Molecular Biology Interdepartmental Program, College of Letters and Science, University of California, Los Angeles, USA.
Blood. 2010 Aug 26;116(8):1254-62. doi: 10.1182/blood-2009-11-254383. Epub 2010 May 14.
The development and emergence of the hematopoietic stem cell involves a series of tightly regulated molecular events that are not well characterized. The hematopoietically expressed homeobox (Hhex) gene, a member of the homeobox gene family, is an essential regulator of embryogenesis and hematopoietic progenitor development. To investigate the role of Hhex in hematopoiesis we adapted a murine embryonic stem (ES) cell coculture system, in which ES cells can differentiate into CD41(+) and CD45(+) hematopoietic progenitors in vitro. Our results show that in addition to delayed hemangioblast development, Hhex(-/-) ES-derived progeny accumulate as CD41(+) and CD41(+)c-kit(+) cells, or the earliest definitive hematopoietic progenitors. In addition, Hhex(-/-) ES-derived progeny display a significantly reduced ability to develop into mature CD45(+) hematopoietic cells. The observed reduction in hematopoietic maturation was accompanied by reduced proliferation, because Hhex(-/-) CD41(+)CD45(-)c-kit(+) hematopoietic progenitors accumulated in the G(2) phase of the cell cycle. Thus, Hhex is a critical regulator of hematopoietic development and is necessary for the maturation and proliferation of the earliest definitive hematopoietic progenitors.
造血干细胞的发生和出现涉及一系列尚未得到很好描述的严格调控的分子事件。造血表达同源盒（Hhex）基因是同源盒基因家族的成员，是胚胎发生和造血祖细胞发育的重要调节因子。为了研究 Hhex 在造血中的作用，我们采用了一种鼠胚胎干细胞（ES）细胞共培养系统，其中 ES 细胞可以在体外分化为 CD41(+)和 CD45(+)造血祖细胞。我们的结果表明，除了延迟的血岛发育外，Hhex(-/-) ES 衍生的后代还会积累为 CD41(+)和 CD41(+)c-kit(+)细胞，或者是最早的确定性造血祖细胞。此外，Hhex(-/-) ES 衍生的后代显示出显著降低的能力发育成成熟的 CD45(+)造血细胞。观察到的造血成熟减少伴随着增殖减少，因为 Hhex(-/-) CD41(+)CD45(-)c-kit(+)造血祖细胞在细胞周期的 G2 期积累。因此，Hhex 是造血发育的关键调节因子，对于最早的确定性造血祖细胞的成熟和增殖是必需的。
