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Fibroblast growth factors (FGF) are a family of
cell signalling In biology, cell signaling (cell signalling in British English) is the process by which a cell interacts with itself, other cells, and the environment. Cell signaling is a fundamental property of all cellular life in both prokaryotes and eukary ...
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
s produced by the
macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s. They are involved in a wide variety of processes, most notably as crucial elements for normal development in animal cells. Any irregularities in their function will lead to a range of developmental defects. These
growth factors A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regu ...
typically act as a systemic or locally circulating molecules of extracellular origin that activate
cell surface receptor Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integra ...
s. A defining property of FGFs is that they bind to
heparin Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan. Heparin is a blood anticoagulant that increases the activity of antithrombin. It is used in the treatment of myocardial infarction, ...
and to
heparan sulfate Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs in a proteoglycan (HSPG, i.e. Heparan Sulfate ProteoGlycan) in which two or three HS chains are attached in close proximity to cell surface or extracellular ma ...
. Thus, some are sequestered in the
extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix (ICM), is a network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and bio ...
of tissues that contains
heparan sulfate proteoglycan Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs in a proteoglycan (HSPG, i.e. Heparan Sulfate ProteoGlycan) in which two or three HS chains are attached in close proximity to cell surface or extracellular ma ...
s, and released locally upon injury or tissue remodeling.


Families

In humans, 23 members of the FGF family have been identified, all of which are ''structurally'' related
signaling molecule In biology, cell signaling (cell signalling in British English) is the Biological process, process by which a Cell (biology), cell interacts with itself, other cells, and the environment. Cell signaling is a fundamental property of all Cell (biol ...
s: * Members FGF1 through FGF10 all bind fibroblast growth factor receptors (FGFRs). FGF1 is also known as ''acidic fibroblast growth factor'', and FGF2 is also known as ''basic fibroblast growth factor''. * Members FGF11, FGF12, FGF13, and FGF14, also known as FGF homologous factors 1-4 (FHF1-FHF4), have been shown to have distinct functions compared to the FGFs. Although these factors possess remarkably similar sequence homology, they do not bind FGFRs and are involved in intracellular processes unrelated to the FGFs. This group is also known as the intracellular fibroblast growth factor subfamily (iFGF). *Human FGF18 is involved in cell development and morphogenesis in various tissues including cartilage. * Human FGF20 was identified based on its homology to ''Xenopus'' FGF-20 (XFGF-20). * FGF15 through FGF23 were described later and functions are still being characterized. FGF15 is the mouse ortholog of human FGF19 (there is no human FGF15) and, where their functions are shared, they are often described as FGF15/19. In contrast to the local activity of the other FGFs, FGF15/19, FGF21 and FGF23 have
hormonal A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physiology and behavior. Hormones a ...
systemic effects.


Receptors

The mammalian fibroblast growth factor receptor family has 4 members, FGFR1,
FGFR2 Fibroblast growth factor receptor 2 (FGFR-2) also known as CD332 (cluster of differentiation 332) is a protein that in humans is encoded by the ''FGFR2'' gene residing on chromosome 10. FGFR2 is a receptor for fibroblast growth factor. FGFR-2 is ...
, FGFR3, and FGFR4. The FGFRs consist of three extracellular immunoglobulin-type domains (D1-D3), a single-span trans-membrane domain and an intracellular split
tyrosine kinase A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cla ...
domain. FGFs interact with the D2 and D3 domains, with the D3 interactions primarily responsible for ligand-binding specificity (see below). Heparan sulfate binding is mediated through the D3 domain. A short stretch of acidic amino acids located between the D1 and D2 domains has auto-inhibitory functions. This 'acid box' motif interacts with the heparan sulfate binding site to prevent receptor activation in the absence of FGFs. Alternate mRNA splicing gives rise to 'b' and 'c' variants of FGFRs 1, 2 and 3. Through this mechanism, seven different signalling FGFR sub-types can be expressed at the cell surface. Each FGFR binds to a specific subset of the FGFs. Similarly, most FGFs can bind to several different FGFR subtypes. FGF1 is sometimes referred to as the 'universal ligand' as it is capable of activating all 7 different FGFRs. In contrast, FGF7 (keratinocyte growth factor, KGF) binds only to FGFR2b (KGFR). The signalling complex at the cell surface is believed to be a
ternary complex A ternary complex is a protein complex containing three different molecules that are bound together. In structural biology, ''ternary complex'' can also be used to describe a crystal containing a protein with two small molecules bound, such as a ...
formed between two identical FGF ligands, two identical FGFR subunits, and either one or two heparan sulfate chains.


History

A
mitogen A mitogen is a small bioactive protein or peptide that induces a cell to begin cell division, or enhances the rate of division (mitosis). Mitogenesis is the induction (triggering) of mitosis, typically via a mitogen. The cell cycle Mitogens a ...
ic growth factor activity was found in
pituitary The pituitary gland or hypophysis is an endocrine gland in vertebrates. In humans, the pituitary gland is located at the base of the brain, protruding off the bottom of the hypothalamus. The pituitary gland and the hypothalamus control much of th ...
extracts by Armelin in 1973 and further work by Gospodarowicz as reported in 1974 described a more defined isolation of proteins from cow brain extract which, when tested in a
bioassay A bioassay is an analytical method to determine the potency or effect of a substance by its effect on animal testing, living animals or plants (''in vivo''), or on living cells or tissues (''in vitro''). A bioassay can be either quantal or quantit ...
that caused
fibroblast A fibroblast is a type of cell (biology), biological cell typically with a spindle shape that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and ...
s to proliferate, led these investigators to apply the name "fibroblast growth factor." In 1975, they further fractionated the extract using
acid An acid is a molecule or ion capable of either donating a proton (i.e. Hydron, hydrogen cation, H+), known as a Brønsted–Lowry acid–base theory, Brønsted–Lowry acid, or forming a covalent bond with an electron pair, known as a Lewis ...
ic and
basic Basic or BASIC may refer to: Science and technology * BASIC, a computer programming language * Basic (chemistry), having the properties of a base * Basic access authentication, in HTTP Entertainment * Basic (film), ''Basic'' (film), a 2003 film ...
pH and isolated two slightly different forms that were named "acidic fibroblast growth factor" (FGF1) and "basic fibroblast growth factor" (FGF2). These proteins had a high degree of sequence homology among their amino acid chains, but were determined to be distinct proteins. Not long after FGF1 and FGF2 were isolated, another group of investigators isolated a pair of
heparin Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan. Heparin is a blood anticoagulant that increases the activity of antithrombin. It is used in the treatment of myocardial infarction, ...
-binding growth factors that they named HBGF-1 and HBGF-2, while a third group isolated a pair of growth factors that caused proliferation of cells in a
bioassay A bioassay is an analytical method to determine the potency or effect of a substance by its effect on animal testing, living animals or plants (''in vivo''), or on living cells or tissues (''in vitro''). A bioassay can be either quantal or quantit ...
containing blood vessel
endothelium The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the r ...
cells, which they called ECGF1 and ECGF2. These independently discovered proteins were eventually demonstrated to be the same sets of molecules, namely FGF1, HBGF-1 and ECGF-1 were all the same acidic fibroblast growth factor described by Gospodarowicz, et al., while FGF2, HBGF-2, and ECGF-2 were all the same basic fibroblast growth factor.


Functions

FGFs are multifunctional proteins with a wide variety of effects; they are most commonly mitogens but also have regulatory, morphological, and endocrine effects. They have been alternately referred to as " pluripotent" growth factors and as "promiscuous" growth factors due to their multiple actions on multiple cell types. Promiscuous refers to the biochemistry and pharmacology concept of how a variety of molecules can bind to and elicit a response from single receptor. In the case of FGF, four receptor subtypes can be activated by more than twenty different FGF
ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...
s. Thus the functions of FGFs in developmental processes include
mesoderm The mesoderm is the middle layer of the three germ layers that develops during gastrulation in the very early development of the embryo of most animals. The outer layer is the ectoderm, and the inner layer is the endoderm.Langman's Medical ...
induction, anterior-posterior patterning, limb development, neural induction and
neural development The development of the nervous system, or neural development (neurodevelopment), refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood. The field ...
, and in mature tissues/systems
angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...
,
keratinocyte Keratinocytes are the primary type of cell found in the epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells. Basal cells in the basal layer (''stratum basale'') of the skin are sometimes referre ...
organization, and
wound healing Wound healing refers to a living organism's replacement of destroyed or damaged tissue by newly produced tissue. In undamaged skin, the epidermis (surface, epithelial layer) and dermis (deeper, connective layer) form a protective barrier again ...
processes. FGF is critical during normal development of both
vertebrates Vertebrates () are animals with a vertebral column (backbone or spine), and a cranium, or skull. The vertebral column surrounds and protects the spinal cord, while the cranium protects the brain. The vertebrates make up the subphylum Vertebra ...
and
invertebrates Invertebrates are animals that neither develop nor retain a vertebral column (commonly known as a ''spine'' or ''backbone''), which evolved from the notochord. It is a paraphyletic grouping including all animals excluding the chordate subphylum ...
and any irregularities in their function leads to a range of developmental defects. FGFs secreted by
hypoblast In amniote embryology, the hypoblast is one of two distinct layers arising from the inner cell mass in the mammalian blastocyst, or from the blastodisc in reptiles and birds. The hypoblast gives rise to the yolk sac. The hypoblast is a layer of ...
s during avian
gastrulation Gastrulation is the stage in the early embryonic development of most animals, during which the blastula (a single-layered hollow sphere of cells), or in mammals, the blastocyst, is reorganized into a two-layered or three-layered embryo known as ...
play a role in stimulating a
Wnt signaling pathway In cellular biology, the Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt, pronounced "wint", is a portmanteau created from the ...
that is involved in the differential movement of Koller's sickle cells during formation of the
primitive streak The primitive streak is a structure that forms in the early embryo in amniotes. In amphibians, the equivalent structure is the blastopore. During early embryonic development, the embryonic disc becomes oval shaped, and then pear-shaped with the ...
.Gilbert SF. Developmental Biology. 10th edition. Sunderland (MA): Sinauer Associates; 2014. Early Development in Birds. Print Left,
angiography Angiography or arteriography is a medical imaging technique used to visualize the inside, or lumen, of blood vessels and organs of the body, with particular interest in the arteries, veins, and the heart chambers. Modern angiography is perfo ...
of the newly formed vascular network in the region of the front wall of the left ventricle. Right, analysis quantifying the angiogenic effect. While many FGFs can be secreted by cells to act on distant targets, some FGF act locally within a tissue, and even within a cell. Human FGF2 occurs in low molecular weight (LMW) and high molecular weight (HMW) isoforms. LMW FGF2 is primarily cytoplasmic and functions in an
autocrine Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with ...
manner, whereas HMW FGF2s are nuclear and exert activities through an
intracrine Intracrine signaling is a mode of hormone and growth factor action in which signaling molecules exert their effects within the same cell that produces them, without being secreted into the extracellular environment. The term intracrine was origin ...
mechanism. One important function of FGF1 and FGF2 is the promotion of
endothelial cell The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and th ...
proliferation and the physical organization of endothelial cells into tube-like structures. They thus promote
angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...
, the growth of new
blood vessel Blood vessels are the tubular structures of a circulatory system that transport blood throughout many Animal, animals’ bodies. Blood vessels transport blood cells, nutrients, and oxygen to most of the Tissue (biology), tissues of a Body (bi ...
s from the pre-existing
vasculature In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart an ...
. FGF1 and FGF2 are more potent angiogenic factors than
vascular endothelial growth factor Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors ...
(VEGF) or
platelet-derived growth factor Platelet-derived growth factor (PDGF) is one among numerous growth factors that regulate cell growth and division. In particular, PDGF plays a significant role in blood vessel formation, the growth of blood vessels from already-existing bloo ...
(PDGF). FGF1 has been shown in clinical experimental studies to induce angiogenesis in the heart. As well as stimulating blood vessel growth, FGFs are important players in wound healing. FGF1 and FGF2 stimulate
angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...
and the proliferation of
fibroblast A fibroblast is a type of cell (biology), biological cell typically with a spindle shape that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and ...
s that give rise to
granulation tissue Granulation tissue is new connective tissue and microscopic blood vessels that form on the surfaces of a wound during the healing process. Granulation tissue typically grows from the base of a wound and is able to fill wounds of almost any size ...
, which fills up a wound space/cavity early in the wound-healing process. FGF7 and FGF10 (also known as keratinocyte growth factors KGF and KGF2, respectively) stimulate the repair of injured skin and mucosal tissues by stimulating the proliferation, migration and differentiation of
epithelial cell Epithelium or epithelial tissue is a thin, continuous, protective layer of Cell (biology), cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial (Mesothelium, mesothelial) tissues line ...
s, and they have direct chemotactic effects on tissue remodelling. During the development of the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
, FGFs play important roles in neural stem cell proliferation,
neurogenesis Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). This occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells ( ...
,
axon An axon (from Greek ἄξων ''áxōn'', axis) or nerve fiber (or nerve fibre: see American and British English spelling differences#-re, -er, spelling differences) is a long, slender cellular extensions, projection of a nerve cell, or neuron, ...
growth, and differentiation. FGF signaling is important in promoting surface area growth of the developing
cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. It is the largest site of Neuron, neural integration in the central nervous system, and plays ...
by reducing
neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
al differentiation and hence permitting the self-renewal of cortical progenitor cells, known as
radial glial cell Radial glial cells, or radial glial progenitor cells (RGPs), are Bipolar neuron, bipolar-shaped progenitor cells that are responsible for producing all of the neurons in the cerebral cortex. RGPs also produce certain lineages of glia, including as ...
s, and FGF2 has been used to induce artificial
gyrification Gyrification is the process of forming the characteristic folds of the cerebral cortex. The peak of such a fold is called a ''gyrus'' (pl. ''gyri''), and its trough is called a ''Sulcus (neuroanatomy), sulcus'' (pl. ''sulci''). The neurons of the ...
of the
mouse brain A mouse (: mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus'' ...
. Another FGF family member, FGF8, regulates the size and positioning of the functional areas of the cerebral cortex (
Brodmann area A Brodmann area is a region of the cerebral cortex, in the human or other primate brain, defined by its cytoarchitecture, or histological structure and organization of cells. The concept was first introduced by the German anatomist Korbinian B ...
s). FGFs are also important for maintenance of the adult brain. Thus, FGFs are major determinants of neuronal survival both during development and during adulthood. Adult neurogenesis within the
hippocampus The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...
e.g. depends greatly on FGF2. In addition, FGF1 and FGF2 seem to be involved in the regulation of
synaptic plasticity In neuroscience, synaptic plasticity is the ability of synapses to Chemical synapse#Synaptic strength, strengthen or weaken over time, in response to increases or decreases in their activity. Since memory, memories are postulated to be represent ...
and processes attributed to learning and memory, at least in the hippocampus. The 15 exparacrine FGFs are secreted proteins that bind
heparan sulfate Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs in a proteoglycan (HSPG, i.e. Heparan Sulfate ProteoGlycan) in which two or three HS chains are attached in close proximity to cell surface or extracellular ma ...
and can, therefore, be bound to the
extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix (ICM), is a network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and bio ...
of tissues that contain heparan sulfate proteoglycans. This local action of FGF proteins is classified as paracrine signalling, most commonly through the JAK-STAT signalling pathway or the
receptor tyrosine kinase Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinas ...
(RTK) pathway. Members of the FGF19 subfamily ( FGF15, FGF19, FGF21, and FGF23) bind less tightly to heparan sulfates, and so can act in an
endocrine The endocrine system is a messenger system in an organism comprising feedback loops of hormones that are released by internal glands directly into the circulatory system and that target and regulate distant organs. In vertebrates, the hypotha ...
fashion on far-away tissues, such as intestine, liver, kidney, adipose, and bone. For example: * FGF15 and FGF19 (FGF15/19) are produced by intestinal cells but act on FGFR4-expressing liver cells to downregulate the key gene ( CYP7A1) in the bile acid synthesis pathway. * FGF23 is produced by bone but acts on FGFR1-expressing kidney cells to regulate the synthesis of vitamin D and phosphate homeostasis.


Structure

The
crystal structure In crystallography, crystal structure is a description of ordered arrangement of atoms, ions, or molecules in a crystalline material. Ordered structures occur from intrinsic nature of constituent particles to form symmetric patterns that repeat ...
s of FGF1 have been solved and found to be related to interleukin 1-beta. Both families have the same beta trefoil fold consisting of 12-stranded
beta-sheet The beta sheet (β-sheet, also β-pleated sheet) is a common structural motif, motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone chain, backbon ...
structure A structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such as ...
, with the beta-sheets are arranged in 3 similar lobes around a central axis, 6 strands forming an anti-parallel beta-barrel. In general, the beta-sheets are well-preserved and the crystal structures superimpose in these areas. The intervening loops are less well-conserved - the loop between beta-strands 6 and 7 is slightly longer in interleukin-1 beta.


Clinical applications

Dysregulation of the FGF signalling system underlies a range of diseases associated with the increased FGF expression. Inhibitors of FGF signalling have shown clinical efficacy. Some FGF ligands (particularly FGF2) have been demonstrated to enhance tissue repair (e.g. skin burns, grafts, and ulcers) in a range of clinical settings.


See also

*
Receptor tyrosine kinase Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinas ...
* Granulocyte-colony stimulating factor (G-CSF) * Granulocyte-macrophage colony stimulating factor (GM-CSF) *
Nerve growth factor Nerve growth factor (NGF) is a neurotrophic factor and neuropeptide primarily involved in the regulation of growth, maintenance, proliferation, and survival of certain target neurons. It is perhaps the prototypical growth factor, in that it was ...
(NGF) *
Neurotrophins Neurotrophins are a family of proteins that induce the survival, development, and function of neurons. They belong to a class of growth factors, exocytosis, secreted proteins that can signal particular cells to survive, differentiate, or grow. G ...
*
Erythropoietin Erythropoietin (; EPO), also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production ( erythropoiesis) in th ...
(EPO) * Thrombopoietin (TPO) * Myostatin (GDF8) * Growth differentiation factor 9 (GDF9) *
Gyrification Gyrification is the process of forming the characteristic folds of the cerebral cortex. The peak of such a fold is called a ''gyrus'' (pl. ''gyri''), and its trough is called a ''Sulcus (neuroanatomy), sulcus'' (pl. ''sulci''). The neurons of the ...
*
Neurogenesis Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). This occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells ( ...


References


External links

*
FGF5 in Hair Tonic Products

FGF1 in Cosmetic Products
{{DEFAULTSORT:Fibroblast Growth Factor Protein domains Fibroblast growth factor Morphogens