The flt3 ligand promotes the survival of primitive hemopoietic progenitor cells with myeloid as well as B lymphoid potential. Suppression of apoptosis and counteraction by TNF-alpha and TGF-beta

• Published in: The Journal of immunology (1950) Vol. 157; no. 7; pp. 2953 - 2960
• Main Authors: Veiby, OP, Jacobsen, FW, Cui, L, Lyman, SD, Jacobsen, SE
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01.10.1996
• Subjects: Animals; Apoptosis - drug effects; B-Lymphocytes - cytology; Cell Division - drug effects; Cell Lineage; Cell Survival - drug effects; Colony-Forming Units Assay; Drug Synergism; fms-Like Tyrosine Kinase 3; Granulocyte Colony-Stimulating Factor - pharmacology; Hematopoiesis - physiology; Hematopoietic Cell Growth Factors - pharmacology; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - drug effects; Humans; Interleukin-1 - pharmacology; Interleukin-7 - pharmacology; Membrane Proteins - pharmacology; Mice; Mice, Inbred C57BL; Proto-Oncogene Proteins - physiology; Radiation Chimera; Receptor Protein-Tyrosine Kinases - physiology; Recombinant Proteins - pharmacology; Stem Cell Factor - pharmacology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.157.7.2953

The recently cloned fIt3 ligand (FL) potently enhances hemopoietic growth factor-induced growth of primitive hemopoietic progenitors. In agreement with previous reports, we found FL alone to be a weak mitogen for primitive Lin-Sca-1+ murine bone marrow progenitors. Using delayed addition of growth-promoting cytokines, we demonstrate that FL potently promotes the in vitro survival of Lin-Sca-1+ progenitors responsive to a potent myeloid growth factor combination (FL, stem cell factor (SCF), granulocyte CSF (G-CSF), and IL-1 alpha). Whereas no such progenitors survived in cultures supplemented with medium alone, 33% survived in FL compared with 75 and 13% in the presence of SCF and IL-1 alpha, respectively. These results were obtained when cells were plated individually, suggesting that the viability-promoting effect of FL is mediated directly on the progenitors. Whereas SCF was superior to FL in promoting the survival of FL-, SCF-, G-CSF-, and IL-1 alpha-stimulated Lin-Sca-1+ progenitors, FL was more efficient than SCF at promoting the survival of progenitors with a B cell potential, as measured by their ability to produce B220+ cells in response to delayed addition of FL, SCF, and IL-7. Seventy-one percent of the B220+ cell production could be recovered following 40-h incubation with FL compared with 2% in response to SCF. Analysis of day 12 spleen CFU content after 40-h preincubation of Lin-Sca-1+ cells in FL or SCF demonstrated that SCF maintained 64% of the day 12 spleen CFU, whereas only 16% survived in the presence of FL. Finally, there was no significant difference between the ability of FL and SCF to maintain the viability of long-term culture-initiating cells (25 and 32%, respectively). The ability of FL to promote the survival of Lin-Sca-1+ progenitor cells was reflected by the finding that FL also suppressed apoptosis. Finally, TGF-beta abrogated and TNF-alpha potently counteracted the survival-promoting effect of FL. Thus, FL promotes the survival of primitive hemopoietic progenitor cells, in particular those with an inherent B lymphoid potential.