The homeobox gene Hhex regulates the earliest stages of definitive hematopoiesis

Abstract

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 G2 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. © 2010 by The American Society of Hematology.