Role of bone morphogenetic protein-4 in primitive human hematopoietic cell fate

Embryonic cell fate and differentiation is directed by a network of proteins and morphogens. The views regarding irreversible cell fate commitment are currently being re-evaluated after demonstrations of muscle- and neural-derived hematopoietic cells and bone marrow-derived mesenchymal cells. The epigenetic signals that are critical to such differentiation events are not known. Bone morphogenetic protein-4 (BMP-4) has demonstrated a potent role in the induction of vertebrate hematopoiesis, the regulation of human hematopoietic stem cells, as well as the induction of cartilage formation and differentiation. Given that BMP-4 is involved in the embryonic cell fate of multiple tissues as well as a role in adult hematopoietic stem cell maintenance and expansion, this factor may be important in the regulation primitive hematopoietic cell fate by promoting hematopoietic differentiation and mediating hematopoietic lineage commitment.; The studies presented here examine the potential role of BMP-4 to differentiate muscle, neural and hematopoietic tissue and/or direct their lineage development. Human muscle- and neural-derived tissues cultured in the presence of BMP-4 demonstrated an increase in hematopoietic progenitor capacity compared to uncultured cells from these tissues. The expansion and lineage development of muscle- and neural-derived hematopoietic progenitors mediated by BMP-4 was unique to isolated non-hematopoietic tissues, as circulating blood cells did not demonstrate the same BMP-4 induced response. Additionally, a previously uncharacterized population of umbilical cord blood cells lacking the characteristic hematopoietic marker CD45 was shown to possess both clonogenic hematopoietic progenitor capacity and the ability to differentiate into cartilage cells after co-culture with BMP-4 and mouse embryonic limb bud cells. Cartilage-specific proteins in the human cells could only be detected when cultured in the presence of BMP-4. Finally, mature and primitive cells from human hematopoietic tissue express the majority of the signaling molecules required to respond to bone morphogenetic proteins while the BMP receptor, ALK6, is preferentially expressed in primitive subpopulations enriched for repopulating cells. Forced expression of a constitutively active form of ALK6 in repopulating cells promoted myeloid differentiation at the expense of lymphopoiesis. These studies indicate that BMP-4 represents a potent regulator of hematopoietic cell fate in the human, broadly affecting both hematopoietic and non-hematopoietic tissue.