Olfactory ensheathing cells (OECs), also known as olfactory ensheathing glia or olfactory ensheathing glial cells, are a type of

macroglia Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cell (biology), cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. They maintain homeos ...

( radial glia) found in the nervous system. They are also known as

olfactory The sense of smell, or olfaction, is the special sense through which smells (or odors) are perceived. The sense of smell has many functions, including detecting desirable foods, hazards, and pheromones, and plays a role in taste. In humans, it ...

Schwann cells, because they ensheath the non- myelinated

axons 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 projection of a nerve cell, or neuron, in vertebrates, th ...

of olfactory neurons in a similar way to which Schwann cells ensheath non-myelinated

peripheral neurons The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brain a ...

. They also share the property of assisting axonal regeneration. OECs are capable of phagocytosing axonal debris in vivo, and in vitro they phagocytose bacteria. Olfactory glia that express the antimicrobial enzyme lysozyme (LYZ) are thought to play an important role in immunoprotection in the

mucosa A mucous membrane or mucosa is a membrane that lines various cavities in the body of an organism and covers the surface of internal organs. It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue. It is ...

, where neurons are directly exposed to the external environment. OECs have been tested successfully in experimental axonal regeneration in adult rats with

traumatic spinal cord damage A spinal cord injury (SCI) is damage to the spinal cord that causes temporary or permanent changes in its function. Symptoms may include loss of muscle function, sensation, or autonomic function in the parts of the body served by the spinal c ...

, and clinical trials are currently being conducted to obtain more information on spinal cord injuries and other neurodegenerative diseases.

Origin

In the peripheral nervous system OECs are dispersed within the olfactory epithelium and the

olfactory nerve The olfactory nerve, also known as the first cranial nerve, cranial nerve I, or simply CN I, is a cranial nerve that contains sensory nerve fibers relating to the sense of smell. The afferent nerve fibers of the olfactory receptor neurons tr ...

. In the central nervous system, OECs are found within the outer two layers of the olfactory bulb. During development, primitive olfactory neurons extend their axons from the olfactory placode, through the

mesenchyme Mesenchyme () is a type of loosely organized animal embryonic connective tissue of undifferentiated cells that give rise to most tissues, such as skin, blood or bone. The interactions between mesenchyme and epithelium help to form nearly every o ...

, towards the telencephalic vesicle. After reaching the telencephalic vesicle, a small layer of cells and axons cover the vesicle. Olfactory axons invade the

basal lamina The basal lamina is a layer of extracellular matrix secreted by the epithelial cells, on which the epithelium sits. It is often incorrectly referred to as the basement membrane, though it does constitute a portion of the basement membrane. The ba ...

of the

glia limitans The glia limitans, or the glial limiting membrane, is a thin barrier of astrocyte foot processes associated with the parenchymal basal lamina surrounding the brain and spinal cord. It is the outermost layer of neural tissue, and among its respons ...

and the olfactory bulb to create the olfactory nerve and

glomerular layer The adrenal cortex is the outer region and also the largest part of an adrenal gland. It is divided into three separate zones: zona glomerulosa, zona fasciculata and zona reticularis. Each zone is responsible for producing specific hormones. I ...

s. A fraction of the epithelial migrating precursors give rise to olfactory ensheathing glia that inhabit the olfactory nerve and glomerular layers. OECs and astrocytes interact with each other to form a new

. OECs are distinct from other glia in their developmental origin for they are present in the peripheral nervous system as well as the central nervous system. They also form on bundles of olfactory sensory neuron axons in a manner distinct from myelination.

Functions

OECs are radial glia that perform a variety of functions. Within the olfactory system they phagocytose axonal debris and dead cells. When

cultured Culture () is an umbrella term which encompasses the social behavior, institutions, and norms found in human societies, as well as the knowledge, beliefs, arts, laws, customs, capabilities, and habits of the individuals in these groups.Tylor ...

in a

petri dish A Petri dish (alternatively known as a Petri plate or cell-culture dish) is a shallow transparent lidded dish that biologists use to hold growth medium in which cells can be cultured,R. C. Dubey (2014): ''A Textbook Of Biotechnology For Class- ...

(in vitro), they phagocytose bacteria. Multiple studies have shown that OECs may assist in treating spinal cord injury (SCI) due to their regenerate properties in the peripheral nervous system and their presence in the central nervous system. OECs are also known to support and guide olfactory axons, grow through glial scars, and secrete many neurotrophic factors. OECs express glial markers such as glial fibrillary acidic protein, s100, and

p75 P75 may refer to: * Boulton Paul P.75 Overstrand, a British bomber aircraft * BRM P75, a Formula One engine * FB P-75, a pistol * Fisher P-75 Eagle, an American fighter aircraft design * IBM PS/2 P75, a portable computer * , a corvette of the ...

, and radial glial markers such as nestin and vimentin, which may further assist researchers with understanding the labeling characteristics of these specialized glia.

Olfactory system regeneration

The mammalian olfactory system is unusual in that it has the ability to continuously regenerate its neurons during adulthood. This ability is associated with olfactory ensheathing glia. New olfactory receptor neurons must project their axons through the central nervous system to an olfactory bulb in order to be functional. The growth and regeneration of olfactory axons can be attributable to OECs, as they form the fascicles through which axons grow from the peripheral nervous system into the central nervous system. Olfactory receptor neurons have an average lifespan of 6–8 weeks and therefore must be replaced by cells differentiated from the stem cells that are within a layer at the nearby epithelium's base. Axonal growth is guided by the glial composition and cytoarchitecture of the olfactory bulb in addition to the presence of OECs. OECs are thought to be in part responsible for the neurogenesis of primary olfactory neurons through the processes of

fasciculation A fasciculation, or muscle twitch, is a spontaneous, involuntary muscle contraction and relaxation, involving fine muscle fibers. They are common, with as many as 70% of people experiencing them. They can be benign, or associated with more serio ...

cell sorting Cell sorting is the process through which a particular cell type is separated from others contained in a sample on the basis of its physical or biological properties, such as size, morphological parameters, viability and both extracellular and intra ...

, and axonal targeting.

Role in spinal cord injuries

Traumatic spinal cord damage A spinal cord injury (SCI) is damage to the spinal cord that causes temporary or permanent changes in its function. Symptoms may include loss of muscle function, sensation, or autonomic function in the parts of the body served by the spinal c ...

causes a permanent loss of motor and sensory functions in the central nervous system, termed

paraplegia Paraplegia, or paraparesis, is an impairment in motor or sensory function of the lower extremities. The word comes from Ionic Greek () "half-stricken". It is usually caused by spinal cord injury or a congenital condition that affects the neural ...

or tetraplegia based on the site of the injury. Other detrimental effects may take place in the respiratory system and renal system as a result of the injury. Unlike the peripheral nervous system, the central nervous system is unable to regenerate damaged axons, so its synaptic connections are lost forever. Current treatment is limited and the primary potential methods are either controversial or noneffective. Studies dating back to the 1990s have begun researching the olfactory system of mammals, rats in particular, to gain a greater understanding of axonal regeneration and

neurogenesis Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). It occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs) ...

, and the possible implementation of these cells at the site of the spinal cord injury. Transplantation of OECs into the spinal cord has become a possible therapy for spinal cord damage and other neural diseases in animal models. Several recent studies have reported that preventing OEC inhibition will present a uniform population of cells in the spinal cord, creating an environment in which damaged axons can be repaired. In October 2014, the Polish firefighter Darek Fidyka became the first paraplegic patient to regain mobility after OEC transplantation. OECs are similar to Schwann cells in that they provide an upregulation of low-affinity NGF receptor p75 following injury; however, unlike Schwann cells they produce lower levels of neurotrophins. Several studies have shown evidence of OECs being able to support regeneration of lesioned axons, but these results are often unable to be reproduced. Regardless, OECs have been investigated thoroughly in relation to spinal cord injuries,

amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...

, and other neurodegenerative diseases. Researchers suggest that these cells possess a unique ability to remyelinate injured neurons.

Peptide-modified gellan gum and OECs

Stem cell transplantation Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produce ...

has been identified as another possible therapy for axonal regeneration in the central nervous system by delivering these cells directly to the site of the spinal cord injury. Both OECs and neural stem/progenitor cells (NSPCs) have been successfully transplanted in the central nervous system of adult rats and have had either positive or neutral results as a method of neurogenesis and axonal regeneration; however, neither method has been shown to have long term beneficial effects, as cell survival is usually less than 1% after transplantation. The inability of these cells to sustain after transplantation is a result of inflammation, the inability of a sufficient matrix to thrive and create a uniform population of cells, or the migratory response of the cells needed to fully repair the site of the injury. Another current issue with the survival of the cells is utilizing the proper biomaterials to deliver them to the site of the injury. One study has investigated the use of peptide modified gellan gum as the biomaterial with OECs and neural stem/progenitor cells to provide an environment that will allow these cells to survive after transplantation. Gellan gum hydrogel can be injected in a minimally

invasive Invasive may refer to: *Invasive (medical) procedure *Invasive species *Invasive observation, especially in reference to surveillance *Invasively progressive spread of disease from one organ in the body to another, especially in reference to cancer ...

manner and is approved by the FDA as a food additive because of its chemical structure. The gellan gum was modified with several fibronectin-derived peptide sequences so the transplantation cells have closely related properties to that of native tissue in the extracellular matrix. By mimicking native tissue, the delivery cells are less likely to be rejected by the body and biological functions such as cell adhesion and growth will be enhanced through cell-cell and cell-matrix interactions. In order to determine the possibility of OECs and NPSCs improving cell viability, both cells were co-cultured in direct contact with each other, along with the peptide-modified gellan gum. The experiment demonstrated that NSPC adhesion, proliferation, and viability are greatly increased when the peptide-modified gellan gum is used as the transplantation device when compared to a gellan gum control. Additionally, the co-culture of OECs and NSPCs shows greater cell survival compared to the cell survival of NSPCs cultured alone. The results provide evidence that this method of cell transplantation is a potential strategy for repairing spinal cord damage in the future.

Side effects of cell transplantation

A study has shown that cell transplantation may cause an increase in body temperature of a subject with an older injury to the spinal cord. In this experiment, the patients' body temperatures were elevated to those of a moderate fever after transplantation, and lasted approximately 3–4 days. However, the study provides evidence that even past spinal cord injuries can benefit from the neurological functional recovery that stem cell transplantation may provide in the future. Transplantation of stem cells is also known to cause toxicity and

graft-versus-host disease Graft-versus-host disease (GvHD) is a syndrome, characterized by inflammation in different organs. GvHD is commonly associated with bone marrow transplants and stem cell transplants. White blood cells of the donor's immune system which remain wit ...

(GVHD). Apoptotic cells have been administered simultaneously with hematopoietic stem cells in experimental transplantation models, in anticipation of an improved outcome. As a result, the combination prevents alloimmunization, up-regulates Regulatory T cells (suppressor T cells) and reduces the severity of GVHD.

Infection susceptibility

OECs have properties similar to those of astrocytes, both of which have been identified as being susceptible to viral infection.

Labeling OECs

Iron oxide particles for MRI

As stem cell transplantation is becoming a more prevalent means of treating traumatic spinal cord damage, many processes between the start and end result need to be addressed and made more efficient. By labeling OECs, these cells can be tracked by a

magnetic resonance imaging Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio wave ...

(MRI) device when being dispersed in the central nervous system A recent study made use of a novel type of micron-sized particles of iron oxide (MPIO) to label and track these transport-mediated cells via MRI. The experiment resulted in an OEC labeling efficiency of more than 90% with an MPIO incubation time as short as 6 hours, without affecting

cell proliferation Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation re ...

, migration and viability. MPIOs have also been successfully transplanted into the

vitreous Vitreous may refer to: Materials * Glass, an amorphous solid material ** Vitreous enamel, a material made by fusing powdered glass to a substrate by firing * Vitreous lustre, a glassy luster or sheen on a mineral surface Biology * Vitreous body, ...

body of adult rat eyes, providing the first detailed protocol for efficient and safe MPIO labeling of OECs for their non-invasive MRI tracking in real time for use in studies of central nervous system repair and axonal regeneration.

Subpopulations

Two distinct subpopulations of OECs have been identified with high or low cell surface expression of low-affinity nerve growth factor receptor (p75).

References

{{reflist Glial cells Epithelial cells Olfactory system