Growth Factors: Definition, Function, Immobilization and Use Potential for the Treatment of Cerebrovascular Diseases

In non-neuronal cells, they stimulate proliferation, but mature neurons are postmitotic and cannot re-enter the cell cycle.

A growth factor is a natural substance that can stimulate cell growth, proliferation, healing, and cell differentiation. It is usually a protein or a steroid hormone. Growth factors are important in regulating a variety of cellular processes.

Growth factors regulate many aspects of cell function , including cell survival and cell migration.

Growth factors typically act as signaling molecules between cells. Examples are cytokines and hormones that bind to specific receptors on the surface of your target cells.

They often promote cell differentiation and maturation, which varies depending on growth factors.

For example, epidermal growth factor (EGF) increases osteogenic differentiation, while fibroblast growth factors and vascular endothelial growth factors stimulate blood vessel differentiation (angiogenesis).

Growth factors are known for their ability to enhance cell proliferation, cell growth, and cell differentiation by regulating tissue morphogenesis, angiogenesis, and neurite outgrowth.

Growth factors typically act as signaling molecules between cells that play an important role in regulating a variety of cellular processes.

Its activities are mediated by binding to transmembrane receptors. The regulation of some growth factors and their receptors are also involved in tumor formation.

Consequently, when considered in the context of the nervous system, growth factors are often referred to as neurotrophic factors. These factors are critical for the proper development of the nervous system from the early embryonic stages.

Growth factors determine the fate of cells, as they differ from being progenitors along neuronal or glial lineages.

Furthermore, during embryonic development, growth factors are crucial for regulating neuronal survival, determining cell fate, and establishing proper connectivity.

Many growth factors that function in the brain have been identified, including factors that were originally identified in other systems, and there is an ever-expanding landscape of interactions of growth factors with cell populations in the nervous system, both during development and during development. the adult.

The nervous system is made up of an extremely heterogeneous population of cells.

In addition to the broad categories of neurons, astrocytes, and oligodendrocytes, there are multiple types of neurons with a diversity of structure, function, location, phenotype, and projections, each with specific needs for trophic support.

Understanding the complexity of these relationships is a great challenge.

Family of neurotrophin factors (nerve growth factor), which were the first growth factors identified for actions in the nervous system.

They have important functions in the peripheral and central nervous systems, including the glial cell line-derived neurotrophic factor (GDNF) family, neuregulins, and neurotrophic cytokines.

Numerous growth factors, whether initially discovered in the nervous system or for effects on other cell populations, have effects on neuronal and glial survival, development, and function.

Other roles of growth factors and cytokines

More and more research of a diverse nature is being conducted showing a growing appreciation of the roles of growth factors in many normal and abnormal processes.

For example, transforming growth factor-α and transforming growth factor-β are expressed with high specificity in the developing mouse embryo, platelet-derived growth factor can mediate normal glyogenesis.

Maternally encoded fibroblast growth factor, transforming growth factor β, and platelet-derived growth factor have been implicated as important in the developing Xenopus embryo.

And basic fibroblast growth factor is a potential neurotrophin during development.

Platelet-derived growth factor has also been identified within plaques and is a potent vasoconstrictor and thus has been implicated in the genesis of atherosclerosis.

In addition, platelet-derived growth factor is secreted from endothelial cells and arterial smooth muscle cells and activated monocytes / macrophages.

Elevated levels of platelet-derived growth factor receptors are found on synovial cells in patients with rheumatoid arthritis.

In each case, however, when in vitro studies are considered in the context of growth factors in inflammation and tissue repair.

It seems likely that the common roles of growth factors are associated with normal development and abnormal remodeling is related to disease states.

This indicates the importance of paying attention to the mechanisms that regulate the type of cells and the temporal levels of expression of growth factors and their related receptors.

What is the rationale behind the immobilization of growth factors?

The immobilization of the growth factor prevents the loss of bioactivity due to diffusion observed in the conventional administration of growth factors in the soluble form. Immobilization also allows for a more controlled release of the growth factor.

How are growth factors immobilized?

The growth factor can be immobilized on the scaffold by non-covalent or non-covalent binding.

Growth factors in the gastrointestinal tract

Growth factors are polypeptides that regulate cellular functions by binding to specific homodimeric or heterodimeric cell surface membrane receptors.

Growth factors are typically secreted, but can also be active in intracellular, transmembrane, or extracellular matrix-associated compartments.

They generally act autocrine or paracrine or both, but generally not classically endocrine.

Biological effects are generally evident at extremely low concentrations, in the nanogram-per-milliliter range.

The growth factor “families” represent their structural and biological similarities, although sometimes, confusingly, their names are based on their most prominent biological activity or the activity that led to their discovery.

The distinctions between growth factors, cytokines, peptides, and hormones are not absolute. Peptides can have effects similar to “growth factor.” On the contrary, growth factors can have non-increasing effects.

Understanding the physiological role of growth factors requires consideration of multiple variables.

The knowledge gained from knockout mice emphasizes the complex spatial, compartmental, and kinetic considerations required in analyzing growth factor function in the gastrointestinal tract.

Growth factors and cerebrovascular diseases

Growth factor treatment represents a promising strategy for treating cerebrovascular diseases.

In the past two decades, the therapeutic use of growth factors for brain injury has provided an encouraging scientific basis for their use in hospitals.

The advent of new biomedical engineering tools may allow growth factors to better infiltrate the brain by bypassing the blood-brain barrier, making it easier to deliver growth factors from the periphery to treat the injured brain.

Ultimately, the exploitation of these growth factors, trophic factors and RNA, either as stand-alone treatments or in conjunction with biomedically designed devices.

It is likely to improve the therapeutic outcome of growth factor therapy for cerebrovascular diseases.

Versus citocinas

Growth factor is sometimes used interchangeably among scientists with the term cytokine. Historically, cytokines have been associated with hematopoietic (blood-forming and lymphatic) cells and cells of the immune system (eg, lymphocytes and cells from spleen, thymus, and lymph node tissues).

For the circulatory system and bone marrow where cells may appear in a liquid suspension and not be attached to solid tissue, it makes sense that they communicate via soluble circulating protein molecules.

However, as the different lines of research converged, it became clear that some of the same signaling proteins used by the hematopoietic and immune systems were also used by all kinds of other cells and tissues, during development and in the mature organism. .

While growth factor implies a positive effect on cell division, cytokine is a neutral term regarding whether a molecule affects proliferation.

While some cytokines can be growth factors, such as G-CSF and GM-CSF, others have an inhibitory effect on cell growth or proliferation.

Some cytokines, such as the Fas ligand, are used as “death” signals; they cause target cells to undergo programmed cell death or apoptosis.

The growth factor was discovered by Rita Levi-Montalcini , who won her the Nobel Prize in Physiology or Medicine.

Growth factors and signal transduction

Growth factor describes a wide range of relatively small, stable, evolutionarily conserved polypeptides that are secreted by cells in the body.

They are present in the secreted extracellular space or in membrane-bound forms; They can also be produced by genetic engineering in the laboratory and used in various clinical therapies.

Growth factors regulate a variety of cellular behaviors, including growth, migration, differentiation, apoptosis, and survival, both positively and negatively.

They also have a number of functions during development, and play important roles in maintaining tissue homeostasis and wound healing in the adult.

Growth factor expression is highly regulated, such that excessive growth factor activity is often associated with cancer.

Secreted growth factors act on nearby cells through contact or paracrine juxtacrine signaling to mediate short-range inter-cell communications.

The response of the cell to growth factors is a complex multi-step process that includes receptors on the cell membrane of the cell that respond and the cascade of interacting proteins necessary and responsible for the amplification and integration of the receptor signal to the nucleus.

Receptors for growth factors are a group of conserved evolutionary proteins on the surface of target cells that bind with high affinity (affinity constant Ka> 108 liters / mol) at relatively low concentrations of growth factors.

Signal transduction for growth factors occurs primarily through enzyme-linked transmembrane receptors.

This class of receptors has a ligand-binding domain on the outer surface of the cell membrane, a transmembrane domain that spans the lipid bilayer, and a cytoplasmic domain on the inner surface of the cell membrane that contains protein kinase domains (tyrosine and / or or serine / threonine kinases).

Protein kinases are enzymes that mediate the binding of phosphate groups (from adenosine triphosphate) to serine, threonine and / or tyrosine residues.

Binding of growth factor to enzyme-linked receptors results in a conformational change in receptor structure, leading to activation of kinase function in the cytoplasmic domain through phosphorylation.

Activation and phosphorylation of the receptor results in the assembly and activation of a group of intracellular signaling proteins.

Leading to changes in the behavior of target cells by direct regulation of transcription factors or by regulation of mRNA stability or protein translation.

Of particular importance in these signal transduction pathways are transcription factors, which activate new genetic programs in the responding cell body.

The end result is an alteration in cellular activity and changes in the program of genes expressed within the responding cells. There are many families of growth factors, including:

The Jagged / Delta / Serrate / Notch Families, Epidermal Growth Factor (EGF), Fibroblast Growth Factor (FGF) Family, Hedgehog Family, Family of Growth Factors Similar to insulin.

IL-1 family, IL-6 family, IL-10 / interferon family, IL-12 family, IL-17 family, platelet-derived growth factor (PDGF) family, transforming factor superfamily growth beta (TGF-beta)

Tumor necrosis factor (TNF) superfamily, vascular endothelial growth factor (VEGF) family, and Wnt gene family.

Functional significance of growth factors as neurotransmitters

Growth factors have a wide range of functions. As the name implies, growth factors support the development and differentiation of neurons.

Therefore, the survival and axonal growth of many neurons to their ultimate goal require certain factors expressed in the target cells. These functions are development specific.

Once a neuron’s axon reaches its target and survives, it generally does not require further support from growth factors under normal conditions.

This ability of growth factors to determine survival, differentiation, and ultimate fate is not part of the normal list of functions attributed to neurotransmitters.

It is not clear whether the release of growth factors is a chemical signal that transmits information to neurons, rather than providing critical sustenance.

What information then supports the claim that growth factors may be unconventional transmitters? First, growth factors are stored and released from neurons.

The release of growth factors is now thought to occur through regulated and constitutive pathways, suggesting some specificity in release.

It is now clear that brain-derived neurotrophic factor is stored in vesicles. The synthesis and release of growth factors are also under transynaptic control.

For example, the expression of nerve growth factor and brain-derived neurotrophic factor is controlled by neuronal activity, with glutamate and acetylcholine increasing the expression and gamma-aminobutyric acid decreasing the expression of these neurotrophic factors.

Furthermore, the induction of brain-derived neurotrophic factor by various treatments is regionally, spatially, and temporally distinct.

Therefore, seizures result in patterns of increases of various exon-specific mRNAs of brain-derived neurotrophic factor that differ across subregions of the hippocampus, and the specific pattern of promoter activation is stimulus-dependent.

All these characteristics suggest that in addition to the synthesis and storage of neurotrophins in neurons, the synthesis and release of these growth factors are regulated by neuronal activity.

And so growth factors can participate both in the reception of information and in the transmission of information between cells.

The second characteristic that suggests a transmitting role for growth factors is that they appear to regulate other neurons. Receptors for neurotrophins, the trk receptors, are expressed in neurons.

These receptors are members of a class of transmembrane receptor tyrosine kinases, and have an intracellular catalytic domain that is activated at ligand binding.

Among the functions that growth factors use are the regulation of growth, differentiation, migration, transcription and protein synthesis in neurons.

Furthermore, neurotrophins appear to change the functional activity of other cells, including the activation of key intracellular signaling pathways in follower neurons.

Brain-derived neurotrophic factor has also been shown to increase NT-3 expression in the cerebellum and hippocampus, again suggesting that growth factors regulate the functional activity of target cells.

The data described above suggest that growth factors can regulate the functional activity of neurons, but do not address a physiological role for growth factors, regardless of their effects on growth and survival.

However, recent studies indicate that brain-derived neurotrophic factor modulates potentiation and long-term learning.