BMP4: its role in development of the hematopoietic system and potential as a hematopoietic growth factor.

Blood formation occurs throughout the life of an individual in a process driven by hematopoietic stem cells (HSCs). The ability of bone marrow (BM) and cord blood (CB) HSC to undergo self-renewal and develop into multiple blood lineages has made these cells an important clinical resource. Transplantation with BM- and CB-derived HSCs is now used extensively for treatment of hematological disorders, malignancies, and immunodeficiencies. An understanding of the embryonic origin of HSC and the factors regulating their generation and expansion in vivo will provide important information for the manipulation of these cells ex vivo. This is critical for the further development of CB transplantation, the potential of which is limited by small numbers of HSC in the donor population. Although the origins of HSCs have become clearer and progress has been made in identifying genes that are critical for the formation and maintenance of HSCs, less is known about the signals that commit specific populations of mesodermal precursors to hematopoietic cell fate. Critical signals acting on these precursor cells are likely to be derived from visceral endoderm in yolk sac and from underlying stroma in the aorta-gonad-mesonephros region. Here we summarize briefly the origin of yolk sac and embryonic HSCs before detailing evidence that bone morphogenic protein-4 (BMP4) has a crucial role in Xenopus and mammalian HSC development. We discuss evidence that BMP4 acts as a hematopoietic growth factor and review its potential to modulate HSC in ex vivo expansion cultures from cord blood.