Flt3-ligand: A Stem Cell Therapy Growth Factor (Cytokine)

Overall Introduction of Flt3-ligand Growth Factor

Flt3-ligand is a cell surface transmembrane protein type I that can be proteolytically processed and released as a soluble protein. Alternative splicing contributes to generation of a soluble Flt3-ligand isoform by a stop codon inserted into the reading frame of the sixth exon. In contrast to the restricted distribution of flt3 receptors, Flt3-ligand mRNA is ubiquitously expressed in hematopoietic and nonhematopoietic tissues. Despite the widespread expression of Flt3-ligand mRNA, the Flt3-ligand protein has only been found in stromal fibroblasts present in the bone marrow microenvironment and T lymphocytes. Both the membrane-bound and soluble isoforms of Flt3-ligand are biologically active and stimulate the tyrosine kinase activity of flt3. Mice lacking Flt3-ligand as a result of targeted gene disruption are viable but have more severe defects than flt3 receptor knockouts, including reduced cellularity in the hematopoietic organs, reduced numbers of myeloid and lymphoid progenitors in the bone marrow, and a marked deficiency of natural killer (NK) cells and dendritic cells (DCs) in lymph nodes, spleen, and thymus. A central role played by Flt3-ligand in the proliferation, survival, and differentiation of early hematopoietic precursor cells is underscored by a broad range of hematopoietic activities mediated by this cytokine in vitro and in vivo.

Flt3-ligand Effects on Hematopoietic Stem Cells

Flt3-Ligand plays a key role in the regulation of early events in the development of multiple hematopoietic lineages. Flt3-Ligand stimulates the development of primitive multipotent precursors, as well as more committed or restricted myeloid precursors. Flt3-Ligand has an effect on early B cell development as well as on T cell development, at least in the embryo. These effects of Flt3-Ligand on hematopoietic stem cells are similar to those observed with Steel factor (SLF), and both of these proteins synergize with a variety of cytokines to stimulate the proliferation of hematopoietic stem cells. However, there are a number of differences between the biological effects of these two hematopoietic factors, the most notable being the lack of effect of Flt3-Ligand on mast cells. Mice lacking the Flt3 receptor have a mild defect in early B cell development, and stem cells isolated from these mice have an impaired ability to reconstitute lethally irradiated recipients. Serum levels of Flt3-Ligand are normally quite low in healthy humans (< 100 pg/ml), but are highly elevated in individuals afflicted with anemias with a stem cell component, such as Fanconi or acquired aplastic anemia, but not in single lineage anemias, such as Diamond­Blackfan. These data suggest that Flt3-Ligand may be a key physiological regulator of stem cells in vivo. Flt3-Ligand may find clinical utility in the treatment of hematopoietic disorders, especially those involving multiple lineages.

Flt3-ligand Effects on mesenchymal stem cells

It was shown that intracellular Flt3 receptors have been found to exist in human mesenchymal stem cells and expansion of human mesenchymal stem cells is highly dependant on the time, duration and concentration of Flt3-Ligand as well as in combination with other growth factors, which work together in a synergistic effect to influence the expansion of human mesenchymal stem cells. Expansion of human mesenchymal stem cells using Flt3-Ligand and other growth factors does not affect the cell's pluripotency, as shown by characterisation of human mesenchymal stem cells before and after expansion.

Flt3-ligand: A Stem Cell Therapy Growth Factor (Cytokine)-Reference

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