Growth factor

Growth factors, along with cytokines and hormones, act as chemical messengers for communication between cells. Historically growth factors were thought to promote cell growth and proliferation while cytokines were considered to cause immunological or hematopoietic responses . Cytokines and growth factors are now known to have similar functions and are often used interchangeably .

Growth factors are produced by tissues where they act on the cells that produce them (autocrine) or over a short distance of several cells (paracrine) . Hormones on the other hand are part of the endocrine system which communicates over large distances. Hormones are secreted in glandular tissues where they enter circulation and affect metabolism in distant tissues in the body . However, new functions for hormones have been discovered where they act like growth factors, in a paracrine or autocrine manner during development and controlling cell differentiation and cell survival .

In cell culture or tissue engineering, growth factors (purified or in serums) are added to cell culture media to provide the correct signals to cells and stem cells to support survival and direct growth and/or differentiation . Cultured mouse embryonic stem cells (ES cells) and human ES cells form distinctively different morphologies and they each require different growth factors to grow and survive . Mouse ES cells need leukemia inhibitory factor (LIF) and Bone Morphogenetic Protein-4 (BMP4) to remain pluripotent and human ES cells require basic fibroblast growth factor (bFGF) and activin or Transforming Growth Factor Beta (TGF-beta) .

The Transforming Growth Factor Beta (TGF-beta) superfamily of growth factors includes proteins from three families, the TFG-beta family, the Bone Morphogenetic Proteins (BMP) family and the Glial-derived Neurotrophic Factors (GDNF) family . All ligand proteins in this superfamily work as two matching proteins in a dimeric structure and bind to receptors that are heterodimeric or composed of two different proteins, one of type I and one of type II . Binding of ligand to the receptor causes the type II receptor to phosphorylate and activate the type I receptor, activating Smad proteins inside the cell which then regulate gene transcription. TGF-beta superfamily members regulate various aspects of embryonic development such as how embryos form their shapes (morphogenesis) and in adults they regulate stem cell differentiation, immune system function, wound healing, inflammation and cancer .

The TGF-beta-like family includes TGF-beta isoforms TGF-beta1, TGF-beta2, TGF-beta3, Activin A/AB/B, Inhibin A/B and Nodal . TGF-beta and Activin maintain pluripotency of human embryonic stem cells . TGF-beta signaling activates hair follicle cells for regeneration . TGF-beta signaling also direct melanocyte stem cells to enter quiescence rather than differentiate into melanin pigment producing cells . Epithelial-mesenchymal transition (EMT) is induced by TGF-beta signaling and is a change in cell characteristics that is a normal part of mammary gland development but EMT occurs aberrantly in breast cancer . During EMT when epithelial cells become mesenchymal cells, they increase mobility which is necessary for embryogenesis but also for cancer invasion and metastasis .

The BMP family includes BMP1-10, BMP15, GDF1-15 and anti-Mullerian hormone (AMH) . BMPs control morphogenesis or shaping of the embryo through regulating cell growth, programmed cell death (apoptosis), and differentiation . BMPs are also involved in maintenance and repair of adult tissues, such as fracture repair, joint integrity maintenance and remodelling of the vasculature .

The GDNF family includes GDNF, Artemin, Neuturin and Persephin which are found in glial cell lines . Glial cells provide insulation and also communicate with neurons. In the nervous system growth factors are often referred to as neurotropic factors and they play a critical role in development of the nervous system, determining cell fate, promoting cell survival and establishing connections between neurons . GDNF protects dopaminergic neurons and has potential as a therapeutic for Parkinson’s disease .

The EGF family includes EGF TGF-alpha, Neuregulins, Amphiregulin and Betacellulin. EGF family members work through EGFR/ErbB receptor tyrosine kinases and stimulate cell proliferation, differentiation and survival. Tumorigenesis is associated with deregulation of EGF family members .

Four PDGF proteins, PDGFA, PDGFB PDGFC and PDGFD, comprise this group which triggers mitogenesis or cell division and act as chemotactic proteins, guiding cell movement . PDGFs have essential roles in early development, wound healing and agiogenesis . PDGFs are produced by macrophages, epithelial and endothelial cells, smooth muscle cells and activated platelets . They work in pairs as heterodimers or homodimers. Two known tyrosine kinase receptors for PDGFs are PDGFR-alpha and PDGFR-beta and upon binding ligand, the receptors dimerize, autophosphorylate and activate cascades of signalling within the cell . PDGFR-alpha induced signalling is involved in the development of the facial skeleton, hair follicles, sperm, lung, intestine, oligodendrocytes and astrocytes . PDGFR-beta are important for blood vessel, kidney and white adipocyte development .

There are 22 FGF members in humans . FGFs bind FGF receptor (FGFR) and the glycosaminoglycan heparin sulfate (HS), on the cell surface forming a complex . FGFs also bind heparin, a similar polysaccharide to HS which unlike the ubiquitous HS is restricted to mast cells . Heparin is used in affinity chromatography to purify FGFs . FGFs are mainly mitogenic (inducing mitosis or cell division) but have other regulatory, morphological and endocrine activities which are important in embryonic development, angiogenesis, keratinocyte organization and wound healing .

Similar in peptide sequence to Insulin, IGFs mediate the actions of the pituitary growth hormone and regulate cell growth . The two types of IGF receptor, IGFI-R and IGFII-R are disulfide-linked heterotetrameric transmembrane proteins with tyrosine kinase on the cytoplasmic side . IGFs are made and secreted by liver and other tissues in response to growth hormones, leading to increase in cell size and number. IGFs are also have protective functions in cartilage and neurons and activate bone cell, osteocytes .

The VEGF family includes VEGF/VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, VEGF-F and Placental Growth Factor (PIGF). VEGFs act in homodimeric pairs as glycoprotein endothelial cell specific growth factors . During embryogenesis, skeletal growth and in female reproductive functions VEGFs regulate angiogenesis and vascular permeability . VEGFs bind tyrosine kinase receptors VEGFR1 and VEGFR2 to promote cell survival, proliferation, migration and/or adhesion . VEGF deregulation is associated with tumors and neovascular disorders of the eye .

Mesenchymal cells secrete HGF which activates tyrosine kinase signaling through HGF receptor (HGFR) on cells mainly of epithelial and endothelial origin . HGF functions in organ development and regeneration and wound healing. It stimulates mitogenesis and cell motility . Since HGF stimulates matrix invasion it has a major role in angiogenesis and tumorigenesis .

The TNF superfamily comprises cytokines involved in tumor cell apoptosis. Family members have a conserved C-terminal domain called the TNF homology domain (THD), which binds receptors. TNFs can promote or inhibit apoptosis or regulate the innate and adaptive immune system .

Interleukins (ILs), secreted mainly by leukocytes, modulate the immune system by regulating growth, differentiation and activation of immune response . There are four major groups of ILs are IL1-like cytokines, class I helical cytokines, class II helical cytokines and IL17-like cytokines. ILs are involved in host defense against pathogens, having both pro- and anti-inflammatory effects . ILs are also secreted by non-immune cells like keratinocytes, chondrocytes, fibroblasts, endothelial cells, epithelial cells and smooth muscle cells .

Interferons (IFNs) are produced by cells in response to viruses, bacteria, parasites or tumor cells where they stimulate infected cells and nearby cells to produce proteins that inhibit replication and growth of the pathogens . IFNs also regulate immune system cells .

Colony-stimulating factors (CSFs) are glycoproteins that are secreted and bind to receptors on hemopoietic stem cells and activate signaling pathways that promote cell proliferation and differentiation into blood cell types . For hematopoietic stem and progenitor cell (HSPC) transplants from peripheral blood, granulocyte colony stimulating factor is given to donors so HSPC will be mobilized from the bone marrow to the blood . CSFs can enhance regeneration of white blood cells damaged by chemotherapy and enhance immune responses against tumors . Stimulation of cell proliferation by CSF may also be associated with leukemia .

Four PDGF proteins, PDGFAPDGFA, PDGFB PDGFC and PDGFD, comprise this group which triggers mitogenesis or cell division and act as chemotactic proteins, guiding cell movement . PDGFs have essential roles in early development, wound healing and agiogenesis . PDGFs are produced by macrophages, epithelial and endothelial cells, smooth muscle cells and activated platelets . They work in pairs as heterodimers or homodimers. Two known tyrosine kinase receptors for PDGFs are PDGFR-alpha and PDGFR-beta and upon binding ligand, the receptors dimerize, autophosphorylate and activate cascades of signalling within the cell . PDGFR-alpha induced signalling is involved in the development of the facial skeleton, hair follicles, sperm, lung, intestine, oligodendrocytes and astrocytes . PDGFR-beta are important for blood vessel, kidney and white adipocyte development .

Colony-stimulating factors (CSFs) are glycoproteins that are secreted and bind to receptors on hemopoietic stem cells and activate signaling pathways that promote cell proliferation and differentiation into blood cell typescell types . For hematopoietic stem and progenitor cell (HSPC) transplants from peripheral blood, granulocyte colony stimulating factor is given to donors so HSPC will be mobilized from the bone marrow to the blood . CSFs can enhance regeneration of white blood cells damaged by chemotherapy and enhance immune responses against tumors . Stimulation of cell proliferation by CSF may also be associated with leukemia .

The BMP family includes BMP1-10, BMP15, GDF1-15 and anti-Mullerian hormone (AMH) . BMPs control morphogenesis or shaping of the embryo through regulating cell growth, programmed cell deathprogrammed cell death (apoptosis), and differentiation . BMPs are also involved in maintenance and repair of adult tissues, such as fracture repair, joint integrity maintenance and remodelling of the vasculature .

The GDNF family includes GDNF, Artemin, Neuturin and PersephinPersephin which are found in glial cell lines . Glial cells provide insulation and also communicate with neurons. In the nervous system growth factors are often referred to as neurotropic factors and they play a critical role in development of the nervous system, determining cell fate, promoting cell survival and establishing connections between neurons . GDNF protects dopaminergic neurons and has potential as a therapeutic for Parkinson’s disease .

Similar in peptide sequence to InsulinInsulin, IGFs mediate the actions of the pituitary growth hormone and regulate cell growth . The two types of IGF receptor, IGFI-R and IGFII-R are disulfide-linked heterotetrameric transmembrane proteins with tyrosine kinase on the cytoplasmic side . IGFs are made and secreted by liver and other tissues in response to growth hormones, leading to increase in cell size and number. IGFs are also have protective functions in cartilage and neurons and activate bone cell, osteocytes .

The VEGF family includes VEGF/VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, VEGF-F and Placental Growth Factor (PIGF). VEGFs act in homodimeric pairs as glycoprotein endothelial cell specific growth factors . During embryogenesis, skeletal growth and in female reproductive functions VEGFs regulate angiogenesis and vascular permeability . VEGFs bind tyrosine kinase receptors VEGFR1VEGFR1 and VEGFR2 to promote cell survival, proliferation, migration and/or adhesion . VEGF deregulation is associated with tumors and neovascular disorders of the eye .

In cell culture or tissue engineering, growth factors (purified or in serums) are added to cell culture media to provide the correct signals to cells and stem cells to support survival and direct growth and/or differentiation . Cultured mouse embryonic stem cells (ES cells) and human ES cells form distinctively different morphologies and they each require different growth factors to grow and survive . Mouse ES cells need leukemia inhibitory factor (LIF) and Bone Morphogenetic Protein-4 (BMP4) to remain pluripotent and human ES cells require basic fibroblast growth factorbasic fibroblast growth factor (bFGF) and activin or Transforming Growth Factor Beta (TGF-beta) .

The EGF family includes EGF TGF-alpha, Neuregulins, AmphiregulinAmphiregulin and Betacellulin. EGF family members work through EGFR/ErbB receptor tyrosine kinases and stimulate cell proliferation, differentiation and survival. Tumorigenesis is associated with deregulation of EGF family members .

The TNF superfamily comprises cytokines involved in tumor cell apoptosis. Family members have a conserved C-terminal domain called the TNF homology domain (THD), which binds receptors. TNFs can promote or inhibit apoptosis or regulate the innate and adaptive immune systemadaptive immune system .