Bone morphogenetic proteins regulate the developmental program of human hematopoietic stem cells

The identification of molecules that regulate human hematopoietic stem cell s has focused mainly on cytokines, of which very few are known to act direc tly on stent cells. Recent studies in lower organisms and the mouse have su ggested that bone morphogenetic proteins (BMPs) may play a critical role in the specification of hematopoietic tissue from the mesodermal germ layer. Here we report that BMPs regulate the proliferation and differentiation of highly purified primitive human hematopoietic cells from adult and neonatal sources. Populations of rare CD34(+)CD38(-)Lin(-) stem cells were isolated from human hematopoietic tissue and were found to express the BMP type I r eceptors activin-like kinase (ALK)-3 and ALK-6, and their downstream transd ucers SMAD-1, -4, and -5. Treatment of isolated stein cell populations with soluble BMP-2, -4, and -7 induced dose-dependent changes ill proliferation , clonogenicity, cell surface phenotype, and multilineage repopulation capa city after transplantation in nonobese diabetic/severe combined immunodefic ient (NOD/SCID) mice. Similar to transforming growth factor beta, treatment of purified cells with BMP-2 or -7 at high concentrations inhibited prolif eration yet maintained the primitive CD34(+)CD38(-) phenotype and repopulat ion capacity. In contrast, low concentrations of BMP-4 induced proliferatio n and differentiation of CD34(+) CD38(-)Lin(-) cells, whereas at higher con centrations BMP-4 extended the length of time that repopulation capacity co uld be: maintained in ex vivo culture, indicating; a direct effect on stem cell survival. The discovery that BMPs are capable of regulating repopulati ng cells provides a new pathway for controlling human stem cell development and a powerful model system for studying the biological mechanism of BMP a ction using primary human cells.