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 cells in the central nervous system (the brain and the spinal cord) and in the peripheral nervous system that do not produce Action potential, electrical impulses. The n ...

(

radial glia Radial glial cells, or radial glial progenitor cells (RGPs), are 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 astrocytes and ol ...

) found in the

nervous system In biology, the nervous system is the complex system, highly complex part of an animal that coordinates its behavior, actions and sense, sensory information by transmitting action potential, signals to and from different parts of its body. Th ...

. 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 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, because they ensheath the non-

myelinated Myelin Sheath ( ) is a lipid-rich material that in most vertebrates surrounds the axons of neurons to insulate them and increase the rate at which electrical impulses (called action potentials) pass along the axon. The myelinated axon can be lik ...

axons An axon (from Greek ἄξων ''áxōn'', axis) or nerve fiber (or nerve fibre: see spelling differences) is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action pot ...

of olfactory neurons in a similar way to which Schwann cells ensheath non-myelinated peripheral neurons. They also share the property of assisting axonal regeneration. OECs are capable of phagocytosing axonal debris

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...

, and

in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

they phagocytose

bacteria Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of Prokaryote, prokaryotic microorganisms. Typically a few micr ...

. Olfactory glia that express the

antimicrobial An antimicrobial is an agent that kills microorganisms (microbicide) or stops their growth (bacteriostatic agent). Antimicrobial medicines can be grouped according to the microorganisms they are used to treat. For example, antibiotics are used aga ...

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

lysozyme Lysozyme (, muramidase, ''N''-acetylmuramide glycanhydrolase; systematic name peptidoglycan ''N''-acetylmuramoylhydrolase) is an antimicrobial enzyme produced by animals that forms part of the innate immune system. It is a glycoside hydrolase ...

(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 ...

, where

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 are directly exposed to the external environment. OECs have been tested successfully in experimental axonal regeneration in adult rats with traumatic spinal cord damage, and

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 are currently being conducted to obtain more information on spinal cord injuries and other

neurodegenerative A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their death. Neurodegenerative diseases include amyotrophic lateral sclerosis, mul ...

diseases.

Origin

In 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 ...

OECs are dispersed within the

olfactory epithelium The olfactory epithelium is a specialized epithelium, epithelial tissue inside the nasal cavity that is involved in olfaction, smell. In humans, it measures and lies on the roof of the nasal cavity about above and behind the nostrils. The olfact ...

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 t ...

. In 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 ...

, OECs are found within the outer two layers of the

olfactory bulb The olfactory bulb (Latin: ''bulbus olfactorius'') is a neural structure of the vertebrate forebrain involved in olfaction, the sense of smell. It sends olfactory information to be further processed in the amygdala, the orbitofrontal cortex (OF ...

. During development, primitive olfactory neurons extend their axons from the

olfactory placode In embryology, the nasal placode (or olfactory placode) gives rise to the olfactory epithelium of the nose. Two nasal placodes arise as thickened ectoderm from the frontonasal process. They give rise to the nose, the philtrum of the upper lip, ...

, 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 ever ...

, 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 b ...

of the glia limitans and the

to create the olfactory nerve and glomerular layers. A fraction of the epithelial migrating precursors give rise to olfactory ensheathing glia that inhabit the olfactory nerve and glomerular layers. OECs and

astrocytes Astrocytes (from Ancient Greek , , "star" and , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of end ...

interact with each other to form a new glia limitans. 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 Myelination, or myelinogenesis, is the formation and development of myelin sheaths in the nervous system, typically initiated in late prenatal neurodevelopment and continuing throughout postnatal development. The term ''myelinogenesis'' is also ...

Functions

OECs are radial glia that perform a variety of functions. Within the olfactory system they phagocytose axonal debris and dead cells. When cultured 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 A spinal cord injury (SCI) is damage to the spinal cord that causes temporary or permanent changes in its function. It is a destructive neurological and pathological state that causes major motor, sensory and autonomic dysfunctions. Symptoms of ...

(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 Neurotrophic factors (NTFs) are a family of biomolecules – nearly all of which are peptides or small proteins – that support the growth, survival, and cell differentiation, differentiation of both developing and mature neurons. Most ...

. OECs express glial markers such as

glial fibrillary acidic protein Glial fibrillary acidic protein (GFAP) is a protein that is encoded by the ''GFAP'' gene in humans. It is a type III intermediate filament (IF) protein that is expressed by numerous cell types of the central nervous system (CNS), including astro ...

, s100, and p75, and radial glial markers such as nestin and

vimentin Vimentin is a structural protein that in humans is encoded by the ''VIM'' gene. Its name comes from the Latin ''vimentum'' which refers to an array of flexible rods. Vimentin is a Intermediate filament#Type III, type III intermediate filamen ...

, which may further assist researchers with understanding the labeling characteristics of these specialized glia.

Olfactory system regeneration

The mammalian

olfactory system The olfactory system, is the sensory nervous system, sensory system used for the sense of smell (olfaction). Olfaction is one of the special senses directly associated with specific organs. Most mammals and reptiles have a main 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 An olfactory receptor neuron (ORN), also called an olfactory sensory neuron (OSN), is a sensory neuron within the olfactory system. Structure Humans have between 10 and 20 million olfactory receptor neurons (ORNs). In vertebrates, ORNs are Bi ...

must project their axons through the central nervous system to an

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 seriou ...

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 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 neura ...

tetraplegia Tetraplegia, also known as quadriplegia, is defined as the dysfunction or loss of motor and/or sensory function in the cervical area of the spinal cord. A loss of motor function can present as either weakness or paralysis leading to partial ...

based on the site of the injury. Other detrimental effects may take place in the

respiratory system The respiratory system (also respiratory apparatus, ventilatory system) is a biological system consisting of specific organs and structures used for gas exchange in animals and plants. The anatomy and physiology that make this happen varies grea ...

and

renal system The human urinary system, also known as the urinary tract or renal system, consists of the kidneys, ureters, bladder, and the urethra. The purpose of the urinary system is to eliminate waste from the body, regulate blood volume and blood pressu ...

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). This occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells ( ...

, 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 Dariusz "Darek" Fidyka (born ) is a Polish firefighter and recovering paraplegic who became the first person in history to verifiably recover sensory and motor function after the complete severing of his spinal cord. Having been paralysed fr ...

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 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 ...

. 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—in the United States—Lou Gehrig's disease (LGD), is a rare, Terminal illness, terminal neurodegenerative disease, neurodegenerative disorder that results i ...

, 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 a patient and produce a ...

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 Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...

, 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

biomaterial A biomaterial is a substance that has been Biological engineering, engineered to interact with biological systems for a medical purpose – either a therapeutic (treat, augment, repair, or replace a tissue function of the body) or a Medical diag ...

s 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 manner and is approved by the FDA as a food additive because of its chemical structure. The gellan gum was modified with several

fibronectin Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as col ...

-derived peptide sequences so the transplantation cells have closely related properties to that of native tissue 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 ...

. 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 Fever or pyrexia in humans is a symptom of an anti-infection defense mechanism that appears with Human body temperature, body temperature exceeding the normal range caused by an increase in the body's temperature Human body temperature#Fever, s ...

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 Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacteria, bacterium, or plant, as well as the effect o ...

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 rema ...

(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 cell The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain immune tolerance, tolerance to self-antigens, and prevent autoimmune disease. Treg ...

s (suppressor T cells) and reduces the severity of GVHD.

Infection susceptibility

OECs have properties similar to those of

, 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 generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and ...

(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 ...

, migration and viability. MPIOs have also been successfully transplanted into the vitreous 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 The p75 neurotrophin receptor (p75NTR) was first identified in 1973 as the low-affinity nerve growth factor receptor (LNGFR) before discovery that p75NTR bound other neurotrophins equally well as nerve growth factor. p75NTR is a neurotrophic fact ...

(p75).

References

{{reflist Glial cells Epithelial cells Olfactory system