood HSPCs vs hESC-derived HSPCs identified HOXA9 as the most downregulated gene in hESC-derived HSPCs, suggesting that expression levels of HOXA9 may be crucial for hematopoietic differentiation of hESC. Here we show that during hematopoietic differentiation of hESCs, HOXA9 expression parallels hematopoietic development, but is restricted to the hemogenic precursors (HEP) (CD31(+)CD34(+)CD45(-)), and diminishes as HEPs differentiate into blood cells (CD45(+)). Different gain-of-function and loss-of-function studies reveal that HOXA9 enhances hematopoietic differentiation of hESCs by specifically promoting the commitment of HEPs into primitive and total CD45(+) blood cells. Gene expression analysis suggests that nuclear factor-kappa B signaling could be collaborating with HOXA9 to increase hematopoietic commitment. However, HOXA9 on its own is not sufficient to confer in vivo long-term engraftment potential to hESC-hematopoietic derivatives, reinforcing the idea that additional molecular regulators are needed for the generation of definitive in vivo functional HSPCs from hESC.