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Self-renewal, maturation, and differentiation of the rat myelomonocytic hematopoietic stem cell

^a Institute of General and Experimental Pathology, A-1090 Vienna, Austria;

^b Institute of Histology and Embryology, A-1090 Vienna, Austria;

^c Institute of Medical Biology and Human Genetics, A-8010 Graz, Austria; and

^d Research Institute of Molecular Pathology, A-1030 Vienna, Austria

Hematopoiesis is viewed as a differentiating system emanating from a pluripotent hematopoietic stem cell capable of both self-renewal and differentiation. By identifying and characterizing a novel and highly specific in vitro mitogenic response to the N-acetyl glucosamyl/sialic acid specific, stem cell-binding lectin wheat germ agglutinin (WGA), we demonstrate the existance of a rare (0.1%), plastic adherent precursor in rat bone marrow capable of proliferation (two to seven divisions) in response to WGA. Stimulated cells possess a lineage (lin)^low/- immunophenotype and immature blastoid morphology (WGA blasts). A subsequent proliferative response to stem cell factor (SCF), the ligand for the proto-oncogene receptor tyrosine kinase c-kit, is characterized by an initial maturation in immunophenotype and subsequent self-renewal of cells (SCF blasts) without differentiation for at least 50 generations. Although granulocyte colony-stimulating factor (G-CSF), interleukin (IL) -6, IL-7, and IL-11 synergize with SCF to increase blast colony formation, cytokines such as granulocyte-macrophage CSF or IL-3 are without significant effect. At all time points in culture, however, cells rapidly differentiate to mature neutrophils with dexamethasone or to mainly monocytes/macrophages in the presence of 1,25-dihydroxyvitamin D₃, characterized by cell morphology and cytochemistry. Removal of SCF during blast maturation, self-renewal, or induction of differentiation phases results in apoptotic cell death. Data indicate a pivotal role for SCF/c-kit interaction during antigenic maturation, self-renewal, and apoptotic protection of these lineage-restricted progenitors during non-CSF-mediated induction of differentiation. This approach provides a source of many normal, proliferating myelomonocytic precursor cells, and introduces possible clinical applications of ex vivo expanded myeloid stem cells.—Lucas, T., Krugluger, W., Samorapoompichit, P., Gamperl, R., Beug, H., Förster, O., Boltz-Nitulescu, G. Self-renewal, maturation, and differentiation of the myelomonocytic hematopoietic stem cell.

Key Words: lectins • stem cell factor • cell proliferation • cell differentiation • dexamethasone • calcitriol