Biology:Stem cell factor

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Stem cell factor (also known as SCF, KIT-ligand, KL, or steel factor) is a cytokine that binds to the c-KIT receptor (CD117). SCF can exist both as a transmembrane protein and a soluble protein. This cytokine plays an important role in hematopoiesis (formation of blood cells), spermatogenesis, and melanogenesis.

Production

The gene encoding stem cell factor (SCF) is found on the Sl locus in mice and on chromosome 12q22-12q24 in humans.[1] The soluble and transmembrane forms of the protein are formed by alternative splicing of the same RNA transcript,[2][3]

Figure 1: Alternative splicing of the same RNA transcript produces soluble and transmembrane forms of stem cell factor (SCF).

The soluble form of SCF contains a proteolytic cleavage site in exon 6. Cleavage at this site allows the extracellular portion of the protein to be released. The transmembrane form of SCF is formed by alternative splicing that excludes exon 6 (Figure 1). Both forms of SCF bind to c-KIT and are biologically active.

Soluble and transmembrane SCF is produced by fibroblasts and endothelial cells. Soluble SCF has a molecular weight of 18,5 KDa and forms a dimer. It is detected in normal human blood serum at 3.3 ng/mL.[4]

Role in development

SCF plays an important role in the hematopoiesis during embryonic development. Sites where hematopoiesis takes place, such as the fetal liver and bone marrow, all express SCF. Mice that do not express SCF die in utero from severe anemia. Mice that do not express the receptor for SCF (c-KIT) also die from anemia.[5] SCF may serve as guidance cues that direct hematopoietic stem cells (HSCs) to their stem cell niche (the microenvironment in which a stem cell resides), and it plays an important role in HSC maintenance. Non-lethal point mutants on the c-KIT receptor can cause anemia, decreased fertility, and decreased pigmentation.[6]

During development, the presence of the SCF also plays an important role in the localization of melanocytes, cells that produce melanin and control pigmentation. In melanogenesis, melanoblasts migrate from the neural crest to their appropriate locations in the epidermis. Melanoblasts express the KIT receptor, and it is believed that SCF guides these cells to their terminal locations. SCF also regulates survival and proliferation of fully differentiated melanocytes in adults.[7]

In spermatogenesis, c-KIT is expressed in primordial germ cells, spermatogonia, and in primordial oocytes.[8] It is also expressed in the primordial germ cells of females. SCF is expressed along the pathways that the germ cells use to reach their terminal destination in the body. It is also expressed in the final destinations for these cells. Like for melanoblasts, this helps guide the cells to their appropriate locations in the body.[5]

Role in hematopoiesis

SCF plays a role in the regulation of HSCs in the stem cell niche in the bone marrow. SCF has been shown to increase the survival of HSCs in vitro and contributes to the self-renewal and maintenance of HSCs in-vivo. HSCs at all stages of development express the same levels of the receptor for SCF (c-KIT).[9] The stromal cells that surround HSCs are a component of the stem cell niche, and they release a number of ligands, including SCF.

Figure 2: A diagram of a hematopoietic stem cell (HSC) inside its niche. It is adjacent to stromal cells that secrete ligands, such as stem cell factor (SCF).

In the bone marrow, HSCs and hematopoietic progenitor cells are adjacent to stromal cells, such as fibroblasts and osteoblasts (Figure 2). These HSCs remain in the niche by adhering to ECM proteins and to the stromal cells themselves. SCF has been shown to increase adhesion and thus may play a large role in ensuring that HSCs remain in the niche.[5]

A small percentage of HSCs regularly leave the bone marrow to enter circulation and then return to their niche in the bone marrow.[10] It is believed that concentration gradients of SCF, along with the chemokine SDF-1, allow HSCs to find their way back to the niche.[11]

In adult mice, the injection of the ACK2 anti-KIT antibody, which binds to the c-Kit receptor and inactivates it, leads to severe problems in hematopoiesis. It causes a significant decrease in the number HSC and other hematopoietic progenitor cells in the bone marrow.[12] This suggests that SCF and c-Kit plays an important role in hematopoietic function in adulthood. SCF also increases the survival of various hematopoietic progenitor cells, such as megakaryocyte progenitors, in vitro.[13] In addition, it works with other cytokines to support the colony growth of BFU-E, CFU-GM, and CFU-GEMM4. Hematopoietic progenitor cells have also been shown to migrate towards a higher concentration gradient of SCF in vitro, which suggests that SCF is involved in chemotaxis for these cells.

Fetal HSCs are more sensitive to SCF than HSCs from adults. In fact, fetal HSCs in cell culture are 6 times more sensitive to SCF than adult HSCs based on the concentration that allows maximum survival.[14]

Expression in mast cells

Mast cells are the only terminally differentiated hematopoietic cells that express the c-Kit receptor. Mice with SCF or c-Kit mutations have severe defects in the production of mast cells, having less than 1% of the normal levels of mast cells. Conversely, the injection of SCF increases mast cell numbers near the site of injection by over 100 times. In addition, SCF promotes mast cell adhesion, migration, proliferation, and survival.[15] It also promotes the release of histamine and tryptase, which are involved in the allergic response.

Soluble and transmembrane forms

The presence of both soluble and transmembrane SCF is required for normal hematopoietic function.[2][16] Mice that produce the soluble SCF but not transmembrane SCF suffer from anemia, are sterile, and lack pigmentation. This suggests that transmembrane SCF plays a special role in vivo that is separate from that of soluble SCF.

c-KIT receptor

Figure 3: c-Kit expression in hematopoietic cells

SCF binds to the c-KIT receptor (CD 117), a receptor tyrosine kinase.[17] c-Kit is expressed in HSCs, mast cells, melanocytes, and germ cells. It is also expressed in hematopoietic progenitor cells including erythroblasts, myeloblasts, and megakaryocytes. However, with the exception of mast cells, expression decreases as these hematopoietic cells mature and c-KIT is not present when these cells are fully differentiated (Figure 3). SCF binding to c-KIT causes the receptor to homodimerize and auto-phosphorylate at tyrosine residues. The activation of c-Kit leads to the activation of multiple signaling cascades, including the RAS/ERK, PI3-Kinase, Src kinase, and JAK/STAT pathways.[17]

Clinical relevance

SCF may be used along with other cytokines to culture HSCs and hematopoietic progenitors. The expansion of these cells ex-vivo (outside the body) would allow advances in bone marrow transplantation, in which HSCs are transferred to a patient to re-establish blood formation.[9] One of the problems of injecting SCF for therapeutic purposes is that SCF activates mast cells. The injection of SCF has been shown to cause allergic-like symptoms and the proliferation of mast cells and melanocytes.[5]

Cardiomyocyte-specific overexpression of transmembrane SCF promotes stem cell migration and improves cardiac function and animal survival after myocardial infarction.[18]

Interactions

Stem cell factor has been shown to interact with CD117.[19][20]

References

  1. ↑ "Stem cell factor (SCF), a novel hematopoietic growth factor and ligand for c-kit tyrosine kinase receptor, maps on human chromosome 12 between 12q14.3 and 12qter". Somat. Cell Mol. Genet. 17 (2): 207–14. March 1991. doi:10.1007/BF01232978. PMID 1707188. 
  2. ↑ 2.0 2.1 "Transmembrane form of the kit ligand growth factor is determined by alternative splicing and is missing in the Sld mutant". Cell 64 (5): 1025–35. March 1991. doi:10.1016/0092-8674(91)90326-t. PMID 1705866. 
  3. ↑ "Alternate splicing of mRNAs encoding human mast cell growth factor and localization of the gene to chromosome 12q22-q24". Cell Growth Differ. 2 (8): 373–8. August 1991. PMID 1724381. 
  4. ↑ "Soluble stem cell factor in human serum". Blood 81 (3): 656–60. February 1993. doi:10.1182/blood.V81.3.656.656. PMID 7678995. 
  5. ↑ 5.0 5.1 5.2 5.3 "Stem cell factor and hematopoiesis". Blood 90 (4): 1345–64. August 1997. doi:10.1182/blood.V90.4.1345. PMID 9269751. 
  6. ↑ "The White spotting and Steel hereditary anaemias of the mouse". Clinical disorders and experimental models of erythropoietic failure. Boca Raton: CRC Press. 1993. ISBN 0-8493-6678-X. 
  7. ↑ "The role of Kit-ligand in melanocyte development and epidermal homeostasis". Pigment Cell Res. 16 (3): 287–96. June 2003. doi:10.1034/j.1600-0749.2003.00055.x. PMID 12753403. 
  8. ↑ "Role of c-kit in mammalian spermatogenesis". J. Endocrinol. Invest. 23 (9): 609–15. October 2000. doi:10.1007/bf03343784. PMID 11079457. https://art.torvergata.it/bitstream/2108/65858/2/Rossi-JEndocrinolInvest-2000.pdf. 
  9. ↑ 9.0 9.1 "Regulation of hematopoietic stem cells by the steel factor/KIT signaling pathway". Clin. Cancer Res. 14 (7): 1926–30. April 2008. doi:10.1158/1078-0432.CCR-07-5134. PMID 18381929. 
  10. ↑ "Haematopoietic stem cell release is regulated by circadian oscillations". Nature 452 (7186): 442–7. March 2008. doi:10.1038/nature06685. PMID 18256599. Bibcode: 2008Natur.452..442M. 
  11. ↑ "Cytokines and hematopoietic stem cell mobilization". J. Cell. Biochem. 99 (3): 690–705. October 2006. doi:10.1002/jcb.21043. PMID 16888804. 
  12. ↑ "Expression and function of c-kit in hemopoietic progenitor cells". J. Exp. Med. 174 (1): 63–71. July 1991. doi:10.1084/jem.174.1.63. PMID 1711568. 
  13. ↑ "Steel factor (c-kit ligand) promotes the survival of hematopoietic stem/progenitor cells in the absence of cell division". Blood 86 (5): 1757–64. September 1995. doi:10.1182/blood.V86.5.1757.bloodjournal8651757. PMID 7544641. 
  14. ↑ "Steel factor responsiveness regulates the high self-renewal phenotype of fetal hematopoietic stem cells". Blood 109 (11): 5043–8. June 2007. doi:10.1182/blood-2006-08-037770. PMID 17327414. 
  15. ↑ "Development, migration, and survival of mast cells". Immunol. Res. 34 (2): 97–115. 2006. doi:10.1385/IR:34:2:97. PMID 16760571. 
  16. ↑ "Steel-Dickie mutation encodes a c-kit ligand lacking transmembrane and cytoplasmic domains". Proc. Natl. Acad. Sci. U.S.A. 88 (11): 4671–4. June 1991. doi:10.1073/pnas.88.11.4671. PMID 1711207. Bibcode: 1991PNAS...88.4671B. 
  17. ↑ 17.0 17.1 "Signal transduction via the stem cell factor receptor/c-Kit". Cell. Mol. Life Sci. 61 (19–20): 2535–48. October 2004. doi:10.1007/s00018-004-4189-6. PMID 15526160. 
  18. ↑ "Cardiomyocyte-specific overexpression of human stem cell factor improves cardiac function and survival after myocardial infarction in mice". Circulation 120 (12): 1065–74, 9 p following 1074. September 2009. doi:10.1161/CIRCULATIONAHA.108.839068. PMID 19738140. 
  19. ↑ "A recombinant ectodomain of the receptor for the stem cell factor (SCF) retains ligand-induced receptor dimerization and antagonizes SCF-stimulated cellular responses". J. Biol. Chem. 267 (15): 10866–73. May 1992. doi:10.1016/S0021-9258(19)50098-9. PMID 1375232. 
  20. ↑ "Soluble c-kit proteins and antireceptor monoclonal antibodies confine the binding site of the stem cell factor". J. Biol. Chem. 268 (6): 4399–406. Feb 1993. doi:10.1016/S0021-9258(18)53623-1. PMID 7680037. 

Further reading

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