Corneal keratocyte
Encyclopedia
Corneal keratocytes are specialized fibroblast
s residing in the stroma. This cornea
l layer, representing about 85-90% of corneal thickness, is built up from highly regular collagenous lamellae and extracellular matrix components. Keratocytes play the major role in keeping it transparent, healing its wounds, and synthesizing its components. In the unperturbed cornea keratocytes stay dormant, coming into action after any kind of injury or inflammation. Some keratocytes underlying the site of injury, even a light one, undergo apoptosis immediately after the injury. Any glitch in the precisely orchestrated process of healing may cloud the cornea, while excessive keratocyte apoptosis may be a part of the pathological process in the degenerative corneal disorders such as keratoconus
, and these considerations prompt the ongoing research into the function of these cells.
cells, from whence they migrate to settle in the mesenchyme
. In some species the migration from neural crest comes in two waves, with the first giving birth to the corneal epithelium
and the second invading the epithelium-secreted stromal anlage devoid of cells; in other species both populations come from a single wave of migration. Once settled in the stroma, keratocytes start synthesizing collagen molecules of different types (I, V, VI) and keratan sulfate
. By the moment of eye opening after birth the proliferation of keratocytes is all but finished and most of them are in the quiescent state.
By the end of eye development an interconnected keratocyte network is established in the cornea, with dendrites of neighbouring cells contacting each over. Quiescent keratocytes synthesize the so-called crystallin
s, known primarily for their role in the lens
. Corneal crystallins, like the lens ones, are thought to help maintain the transparency and optimal refraction. They are also part of corneal antioxidant defense. Crystallins expressed by human keratocytes are ALDH1A1
, ALDH3A1
, ALDH2
and TKT. Different sets of crystallins are typical to distinct species. Keratan sulfate produced by keratocytes is thought to help maintain optimal corneal hydration; genetic disruption of its synthesis leads to the macular corneal dystrophy
.
According to one study, average keratocyte density in the human stroma is about 20500 cells per mm3, or 9600 in a column of 1 mm2 in section. The highest density is observed in the upper 10% of the stroma. The number of keratocytes declines with age, at a rate approximately 0.45% per year.
After an injury to the cornea, some keratocytes undergo apoptosis, prompted by the signaling molecules secreted by the upper layers, such as IL1 alpha
and TNF-alpha. Other neighbouring keratocytes, when acted upon by the same molecules, become active, proliferate and start synthesizing matrix metalloproteinase
s that cause tissue remodeling. These activated cells are designated in different sources either as "active keratocytes" or "fibroblasts" or are said to assume a "repair phenotype". After heavier injuries or at the advanced stages of healing process a number of keratocytes transforms into myofibroblast
s actively secreting ECM
components; this transformation is thought to be caused by TGF-beta. As soon as the basement membrane
of corneal epithelium
is restored, TGF beta
inflow into the stroma drastically decreases and myofibroblasts disappear, after which the remaining activated keratocytes continue for some time to reshape the extracellular matrix, secreting IL1-alpha
in order to maintain their "repair phenotype".
Apoptosis
of keratocytes, either in quiescent or active state, is a process that attracts special attention. In a healthy cornea
the programmed cell
death
is a rare occasion, but immediately after an injury
to the uppermost layer keratocytes directly under the injury site commit apoptosis. One hypothesis
explains such rapid reaction by the need to stem the possible infection
from spreading into the cornea, because due to the limitations of ocular immune system
the immune cells take up to several hour
s to arrive at the site of injury. In a normal course of events, the lack of keratocytes in gradually replenished by the mitosis
of the adjacent cells. Apoptosis is observed after eye operations, including keratotomy and laser surgery
, and may play a role in the development of post-surgery complications.
, the most frequent form of corneal dystrophy
. In keratoconic corneas they have been shown to commit apoptosis far away from any epithelial injury; a hypothesis exists that presents excessive keratocyte apoptosis as a major pathological event in keratoconus. According to one study, patient's keratocytes have decreased levels of one of the alcohol dehydrogenase subforms
, they secrete significantly less superoxide dismutase 3
, according to another.
Fibroblast
A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...
s residing in the stroma. This cornea
Cornea
The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Together with the lens, the cornea refracts light, with the cornea accounting for approximately two-thirds of the eye's total optical power. In humans, the refractive power of the cornea is...
l layer, representing about 85-90% of corneal thickness, is built up from highly regular collagenous lamellae and extracellular matrix components. Keratocytes play the major role in keeping it transparent, healing its wounds, and synthesizing its components. In the unperturbed cornea keratocytes stay dormant, coming into action after any kind of injury or inflammation. Some keratocytes underlying the site of injury, even a light one, undergo apoptosis immediately after the injury. Any glitch in the precisely orchestrated process of healing may cloud the cornea, while excessive keratocyte apoptosis may be a part of the pathological process in the degenerative corneal disorders such as keratoconus
Keratoconus
Keratoconus , is a degenerative disorder of the eye in which structural changes within the cornea cause it to thin and change to a more conical shape than its normal gradual curve....
, and these considerations prompt the ongoing research into the function of these cells.
Origin and functions
Keratocytes are developmentally derived from the cranial population of neural crestNeural crest
Neural crest cells are a transient, multipotent, migratory cell population unique to vertebrates that gives rise to a diverse cell lineage including melanocytes, craniofacial cartilage and bone, smooth muscle, peripheral and enteric neurons and glia....
cells, from whence they migrate to settle in the mesenchyme
Mesenchyme
Mesenchyme, or mesenchymal connective tissue, is a type of undifferentiated loose connective tissue that is derived mostly from mesoderm, although some are derived from other germ layers; e.g. some mesenchyme is derived from neural crest cells and thus originates from the ectoderm...
. In some species the migration from neural crest comes in two waves, with the first giving birth to the corneal epithelium
Corneal epithelium
The corneal epithelium is made up of epithelial tissue and covers the front of the cornea. It acts as a barrier to protect the cornea, resisting the free flow of fluids from the tears, and prevents bacteria from entering the epithelium and corneal stroma.The corneal epithelium consists of several...
and the second invading the epithelium-secreted stromal anlage devoid of cells; in other species both populations come from a single wave of migration. Once settled in the stroma, keratocytes start synthesizing collagen molecules of different types (I, V, VI) and keratan sulfate
Keratan sulfate
Keratan sulfate , also called keratosulfate, is any of several sulfated glycosaminoglycans that have been found especially in the cornea, cartilage, and bone. It is also synthesized in the central nervous system where it participates both in development and in the glial scar formation following an...
. By the moment of eye opening after birth the proliferation of keratocytes is all but finished and most of them are in the quiescent state.
By the end of eye development an interconnected keratocyte network is established in the cornea, with dendrites of neighbouring cells contacting each over. Quiescent keratocytes synthesize the so-called crystallin
Crystallin
In anatomy, a crystallin is a water-soluble structural protein found in the lens and the cornea of the eye accounting for the transparency of the structure. It has also been identified in other places such as the heart, and in aggressive breast cancer tumors....
s, known primarily for their role in the lens
Lens (anatomy)
The crystalline lens is a transparent, biconvex structure in the eye that, along with the cornea, helps to refract light to be focused on the retina. The lens, by changing shape, functions to change the focal distance of the eye so that it can focus on objects at various distances, thus allowing a...
. Corneal crystallins, like the lens ones, are thought to help maintain the transparency and optimal refraction. They are also part of corneal antioxidant defense. Crystallins expressed by human keratocytes are ALDH1A1
ALDH1A1
Aldehyde dehydrogenase 1 family, member A1 also known as ALDH1A1 is an enzyme that in humans is encoded by the ALDH1A1 gene.- Function :...
, ALDH3A1
ALDH3A1
Aldehyde dehydrogenase, dimeric NADP-preferring is an enzyme that in humans is encoded by the ALDH3A1 gene.Aldehyde dehydrogenases oxidize various aldehydes to the corresponding acids. They are involved in the detoxification of alcohol-derived acetaldehyde and in the metabolism of corticosteroids,...
, ALDH2
ALDH2
Aldehyde dehydrogenase 2 family , also known as ALDH2, is a human gene found on chromosome 12.-Function:The enzyme encoded by this gene belongs to the aldehyde dehydrogenase family of enzymes that catalyze the chemical transformation from acetaldehyde to acetic acid...
and TKT. Different sets of crystallins are typical to distinct species. Keratan sulfate produced by keratocytes is thought to help maintain optimal corneal hydration; genetic disruption of its synthesis leads to the macular corneal dystrophy
Macular corneal dystrophy
Macular corneal dystrophy is a rare pathological condition affecting the stroma of cornea. The first signs are usually noticed in the first decade of life, and progress afterwards, with opacities developing in the cornea and attacks of pain...
.
According to one study, average keratocyte density in the human stroma is about 20500 cells per mm3, or 9600 in a column of 1 mm2 in section. The highest density is observed in the upper 10% of the stroma. The number of keratocytes declines with age, at a rate approximately 0.45% per year.
After an injury to the cornea, some keratocytes undergo apoptosis, prompted by the signaling molecules secreted by the upper layers, such as IL1 alpha
IL1A
Interleukin-1 alpha is a protein that in humans is encoded by the IL1A gene.The protein encoded by this gene is a cytokine of the interleukin-1 family. Interleukin-1 alpha possesses a wide spectrum of metabolic, physiological, haematopoietic activities, and plays one of the central roles in the...
and TNF-alpha. Other neighbouring keratocytes, when acted upon by the same molecules, become active, proliferate and start synthesizing matrix metalloproteinase
Matrix metalloproteinase
Matrix metalloproteinases are zinc-dependent endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs belong to a larger family of proteases known as the metzincin superfamily....
s that cause tissue remodeling. These activated cells are designated in different sources either as "active keratocytes" or "fibroblasts" or are said to assume a "repair phenotype". After heavier injuries or at the advanced stages of healing process a number of keratocytes transforms into myofibroblast
Myofibroblast
A Myofibroblast is a cell that is in between a fibroblast and a smooth muscle cell in differentiation.-Developmental origin:There are many possible ways of myofibroblast development:#Partial smooth muscle differentiation of a fibroblastic cell...
s actively secreting ECM
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
components; this transformation is thought to be caused by TGF-beta. As soon as the basement membrane
Basement membrane
The basement membrane is a thin sheet of fibers that underlies the epithelium, which lines the cavities and surfaces of organs including skin, or the endothelium, which lines the interior surface of blood vessels.- Composition :...
of corneal epithelium
Corneal epithelium
The corneal epithelium is made up of epithelial tissue and covers the front of the cornea. It acts as a barrier to protect the cornea, resisting the free flow of fluids from the tears, and prevents bacteria from entering the epithelium and corneal stroma.The corneal epithelium consists of several...
is restored, TGF beta
TGF beta
Transforming growth factor beta is a protein that controls proliferation, cellular differentiation, and other functions in most cells. It plays a role in immunity, cancer, heart disease, diabetes, Marfan syndrome, and Loeys–Dietz syndrome....
inflow into the stroma drastically decreases and myofibroblasts disappear, after which the remaining activated keratocytes continue for some time to reshape the extracellular matrix, secreting IL1-alpha
IL1A
Interleukin-1 alpha is a protein that in humans is encoded by the IL1A gene.The protein encoded by this gene is a cytokine of the interleukin-1 family. Interleukin-1 alpha possesses a wide spectrum of metabolic, physiological, haematopoietic activities, and plays one of the central roles in the...
in order to maintain their "repair phenotype".
Apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
of keratocytes, either in quiescent or active state, is a process that attracts special attention. In a healthy cornea
Cornea
The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Together with the lens, the cornea refracts light, with the cornea accounting for approximately two-thirds of the eye's total optical power. In humans, the refractive power of the cornea is...
the programmed cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
death
Death
Death is the permanent termination of the biological functions that sustain a living organism. Phenomena which commonly bring about death include old age, predation, malnutrition, disease, and accidents or trauma resulting in terminal injury....
is a rare occasion, but immediately after an injury
Injury
-By cause:*Traumatic injury, a body wound or shock produced by sudden physical injury, as from violence or accident*Other injuries from external physical causes, such as radiation injury, burn injury or frostbite*Injury from infection...
to the uppermost layer keratocytes directly under the injury site commit apoptosis. One hypothesis
Hypothesis
A hypothesis is a proposed explanation for a phenomenon. The term derives from the Greek, ὑποτιθέναι – hypotithenai meaning "to put under" or "to suppose". For a hypothesis to be put forward as a scientific hypothesis, the scientific method requires that one can test it...
explains such rapid reaction by the need to stem the possible infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
from spreading into the cornea, because due to the limitations of ocular immune system
Ocular immune system
Ocular immune system protects the eye from infection and regulates healing processes following injuries. The interior of the eye lacks lymph vessels but is highly vascularized, and many immune cells reside in the uvea, including mostly macrophages, dendritic cells, and mast cells...
the immune cells take up to several hour
Hour
The hour is a unit of measurement of time. In modern usage, an hour comprises 60 minutes, or 3,600 seconds...
s to arrive at the site of injury. In a normal course of events, the lack of keratocytes in gradually replenished by the mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
of the adjacent cells. Apoptosis is observed after eye operations, including keratotomy and laser surgery
Laser surgery
Laser surgery is surgery using a laser to cut tissue instead of a scalpel. Examples include the use of a laser scalpel in otherwise conventional surgery, and soft tissue laser surgery, in which the laser beam vaporizes soft tissue with high water content...
, and may play a role in the development of post-surgery complications.
Clinical significance
Keratocytes may play a role in different corneal disorders. According to comparative research, their functions drastically diverge from the norm in keratoconusKeratoconus
Keratoconus , is a degenerative disorder of the eye in which structural changes within the cornea cause it to thin and change to a more conical shape than its normal gradual curve....
, the most frequent form of corneal dystrophy
Corneal dystrophy
Corneal dystrophy is a group of disorders, characterised by a noninflammatory, inherited, bilateral opacity of the transparent front part of the eye called the cornea.The distrophies could be subdivided based on specie affected:...
. In keratoconic corneas they have been shown to commit apoptosis far away from any epithelial injury; a hypothesis exists that presents excessive keratocyte apoptosis as a major pathological event in keratoconus. According to one study, patient's keratocytes have decreased levels of one of the alcohol dehydrogenase subforms
ADH1B
Alcohol dehydrogenase 1B is an enzyme that in humans is encoded by the ADH1B gene.The protein encoded by this gene is a member of the alcohol dehydrogenase family. Members of this enzyme family metabolize a wide variety of substrates, including ethanol, retinol, other aliphatic alcohols,...
, they secrete significantly less superoxide dismutase 3
SOD3
Extracellular superoxide dismutase [Cu-Zn] is an enzyme that in humans is encoded by the SOD3 gene.This gene encodes a member of the superoxide dismutase protein family. SODs are antioxidant enzymes that catalyze the dismutation of two superoxide radicals into hydrogen peroxide and oxygen...
, according to another.
External links
- Nigel Brookes - researcher