Fibroblast Growth Factor Activity

Fibroblast growth factor (FGF) signaling is involved in a wide range of important biological activities with differential effects in various cell types. The activity of FGF is modulated by glycosaminoglycans, found both in the extracellular matrix and on the cell surface. They affect FGF signaling by interacting with both the growth factor and the FGF receptor.

These molecules are critical in wound healing as such dynamic process is interactive and depends on proper regulation of fibroblasts. Without regulation excessive scarring results as a feature of impaired healing (keloid and hypertrophic scars), a serious health problem that most of the time affects people's quality of life for the treatment cost of such lesions is high, and often, the results are unsatisfactory.

Fibroblast: a type of cell that promotes the proliferation of keratinocytes and the synthesis of collagens, glycosaminoglycans, reticular and elastic fibers, and glycoproteins found in the extracellular matrix. The proliferation of fibroblasts improves the epidermal morphology. In growing individuals fibroblasts are dividing and synthesizing ground substances.

Keratinocytes originate in the basal layer from the division of keratinocyte stem cells. They are pushed up through the layers of the epidermis, undergoing gradual differentiation until they reach the stratum corneum where they form a layer of enucleated, flattened, highly keratinized cells called squamous cells. This layer forms an effective barrier to the entry of foreign matter and infectious agents into the body and minimises moisture loss.

Keratinocytes are shed and replaced continuously from the stratum corneum. The time of transit from basal layer to shedding is approximately one month although this can be accelerated in conditions of keratinocyte hyperproliferation such as psoriasis.

The simplest definition of a stem cell in an adult tissue is that it is any cell with a high capacity for self-renewal that extends throughout adult life. In addition, stem cells are usually considered to have the potential to produce differentiated progeny. According to these criteria the epidermis has long been recognized as having a resident stem cell population. The tissue consists of a stratified squamous epithelium (interfollicular epidermis; IFE) with associated hair follicles and glandular structures (the sebaceous glands and sweat glands). The IFE undergoes continuous turnover and there is a constant requirement to replace the dead, terminally differentiated cells of the outermost cornified layers through proliferation of cells in the basal layer. Hair follicles undergo repeated cycles of growth, regression, and rest and the cells of the mature hair, like the cells of the outermost interfollicular epidermis layers, are dead, terminally differentiated cells.

It is now well accepted that stem cells within the epidermis are multipotent, capable of producing daughter cells that differentiate along multiple lineages. Stem cells within the hair follicle bulge can produce progeny that differentiate not only into all the hair follicle lineages, but also into sebocytes and interfollicular epidermis. Following exposure to appropriate mesenchymal signals (such as that provided by the glycoconjugates in BIOSKINCARE), cells of the interfollicular epidermis are capable of giving rise to hair or sebaceous lineages. There is, nevertheless, evidence for the existence of distinct stem cell populations within the IFE and sebaceous gland. These observations can be reconciled by proposing that there are separate stem cell populations within the hair, sebaceous gland and IFE. Each of these is capable of generating daughters that differentiate along any of the epidermal lineages. Under steady-state conditions, however, the stem cells normally give rise to a more restricted repertoire in response to signals from the local microenvironment.

Two types of cells can be differentiated in the basal layer of the skin. Slow cycling cells that are designated as stem cells and rapidly cycling cells designated as transit amplifying cells, cells destined to undergo terminal differentiation and leave the basal layer after a few rounds of division. The keratinocytes with the highest ability of a single cell to proliferate independently to form a colony in the human follicle are located in the region directly below the bulge (the entire permanent portion of the follicle below the sebaceous glands).

Although it is thought that stem cells divide infrequently in undamaged epidermis they are the cells that are capable of sustained proliferation in response to a stimulus such as wounding.

The Helix Aspersa Müller Glycoconjugates Have Fibroblast Growth Factor Activity:

Induces significant fibroblast proliferation

Facilitates the migration of keratinocytes, thus helping to repair wounds

Enhances fibroblast functional capability, thus improving fibroplasias

Induces synthesis of new collagen

Provides hyaluronic acid (essential in all repair process)

The glycoconjugates help achieve the correct balance between the synthesis and degradation of important structural elements such as collagen and elastin

Collagenase: Enzymes that catalyze the hydrolysis of collagen and gelatin.

Gelatinase activity: A protease that begins the hydrolytic breakdown of proteins usually by splitting them into polypeptide chains. They are involved in early tissue repair and in prolonged tissue remodeling. Various types of matrix metalloproteinases (collagenase and gelatinase enzymes) are selectively expressed or activated at the various periods of wound healing and determine the presence or absence of abnormal scars: keloids or hypertrophic scars.

The matrix metalloproteinases (MMP) are a group of zinc-dependent enzymes , which degrade varying components of the extracellular skin matrix in both normal and diseased tissue. Skin matrix is a framework that holds the skin together and consists mainly of intermeshed polymers such as collagen and elastin. The skin matrix is responsible for the skin's mechanical properties, including firmness, strength, suppleness, and elasticity. The weaker and less regular the matrix, the more wrinkles, roughness, and sag one tends to have. Whenever skin is damaged, malformed or worn out, skin matrix is broken down by the MMP enzymes and then is synthesized by the fibroblasts. Therefore, MMP enzymes play a critical role in skin physiology.

The latest approach in skin care is to maintain a healthy balance of these enzymes.

In healthy, youthful skin, the synthesis and degradation of the matrix are in balance; damaged or redundant matrix is degraded while the deficit is replenished by the ongoing synthesis. Unfortunately, this intricate balance gets disrupted with age; too little of the matrix is synthesized and too much is degraded. MMP levels rise excessively with age. Research indicates that reversal of MMP levels to normal youthful levels in aged individuals is an effective method to remove the damaged matrix and preserve the healthy one. For this purpose, the utilization of MMP inhibitors in the form of drugs, cosmetic formulations, and lifestyle changes is the new cosmetic find.

Function of fibroblasts

The main function of fibroblasts is to maintain the structural integrity of connective tissue by continuously secreting precursors of the extracellular matrix. Fibroblasts secrete the precursors of all the components of the extracellular matrix, primarily the ground substance and a variety of fibers. The composition of the extracellular matrix determines the physical properties of connective tissues. Proteoglycans (proteins bound to glycosaminoglycans or glycoproteins) bind multiple components of the extracellular matrix by serving as important regulators of cell behavior. Tissue damage stimulates fibrocytes and induces migration and readily proliferation of fibroblasts in multiple stages of tissue repair including wound contraction. Fibroblasts can give rise to other cells, such as bone cells, fat cells, and smooth muscle cells. All those are cells of mesodermal origin, which means a layer from which the organs and tissues of the body develop through further differentiation.

Growth factors are polypeptides (proteins) that bind to receptors on the cell surface, with the primary result of activating cellular proliferation and/or differentiation. Many growth factors are quite versatile, stimulating cellular division in numerous different cell types; while others are specific to a particular cell-type. There are at least 21 distinct members of the FGF family of growth factors.

Fibroblast growth factors act specifically on various types of epithelial cells including keratinocytes of the skin, intestinal epithelial cells and hepatocytes. In addition, some types of Fibroblast Growth Factor have been shown to be more than growth factors: they can protect epithelial cells from damaging effects induced, for example, by radiation and oxidative stress. Therefore, they are currently in clinical trials for the treatment of oral mucositis, a severe side-effect of cancer therapy characterized by painful inflammation and ulceration of the oral epithelium. Reference: “Fibroblast growth factors in epithelial repair and cytoprotection”. Susanne Braun, Ulrich auf dem Keller, Heike Steiling and Sabine Werner Institute of Cell Biology, Department of Biology, ETH Zurich, Honggerberg, CH-8093 Zurich, Switzerland. April 2004.

Cartoon to illustrate the functions of FGFs in a healing skin wound. Upon injury, dermal fibroblasts (violet) and __ T cells (red) secrete FGF-7 and FGF-10; suprabasal keratinocytes (green) express FGF-22. In a paracrine (blue and red arrows) or autocrine manner (green arrow), respectively, they activate keratinocytes at the wound edge and stimulate reepithelialization. In addition, they induce the expression of cytoprotective genes in keratinocytes, including the gene that encodes the Nrf2 transcription factor. Nrf2 then regulates the expression of proteins involved in the detoxification of ROS (Reactive Oxygen Species). The latter are produced in large amounts by neutrophils and macrophages as a defense against invading bacteria.