Neuroregeneration is the regrowth or repair of
nervous tissue
Nervous tissue, also called neural tissue, is the main tissue component of the nervous system. The nervous system regulates and controls body functions and activity. It consists of two parts: the central nervous system (CNS) comprising the brain ...
s,
cells or cell products. Neuroregenerative mechanisms may include generation of new
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 ...
s,
glia,
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, ...
s,
myelin, or
synapses. Neuroregeneration differs between the
peripheral nervous system
The peripheral nervous system (PNS) is one of two components that make up the nervous system of Bilateria, bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside t ...
(PNS) and 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 ...
(CNS) by the functional mechanisms involved, especially in the extent and speed of repair. When an axon is damaged, the distal segment undergoes
Wallerian degeneration, losing its
myelin sheath. The proximal segment can either die by
apoptosis
Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
or undergo the
chromatolytic reaction, which is an attempt at repair. In the CNS, synaptic stripping occurs as glial foot processes invade the dead synapse.
Nervous system injuries affect over 90,000 people every year.
Spinal cord injuries alone affect an estimated 10,000 people each year.
As a result of this high incidence of neurological injuries, nerve
regeneration and repair, a subfield of
neural tissue engineering, is becoming a rapidly growing field dedicated to the discovery of new ways to recover nerve functionality after injury.
The nervous system is divided by neurologists into two parts: 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 ...
(which consists of the
brain
The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
and
spinal cord
The spinal cord is a long, thin, tubular structure made up of nervous tissue that extends from the medulla oblongata in the lower brainstem to the lumbar region of the vertebral column (backbone) of vertebrate animals. The center of the spinal c ...
) and the
peripheral nervous system
The peripheral nervous system (PNS) is one of two components that make up the nervous system of Bilateria, bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside t ...
(which consists of
cranial and
spinal nerves along with their associated
ganglia). While the peripheral nervous system has an intrinsic ability for repair and regeneration, the central nervous system is, for the most part, incapable of self-repair and regeneration. There is no treatment for recovering human nerve-function after injury to the central nervous system.
[
] Multiple attempts at nerve re-growth across the PNS-CNS transition have not been successful.
There is simply not enough knowledge about regeneration in the central nervous system. In addition, although the peripheral nervous system has the capability for regeneration, much research still needs to be done to optimize the environment for maximum regrowth potential. Neuroregeneration is important clinically, as it is part of the
pathogenesis of many diseases, including
multiple sclerosis
Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...
.
Peripheral nervous system regeneration
Neuroregeneration in the peripheral nervous system (PNS) occurs to a significant degree.
After an injury to the axon, peripheral neurons activate a variety of signaling pathways which turn on pro-growth genes, leading to reformation of a functional growth cone and regeneration. The growth of these axons is also governed by
chemotactic factors secreted from
Schwann cell
Schwann cells or neurolemmocytes (named after German physiologist Theodor Schwann) are the principal glia of the peripheral nervous system (PNS). Glial cells function to support neurons and in the PNS, also include Satellite glial cell, satellite ...
s. Injury to the peripheral nervous system immediately elicits the migration of
phagocytes, Schwann cells, and
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 to the
lesion site in order to clear away debris such as damaged tissue which is inhibitory to regeneration. When a nerve axon is severed, the end still attached to the cell body is labeled the proximal segment, while the other end is called the distal segment. After injury, the proximal end swells and experiences some retrograde degeneration, but once the debris is cleared, it begins to sprout axons and the presence of growth cones can be detected. The proximal axons are able to regrow as long as the
cell body is intact, and they have made contact with the Schwann cells in the
endoneurium (also known as the endoneurial tube or channel). Human axon growth rates can reach 2 mm/day in small nerves and 5 mm/day in large nerves.
The distal segment, however, experiences
Wallerian degeneration within hours of the injury; the axons and myelin degenerate, but the endoneurium remains. In the later stages of regeneration the remaining endoneurial tube directs axon growth back to the correct targets. During Wallerian degeneration, Schwann cells grow in ordered columns along the endoneurial tube, creating a band of Büngner cells that protects and preserves the endoneurial channel. Also, macrophages and Schwann cells release
neurotrophic factors that enhance re-growth.
Central nervous system regeneration
Unlike peripheral nervous system injury, injury to the central nervous system is not followed by extensive regeneration. It is limited by the inhibitory influences of the glial and
extracellular
This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
environment. The hostile, non-permissive growth environment is, in part, created by the migration of myelin-associated inhibitors, astrocytes, oligodendrocytes, oligodendrocyte precursors, and microglia. The environment within the CNS, especially following trauma, counteracts the repair of myelin and neurons.
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 ...
are not expressed or re-expressed; for instance, the extracellular matrix is lacking
laminins.
Glial scars rapidly form, and the glia actually produce factors that inhibit remyelination and axon repair; for instance, NOGO and NI-35.
The axons themselves also lose the potential for growth with age, due to a decrease in
GAP43 expression, among others.
Slower degeneration of the distal segment than that which occurs in the peripheral nervous system also contributes to the inhibitory environment because inhibitory myelin and axonal debris are not cleared away as quickly. All these factors contribute to the formation of what is known as a
glial scar, which axons cannot grow across. The proximal segment attempts to regenerate after injury, but its growth is hindered by the environment. It is important to note that central nervous system axons have been proven to regrow in permissive environments; therefore, the primary problem to central nervous system axonal regeneration is crossing or eliminating the inhibitory lesion site.
Another problem is that the morphology and functional properties of central nervous system neurons are highly complex, for this reason a neuron functionally identical cannot be replaced by one of another type (
Llinás' law).
Research and clinical treatments
Neurons replacement
in vivo glias to neurons reprogramming
Transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
s,
activation of genes (using
CRISPR activation) or
small molecules are used to
reprogram glias into neurons.
The most commonly targeted glias are astrocytes (usually using
GFAP) because they share the same lineage as neurons and region—specific transcription signatures,
while the
vector used is typically an
adeno-associated virus because some serotypes pass the
blood brain barrier and it does not cause disease.
Targeted genes usually depend on the type of neuron sought; (
NGN2 is known to produce
glutamatergic,
ASCL1:
GABAergic...); RBPJ-k blocks the
Notch pathway and elicits a neurogenic program
and
Sox2 can also increase reprogramming efficiency by causing a
dedifferentiation and self-amplification phase before maturating as neurons.
While theses techniques show lot of promise in animal models for many otherwise incurable
neurodegenerative diseases and
brain injuries, no
clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...
s have started as of 2023.
Neural stem cells grafting
Tissue regrowth
Peripheral
=Surgery
=
Surgery can be done in case a peripheral nerve has become cut or otherwise divided. This is called
peripheral nerve reconstruction. The injured nerve is identified and exposed so that normal nerve tissue can be examined above and below the level of injury, usually with magnification, using either
loupes or an
operating microscope. If a large segment of nerve is harmed, as can happen in a crush or stretch injury, the nerve will need to be exposed over a larger area. Injured portions of the nerve are removed. The cut nerve endings are then carefully reapproximated using very small sutures. The nerve repair must be covered by healthy tissue, which can be as simple as closing the skin or it can require moving skin or muscle to provide healthy padded coverage over the nerve.
The type of anesthesia used depends on the complexity of the injury. A
surgical tourniquet is almost always used.
Prognosis
The expectations after surgical repair of a divided peripheral nerve depends on several factors:
* Age: Recovery of a nerve after surgical repair depends mainly on the age of the patient. Young children can recover close-to-normal nerve function. In contrast, a patient over 60 years old with a cut nerve in the hand would expect to recover only protective sensation; that is, the ability to distinguish hot/cold or sharp/dull.
*The mechanism of injury: Sharp injuries, such as a knife wound, damage only a very short segment of the nerve, availing for direct suture. In contrast, nerves that are divided by stretch or crush may be damaged over long segments. These nerve injuries are more difficult to treat and generally have a poorer outcome. In addition, associated injuries, like injury to bone, muscle and skin, can make nerve recovery more difficult.
*The level of injury: After a nerve is repaired, the regenerating nerve endings must grow all the way to their target. For example, a nerve injured at the wrist that normally provides sensation to the thumb must grow to the end of the thumb in order to provide sensation. The return of function decreases with increased distance over which a nerve must grow.
Autologous nerve grafting
Currently, autologous nerve grafting, or a nerve autograft, is known as the gold standard for clinical treatments used to repair large lesion gaps in the peripheral nervous system. It is important that nerves are not repaired under tension,
which could otherwise happen if cut ends are reapproximated across a gap. Nerve segments are taken from another part of the body (the donor site) and inserted into the lesion to provide
endoneurial tubes for axonal regeneration across the gap. However, this is not a perfect treatment; often the outcome is only limited function recovery. Also, partial de-innervation is frequently experienced at the donor site, and multiple surgeries are required to harvest the tissue and implant it.
When appropriate, a nearby donor may be used to supply innervation to lesioned nerves. Trauma to the donor can be minimized by utilizing a technique known as end-to-side repair. In this procedure, an epineurial window is created in the donor nerve and the proximal stump of the lesioned nerve is sutured over the window. Regenerating axons are redirected into the stump. Efficacy of this technique is partially dependent upon the degree of partial neurectomy performed on the donor, with increasing degrees of neurectomy giving rise to increasing axon regeneration within the lesioned nerve, but with the consequence of increasing deficit to the donor.
Some evidence suggests that local delivery of soluble neurotrophic factors at the site of autologous nerve grafting may enhance axon regeneration within the graft and help expedite functional recovery of a paralyzed target.
Other evidence suggests that gene-therapy induced expression of neurotrophic factors within the target muscle itself can also help enhance axon regeneration.
Accelerating neuroregeneration and the
reinnervation of a
denervated target is critically important in order to reduce the possibility of permanent paralysis due to muscular atrophy.
Allografts and xenografts
Variations on the nerve autograft include the
allograft
Allotransplant (''allo-'' meaning "other" in Ancient Greek, Greek) is the Organ transplant, transplantation of cell (biology), cells, Biological tissue, tissues, or Organ (anatomy), organs to a recipient from a genetically non-identical donor of ...
and the
xenograft. In allografts, the tissue for the graft is taken from another person, the donor, and implanted in the recipient. Xenografts involve taking donor tissue from another species. Allografts and xenografts have the same disadvantages as autografts, but in addition, tissue rejection from immune responses must also be taken into account. Often immunosuppression is required with these grafts. Disease transmission also becomes a factor when introducing tissue from another person or animal. Overall, allografts and xenografts do not match the quality of outcomes seen with autografts, but they are necessary when there is a lack of autologous nerve tissue.
= Nerve guidance conduit
=
Because of the limited functionality received from autografts, the current gold standard for nerve regeneration and repair, recent
neural tissue engineering research has focused on the development of
bioartificial nerve guidance conduits in order to guide axonal regrowth. The creation of artificial nerve conduits is also known as entubulation because the nerve ends and intervening gap are enclosed within a tube composed of biological or synthetic materials.
= Immunisation
=
A direction of research is towards the use of drugs that target remyelinating inhibitor proteins, or other inhibitors. Possible strategies include vaccination against these proteins (active immunisation), or treatment with previously created antibodies (
passive immunisation). These strategies appear promising on animal models with
experimental autoimmune encephalomyelitis (EAE), a model of
MS.
Monoclonal antibodies have also been used against inhibitory factors such as NI-35 and NOGO.
Hindrance: Inhibition of axonal regrowth after damage
Glial cell scar formation is induced following damage to the nervous system. In the central nervous system, this glial scar formation significantly inhibits nerve regeneration, which leads to a loss of function. Several families of molecules are released that promote and drive glial scar formation. For instance, transforming growth factors B-1 and -2, interleukins, and cytokines play a role in the initiation of scar formation. The accumulation of reactive astrocytes at the site of injury and the up regulation of molecules that are inhibitory for neurite outgrowth contribute to the failure of neuroregeneration.
The up-regulated molecules alter the composition of the extracellular matrix in a way that has been shown to inhibit neurite outgrowth extension. This scar formation involves several cell types and families of molecules.
Chondroitin sulfate proteoglycan
In response to scar-inducing factors,
astrocytes up regulate the production of
chondroitin sulfate proteoglycans. Astrocytes are a predominant type of glial cell in the central nervous system that provide many functions including damage mitigation, repair, and glial scar formation.
The
RhoA pathway is involved. Chondroitin sulfate proteoglycans (CSPGs) have been shown to be up regulated in the central nervous system (CNS) following injury. Repeating disaccharides of glucuronic acid and galactosamine,
glycosaminoglycans (CS-GAGs), are covalently coupled to the protein core CSPGs. CSPGs have been shown to inhibit regeneration in vitro and in vivo, but the role that the CSPG core protein vs. CS-GAGs had not been studied until recently.
Keratan sulfate proteoglycans
Like the chondroitin sulfate proteoglycans, keratan sulfate proteoglycan (KSPG) production is up regulated in reactive astrocytes as part of glial scar formation. KSPGs have also been shown to inhibit neurite outgrowth extension, limiting nerve regeneration.
Keratan sulfate, also called keratosulfate, is formed from repeating disaccharide galactose units and N-acetylglucosamines. It is also 6-sulfated. This sulfation is crucial to the elongation of the keratan sulfate chain. A study was done using N-acetylglucosamine 6-O-sulfotransferase-1 deficient mice. The wild type mouse showed a significant up regulation of mRNA expressing N-acetylglucosamine 6-O-sulfotransferase-1 at the site of cortical injury. However, in the N-acetylglucosamine 6-O-sulfotransferase-1 deficient mice, the expression of keratan sulfate was significantly decreased when compared to the wild type mice. Similarly, glial scar formation was significantly reduced in the N-acetylglucosamine 6-O-sulfotransferase-1 mice, and as a result, nerve regeneration was less inhibited.
Other inhibitory factors
Proteins of oligodendritic or glial debris origin that influence neuroregeneration:
*NOGO –The protein family Nogo, particularly
Nogo-A, has been identified as an inhibitor of remyelination in the CNS, especially in autoimmune mediated demyelination, such as found in
experimental autoimmune encephalomyelitis (EAE), and
multiple sclerosis
Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...
(MS). Nogo A functions via either its amino-Nogo terminus through an unknown receptor, or by its Nogo-66 terminus through NgR1,
p75,
TROY
Troy (/; ; ) or Ilion (; ) was an ancient city located in present-day Hisarlik, Turkey. It is best known as the setting for the Greek mythology, Greek myth of the Trojan War. The archaeological site is open to the public as a tourist destina ...
or
LINGO1. Antagonising this inhibitor results in improved remyelination, as it is involved in the RhoA pathway.
*NI-35 a non-permissive growth factor from myelin.
*MAG –
Myelin-associated glycoprotein acts via the receptors NgR2, GT1b, NgR1, p75, TROY and LINGO1.
*OMgp –
Oligodendrocyte myelin glycoprotein
*Ephrin B3 functions through the EphA4 receptor and inhibits remyelination.
*Sema 4D(Semaphorin 4D) functions through the PlexinB1 receptor and inhibits remyelination.
*Sema 3A (Semaphorin 3A) is present in the scar that forms in both central nervous system
and peripheral nerve injuries
and contributes to the outgrowth-inhibitory properties of these scars.
See also
*
PTEN
*
Muscle LIM protein
*
Microtubule detyrosination
*
Myelinogenesis
*
Magnetic field
A magnetic field (sometimes called B-field) is a physical field that describes the magnetic influence on moving electric charges, electric currents, and magnetic materials. A moving charge in a magnetic field experiences a force perpendicular ...
*
Magnetic nanoparticles
*
Neuroprotection
*
Regenerative medicine
*
SPIONs
*
Spinal cord injury research
References
Further reading
{{Nervous system physiology, state=collapsed
Neurophysiology