|Budget Amount *help
¥3,300,000 (Direct Cost : ¥3,300,000)
Fiscal Year 1999 : ¥1,500,000 (Direct Cost : ¥1,500,000)
Fiscal Year 1998 : ¥1,800,000 (Direct Cost : ¥1,800,000)
Fetal liver, the major site of hematopoiesis during embryonic development, acquires additional various metabolic functions near birth. Although liver development has been characterized biologically to consist of several distinct steps, the molecular events accompanying this process are just beginning to be characterized. In this study, we have established a novel culture system of fetal murine hepatocytes and investigated factors. required for development of hepatocytes. Oncostatin M (OSM), an IL-6-family cytokine, in combination with glucocorticoid induced maturation of hepatocytes as evidenced by morphological changes that closely resemble more-differentiated hepatocytes, expression of hepatic differentiation markers and intracellular glycogen accumulation. Consistent with these in vitro observations, livers from mice deficient for gp 130, an OSM receptor subunit, display defects in maturation of hepatocytes. Interestingly, OSM is expressed in CD45+- hematopoietic cells in the develo
ping liver, whereas the OSM receptor is predominantly expressed in hepatocytes. These results suggest a paracrine mechanism of hepatogenesis ; blood cells, transiently expanding in the fetal liver, produce OSM to promote development of hepatocytes in vivo.
While the liver starts organizing its own structure and develops numerous metabolic functions toward adult, hematopoietic cells relocate from the liver to their final destinations along with maturation of the bone *arrow and spleen. As described above, the signal exerted by OSM through gp130 plays a pivotal role in the maturation process of the liver both in vitro and in vivo. However, the molecular basis underlying the termination of embryonic hematopoiesis remains unknown. We therefore analyzed our culture system in detail and showed that primary culture of fetal hepatic cells from E14.5-murine embryos supported expansion of blood cells from Lin-Sca-1+c-Kit+ cells, giving rise to myeloid, lymphoid and erythroid lineages. Interestingly, promotion of hepatic development by OSM and glucocorticoid strongly suppressed in vitro hematopoiesis. Consistent with these results, hepatic culture from the E18.5-embryonic liver no longer supported hematopoiesis. These data suggest that the signals generated by OSM and glucocorticoid induce hepatic differentiation which in turn terminate embryonic hematopoiesis and promote relocation of hematopoietic cells. Less