THE IN-VITRO AND IN-VIVO EFFECTS OF STEM-CELL FACTOR ON HUMAN HEMATOPOIESIS

The c-kit ligand or stem cell factor (SCF) and the c-kit ligand recept or (KR) are thought to play pivotal roles in the regulation of human h ematopoiesis. When added to interleukin 3 (IL-3) and/or granulocyte-ma crophage colony stimulating factor (GM-CSF), SCF has an especially pro found effect on the in vitro proliferation of several classes of primi tive hematopoietic progenitor cells including the burst forming unit m egakaryocyte (BFU-MK), the high proliferative potential colony forming cell (HPP-CFC) and the long-term bone marrow culture-initiating cell (LTBMC-IC). These primitive hematopoietic progenitor cells are present in a CD34+HLA-DR- fraction of marrow which has in vivo marrow populat ing ability and thereby resembles the pluripotent hematopoietic stem c ell. Furthermore, the CD34+HLA-DR- marrow subpopulation which expresse s KR contains virtually all of the marrow BFU-MK, HPP-CFC and LTBMC-IC , indicating that the human stem cell is KR positive. The addition of SCF, IL-3 and GM-CSF to suspension cultures initiated with CD34+HLA-DR - cells results in an exponential expansion of the numbers of hematopo ietic progenitor cells. Large numbers of such progenitor cells generat ed ex vivo may be useful as transfusion products for the treatment of chemotherapy induced cytopenias. The therapeutic potential of the in v ivo administration of SCF has also been evaluated in a phase I trial o f recombinant methionyl SCF. SCF administration led to an increase in both differentiated and primitive hematopoietic progenitor cells withi n the marrow. Such studies suggest that in vivo SCF administration may be useful for improving the quality of bone marrow grafts to be used either for autologous or allogeneic bone marrow transplantation. SCF t herefore appears to be a pivotal cytokine within the regulatory framew ork of human hematopoiesis which has potentially important clinical us es.