Mature stem cell factor consists of a 189 amino acid (aa) extracellular domain (ECD), a 23 aa transmembrane domain, and a 36 aa cytoplasmic tail (10). The ECD shows both N linked and O-linked glycosylation (11). SCF protein exists in two forms, a membrane-bound form and a proteolytically processed soluble form that lacks the transmembrane domain and cytoplasmic tail. The soluble form is created by proteolytic cleavage at two alternate sites in the extracellular juxtamembrane region releasing a 25 kDa soluble SCF protein which is comparable to the only form produced by Steel-dickie mutant mice (12, 13). There is also an alternately spliced isoform of human SCF that lacks 28 amino acids that encompasses the primary proteolytic recognition site (14). This form cannot be cleaved and is only membrane bound. SCF binds to C-kit (CD117). C-kit is expressed on many different cell types including HSCs, mast cells, germ cells, and melanocytes. Binding of SCF to C-kit induces receptor dimerization and autophosphorylation of tyrosine residues in the cytoplasmic domain (15). Tyrosine phosphorylation initiates multiple signaling pathways including RAS, PI3 kinase, Src, and JAK/STAT. Stem cell factor is highly conserved among mammals. Human SCF protein shares 79% 87% aa sequence identity with dog, cat, mouse, and rat SCF. Rat SCF is active on mouse and human cells, but human SCF is only weakly active on mouse cells (10).
SCF is a versatile factor in the differentiation
of many specific cell types like spermatogonial stem cells (16) and megakaryocyte
progenitors (17). Apart from differentiation, SCF also can maintain stemness in
cells. This is the case for human bone marrow mesenchymal cells, which require
SCF and hepatocyte growth factor for maintenance (18). Hematopoietic stem cells
similarly require SCF from surrounding cells in their niche to maintain their
stemness and their progenitors (19). SCF has also improved protocols for
continuous generation of cells in culture systems, like granulocytes and
macrophages (20).
For
treatment of graft versus host disease, SCF is used in combination with other
cytokines to generate myeloid-derived suppressor cells from human umbilical
cord blood (21). SCF is also used to generate T cells for cell-based therapies,
drug screening and disease modeling (22). In regenerative studies, SCF is applied
in wound healing hydrogel as a means of increasing its adhesion strength and
tissue regeneration (23).
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