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.
The gene encoding stem cell factor (SCF) is found on the Sl locus in mice and on chromosome 12q22-12q24 in humans. [5] The soluble and transmembrane forms of the protein are formed by alternative splicing of the same RNA transcript, [6] [7]
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. [8]
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. [9] 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. [10]
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. [11]
In spermatogenesis, c-KIT is expressed in primordial germ cells, spermatogonia, and in primordial oocytes. [12] 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. [9]
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). [13] The stromal cells that surround HSCs are a component of the stem cell niche, and they release a number of ligands, including 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. [9]
A small percentage of HSCs regularly leave the bone marrow to enter circulation and then return to their niche in the bone marrow. [14] It is believed that concentration gradients of SCF, along with the chemokine SDF-1, allow HSCs to find their way back to the niche. [15]
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. [16] 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. [17] 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. [18]
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. [19] It also promotes the release of histamine and tryptase, which are involved in the allergic response.
The presence of both soluble and transmembrane SCF is required for normal hematopoietic function. [6] [20] 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.
SCF binds to the c-KIT receptor (CD 117), a receptor tyrosine kinase. [21] 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. [21]
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. [13] 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. [9]
Cardiomyocyte-specific overexpression of transmembrane SCF promotes stem cell migration and improves cardiac function and animal survival after myocardial infarction. [22]
Stem cell factor has been shown to interact with CD117. [23] [24]
Haematopoiesis is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. In a healthy adult human, roughly ten billion to a hundred billion new blood cells are produced per day, in order to maintain steady state levels in the peripheral circulation.
Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within the (midgestational) aorta-gonad-mesonephros region, through a process known as endothelial-to-hematopoietic transition. In adults, haematopoiesis occurs in the red bone marrow, in the core of most bones. The red bone marrow is derived from the layer of the embryo called the mesoderm.
Interleukin 3 (IL-3) is a protein that in humans is encoded by the IL3 gene localized on chromosome 5q31.1. Sometimes also called colony-stimulating factor, multi-CSF, mast cell growth factor, MULTI-CSF, MCGF; MGC79398, MGC79399: after removal of the signal peptide sequence, the mature protein contains 133 amino acids in its polypeptide chain. IL-3 is produced as a monomer by activated T cells, monocytes/macrophages and stroma cells. The major function of IL-3 cytokine is to regulate the concentrations of various blood-cell types. It induces proliferation and differentiation in both early pluripotent stem cells and committed progenitors. It also has many more specific effects like the regeneration of platelets and potentially aids in early antibody isotype switching.
CD34 is a transmembrane phosphoglycoprotein protein encoded by the CD34 gene in humans, mice, rats and other species.
C-X-C chemokine receptor type 4 (CXCR-4) also known as fusin or CD184 is a protein that in humans is encoded by the CXCR4 gene. The protein is a CXC chemokine receptor.
In immunology, central tolerance is the process of eliminating any developing T or B lymphocytes that are autoreactive, i.e. reactive to the body itself. Through elimination of autoreactive lymphocytes, tolerance ensures that the immune system does not attack self peptides. Lymphocyte maturation occurs in primary lymphoid organs such as the bone marrow and the thymus. In mammals, B cells mature in the bone marrow and T cells mature in the thymus.
Extramedullary hematopoiesis refers to hematopoiesis occurring outside of the medulla of the bone. It can be physiologic or pathologic.
The CD44 antigen is a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the CD44 gene on chromosome 11. CD44 has been referred to as HCAM, Pgp-1, Hermes antigen, lymphocyte homing receptor, ECM-III, and HUTCH-1.
Endothelial stem cells (ESCs) are one of three types of stem cells found in bone marrow. They are multipotent, which describes the ability to give rise to many cell types, whereas a pluripotent stem cell can give rise to all types. ESCs have the characteristic properties of a stem cell: self-renewal and differentiation. These parent stem cells, ESCs, give rise to progenitor cells, which are intermediate stem cells that lose potency. Progenitor stem cells are committed to differentiating along a particular cell developmental pathway. ESCs will eventually produce endothelial cells (ECs), which create the thin-walled endothelium that lines the inner surface of blood vessels and lymphatic vessels. The blood vessels include arteries and veins. Endothelial cells can be found throughout the whole vascular system and they also play a vital role in the movement of white blood cells
Granulopoiesis is a part of haematopoiesis, that leads to the production of granulocytes. A granulocyte, also referred to as a polymorphonuclear leukocyte (PMN), is a type of white blood cell that has multi lobed nuclei, usually containing three lobes, and has a significant amount of cytoplasmic granules within the cell. Granulopoiesis takes place in the bone marrow. It leads to the production of three types of mature granulocytes: neutrophils, eosinophils and basophils.
Proto-oncogene c-KIT is the gene encoding the receptor tyrosine kinase protein known as tyrosine-protein kinase KIT, CD117 or mast/stem cell growth factor receptor (SCFR). Multiple transcript variants encoding different isoforms have been found for this gene. KIT was first described by the German biochemist Axel Ullrich in 1987 as the cellular homolog of the feline sarcoma viral oncogene v-kit.
Cluster of differentiation antigen 135 (CD135) also known as fms like tyrosine kinase 3, receptor-type tyrosine-protein kinase FLT3, or fetal liver kinase-2 (Flk2) is a protein that in humans is encoded by the FLT3 gene. FLT3 is a cytokine receptor which belongs to the receptor tyrosine kinase class III. CD135 is the receptor for the cytokine Flt3 ligand (FLT3L).
The granulocyte-macrophage colony-stimulating factor receptor, also known as CD116, is a receptor for granulocyte-macrophage colony-stimulating factor, which stimulates the production of white blood cells. In contrast to M-CSF and G-CSF which are lineage specific, GM-CSF and its receptor play a role in earlier stages of development. The receptor is primarily located on neutrophils, eosinophils and monocytes/macrophages, it is also on CD34+ progenitor cells (myeloblasts) and precursors for erythroid and megakaryocytic lineages, but only in the beginning of their development.
Fms-related tyrosine kinase 3 ligand (FLT3LG) is a protein which in humans is encoded by the FLT3LG gene.
Homeobox protein Hox-A9 is a protein that in humans is encoded by the HOXA9 gene.
Endothelial protein C receptor (EPCR) also known as activated protein C receptor is a protein that in humans is encoded by the PROCR gene. PROCR has also recently been designated CD201.
CFU-GEMM is a colony forming unit that generates myeloid cells. CFU-GEMM cells are the oligopotential progenitor cells for myeloid cells; they are thus also called common myeloid progenitor cells or myeloid stem cells. "GEMM" stands for granulocyte, erythrocyte, monocyte, megakaryocyte.
The haematopoietic system is the system in the body involved in the creation of the cells of blood.
Many human blood cells, such as red blood cells (RBCs), immune cells, and even platelets all originate from the same progenitor cell, the hematopoietic stem cell (HSC). As these cells are short-lived, there needs to be a steady turnover of new blood cells and the maintenance of an HSC pool. This is broadly termed hematopoiesis. This event requires a special environment, termed the hematopoietic stem cell niche, which provides the protection and signals necessary to carry out the differentiation of cells from HSC progenitors. This stem-cell niche relocates from the yolk sac to eventually rest in the bone marrow of mammals. Many pathological states can arise from disturbances in this niche environment, highlighting its importance in maintaining hematopoiesis.
Since haematopoietic stem cells cannot be isolated as a pure population, it is not possible to identify them under a microscope. Therefore, there are many techniques to isolate haematopoietic stem cells (HSCs). HSCs can be identified or isolated by the use of flow cytometry where the combination of several different cell surface markers is used to separate the rare HSCs from the surrounding blood cells. HSCs lack expression of mature blood cell markers and are thus, called Lin-. Lack of expression of lineage markers is used in combination with detection of several positive cell-surface markers to isolate HSCs. In addition, HSCs are characterized by their small size and low staining with vital dyes such as rhodamine 123 or Hoechst 33342.
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