Corneal keratocyte

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Keratocytes movement

Corneal keratocytes (corneal fibroblasts) are specialized fibroblasts residing in the stroma. This corneal 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. [1] 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.

Contents

Origin and functions

Keratocytes are developmentally derived from the cranial population of neural crest 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 endothelium 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. [2]

By the end of eye development an interconnected keratocyte network is established in the cornea, with dendrites of neighbouring cells contacting each other. [3] Quiescent keratocytes synthesize the so-called crystallins, known primarily for their role in the lens. Corneal crystallins, like the lens ones, are thought to help maintain the transparency and optimal refraction. [4] They are also part of corneal antioxidant defense. [5] Crystallins expressed by human keratocytes are ALDH1A1, ALDH3A1, [6] ALDH2 and TKT. Different sets of crystallins are typical to distinct species. [7] Keratan sulfate produced by keratocytes is thought to help maintain optimal corneal hydration; [8] genetic disruption of its synthesis leads to the macular corneal dystrophy. [9]

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. [10]

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 metalloproteinases 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 myofibroblasts 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". [1]

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. [11] 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 hours to arrive at the site of injury. [12] In a normal course of events, the lack of keratocytes is gradually replenished by the mitosis of the adjacent cells. [2] Apoptosis is observed after eye operations, including keratotomy and laser surgery, [13] and may play a role in the development of post-surgery complications.

Clinical significance

Alcohol dehydrogenase immunoreactivity in a healthy cornea (top), in Fuchs' dystrophy and keratoconic cornea. Diaminobenzidine stains keratocytes in the cross-section of cornea. From Mootha et al., 2009. Keratoconus keratocytes alcohol dehydrogenase 3.jpg
Alcohol dehydrogenase immunoreactivity in a healthy cornea (top), in Fuchs' dystrophy and keratoconic cornea. Diaminobenzidine stains keratocytes in the cross-section of cornea. From Mootha et al., 2009.

Keratocytes may play a role in different corneal disorders. According to comparative research, their functions drastically diverge from the norm in keratoconus, 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. [15] According to one study, patient's keratocytes have decreased levels of one of the alcohol dehydrogenase subforms, [14] they secrete significantly less superoxide dismutase 3, according to another. [16]

See also

Related Research Articles

Keratoconus Medical condition

Keratoconus (KC) is a disorder of the eye that results in progressive thinning of the cornea. This may result in blurry vision, double vision, nearsightedness, irregular astigmatism, and light sensitivity leading to poor quality-of-life. Usually both eyes are affected. In more severe cases a scarring or a circle may be seen within the cornea.

Cornea Structure of the eye

The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. The cornea, with the anterior chamber and lens, 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 approximately 43 dioptres. The cornea can be reshaped by surgical procedures such as LASIK.

Corneal endothelium

The corneal endothelium is a single layer of endothelial cells on the inner surface of the cornea. It faces the chamber formed between the cornea and the iris.

Keratin 12

Keratin 12 is a protein that in humans is encoded by the KRT12 gene.

Corneal transplantation Surgical procedure

Corneal transplantation, also known as corneal grafting, is a surgical procedure where a damaged or diseased cornea is replaced by donated corneal tissue. When the entire cornea is replaced it is known as penetrating keratoplasty and when only part of the cornea is replaced it is known as lamellar keratoplasty. Keratoplasty simply means surgery to the cornea. The graft is taken from a recently deceased individual with no known diseases or other factors that may affect the chance of survival of the donated tissue or the health of the recipient.

Fuchs dystrophy Medical condition

Fuchs dystrophy, also referred to as Fuchs endothelial corneal dystrophy (FECD) and Fuchs endothelial dystrophy (FED), is a slowly progressing corneal dystrophy that usually affects both eyes and is slightly more common in women than in men. Although early signs of Fuchs dystrophy are sometimes seen in people in their 30s and 40s, the disease rarely affects vision until people reach their 50s and 60s.

Corneal cross-linking

Corneal cross-linking with riboflavin (vitamin B2) and UV-A light is a surgical treatment for corneal ectasia such as keratoconus, PMD, and post-LASIK ectasia.

Intrastromal corneal ring segment

An intrastromal corneal ring segment (ICRS) is a small device implanted in the eye to correct vision. The procedure involves an ophthalmologist who makes a small incision in the cornea of the eye and inserts two crescent or semi-circular shaped ring segments between the layers of the corneal stroma, one on each side of the pupil. The embedding of the two rings in the cornea is intended to flatten the cornea and change the refraction of light passing through the cornea on its way into the eye.

Keratan sulfate

Keratan sulfate (KS), 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 injury. Keratan sulfates are large, highly hydrated molecules which in joints can act as a cushion to absorb mechanical shock.

Stroma of cornea

The stroma of the cornea is a fibrous, tough, unyielding, perfectly transparent and the thickest layer of the cornea of the eye. It is between Bowman's membrane anteriorly, and Descemet's membrane posteriorly.

Aldehyde dehydrogenase 3 family, member A1

Aldehyde dehydrogenase, dimeric NADP-preferring is an enzyme that in humans is encoded by the ALDH3A1 gene.

Keratocan

Keratocan (KTN) also known as keratan sulfate proteoglycan keratocan, is a protein that in humans is encoded by the KERA gene.

VSX1

Visual system homeobox 1 is a protein that in humans is encoded by the VSX1 gene.

Integrin alpha 11

Integrin alpha-11 is a protein that, in humans, is encoded by the ITGA11 gene.

Desmoplasia

In medicine, desmoplasia is the growth of fibrous or connective tissue. It is also called desmoplastic reaction to emphasize that it is secondary to an insult. Desmoplasia may occur around a neoplasm, causing dense fibrosis around the tumor, or scar tissue (adhesions) within the abdomen after abdominal surgery.

Ocular immune system

The 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. These cells fight off intraocular infections, and intraocular inflammation can manifest as uveitis or retinitis. The cornea of the eye is immunologically a very special tissue. Its constant exposure to the exterior world means that it is vulnerable to a wide range of microorganisms while its moist mucosal surface makes the cornea particularly susceptible to attack. At the same time, its lack of vasculature and relative immune separation from the rest of the body makes immune defense difficult. Lastly, the cornea is a multifunctional tissue. It provides a large part of the eye's refractive power, meaning it has to maintain remarkable transparency, but must also serve as a barrier to keep pathogens from reaching the rest of the eye, similar to function of the dermis and epidermis in keeping underlying tissues protected. Immune reactions within the cornea come from surrounding vascularized tissues as well as innate immune responsive cells that reside within the cornea.

Effects of long-term contact lens wear on the cornea Overview of the effects of long-term contact lens wear on the cornea

Long-term contact lens use can lead to alterations in corneal thickness, stromal thickness, curvature, corneal sensitivity, cell density, and epithelial oxygen uptake, etc. Other changes may include the formation of epithelial vacuoles and microcysts as well as the emergence of polymegethism in the corneal endothelium. Decreased corneal sensitivity, vision loss, and photophobia have also been observed in patients who have worn contact lenses for an extended period of time. Many contact lens-induced changes in corneal structure are reversible if contact lenses are removed for an extended period of time.

Post-LASIK ectasia is a condition similar to keratoconus where the cornea starts to bulge forwards at a variable time after LASIK, PRK, or SMILE corneal laser eye surgery. However, the physiological processes of Post-Lasik ectasia seem to be different from Keratoconus. The visible changes in the basal epithelial cell and anterior and posterior keratocytes linked with keratoconus were not observed in post-LASIK ectasia.

Corneal ectatic disorders or corneal ectasia are a group of uncommon, noninflammatory, eye disorders characterised by bilateral thinning of the central, paracentral, or peripheral cornea.

Corneal opacity Medical condition

The human cornea is a transparent membrane which allows light to pass through it. The word corneal opacification literally means loss of normal transparency of cornea. The term corneal opacity is used particularly for the loss of transparency of cornea due to scarring. Transparency of the cornea is dependent on the uniform diameter and the regular spacing and arrangement of the collagen fibrils within the stroma. Alterations in the spacing of collagen fibrils in a variety of conditions including corneal edema, scars, and macular corneal dystrophy is clinically manifested as corneal opacity. The word 'Corneal blindness' is commonly used to describe blindness due to corneal opacity.

References

  1. 1 2 Wilson SE, Chaurasia SS, Medeiros FW (September 2007). "Apoptosis in the initiation, modulation and termination of the corneal wound healing response". Exp. Eye Res. 85 (3): 305–11. doi:10.1016/j.exer.2007.06.009. PMC   2039895 . PMID   17655845.
  2. 1 2 West-Mays JA, Dwivedi DJ (2006). "The keratocyte: corneal stromal cell with variable repair phenotypes". Int. J. Biochem. Cell Biol. 38 (10): 1625–31. doi:10.1016/j.biocel.2006.03.010. PMC   2505273 . PMID   16675284.
  3. ↑ Müller LJ, Pels L, Vrensen GF (December 1995). "Novel aspects of the ultrastructural organization of human corneal keratocytes". Invest. Ophthalmol. Vis. Sci. 36 (13): 2557–67. PMID   7499078. Archived from the original on 2013-01-12. Retrieved 2009-06-13.
  4. ↑ Jester JV (April 2008). "Corneal crystallins and the development of cellular transparency". Semin. Cell Dev. Biol. 19 (2): 82–93. doi:10.1016/j.semcdb.2007.09.015. PMC   2275913 . PMID   17997336.
  5. ↑ Lassen N, Black WJ, Estey T, Vasiliou V (April 2008). "The role of corneal crystallins in the cellular defense mechanisms against oxidative stress". Semin. Cell Dev. Biol. 19 (2): 100–12. doi:10.1016/j.semcdb.2007.10.004. PMID   18077195.
  6. ↑ Lassen N, Pappa A, Black WJ, Jester JV, Day BJ, Min E, Vasiliou V (November 2006). "Antioxidant function of corneal ALDH3A1 in cultured stromal fibroblasts". Free Radic. Biol. Med. 41 (9): 1459–69. doi:10.1016/j.freeradbiomed.2006.08.009. PMID   17023273.
  7. ↑ Jester JV (April 2008). "Corneal crystallins and the development of cellular transparency". Semin. Cell Dev. Biol. 19 (2): 82–93. doi:10.1016/j.semcdb.2007.09.015. PMC   2275913 . PMID   17997336.
  8. ↑ Funderburgh JL (October 2000). "Keratan sulfate: structure, biosynthesis, and function". Glycobiology . 10 (10): 951–8. doi: 10.1093/glycob/10.10.951 . PMID   11030741.
  9. ↑ MACULAR DYSTROPHY, CORNEAL, 1; MCDC1 - OMIM.
  10. ↑ Patel S, McLaren J, Hodge D, Bourne W (February 2001). "Normal human keratocyte density and corneal thickness measurement by using confocal microscopy in vivo". Invest. Ophthalmol. Vis. Sci. 42 (2): 333–9. PMID   11157863. Archived from the original on 2013-01-13. Retrieved 2009-06-14.
  11. ↑ Wilson SE, He YG, Weng J, Li Q, McDowall AW, Vital M, Chwang EL (April 1996). "Epithelial injury induces keratocyte apoptosis: hypothesized role for the interleukin-1 system in the modulation of corneal tissue organization and wound healing". Exp. Eye Res. 62 (4): 325–7. doi:10.1006/exer.1996.0038. PMID   8795451.
  12. ↑ Wilson SE, Pedroza L, Beuerman R, Hill JM (May 1997). "Herpes simplex virus type-1 infection of corneal epithelial cells induces apoptosis of the underlying keratocytes". Exp. Eye Res. 64 (5): 775–9. doi:10.1006/exer.1996.0266. PMID   9245908.
  13. ↑ Erie JC, McLaren JW, Hodge DO, Bourne WM (2005). "Long-term corneal keratoctye deficits after photorefractive keratectomy and laser in situ keratomileusis" (PDF). Trans Am Ophthalmol Soc . 103: 56–66, discussion 67–8. PMC   1447559 . PMID   17057788. Archived from the original (PDF) on 2008-10-12. Retrieved 2009-06-14.
  14. 1 2 Mootha VV, Kanoff JM, Shankardas J, Dimitrijevich S (2009). "Marked reduction of alcohol dehydrogenase in keratoconus corneal fibroblasts". Mol. Vis. 15: 706–12. PMC   2666775 . PMID   19365573.
  15. ↑ Kim WJ, Rabinowitz YS, Meisler DM, Wilson SE (November 1999). "Keratocyte apoptosis associated with keratoconus". Exp. Eye Res. 69 (5): 475–81. CiteSeerX   10.1.1.610.7418 . doi:10.1006/exer.1999.0719. PMID   10548467.
  16. ↑ Olofsson EM, Marklund SL, Pedrosa-Domellöf F, Behndig A (2007). "Interleukin-1alpha downregulates extracellular-superoxide dismutase in human corneal keratoconus stromal cells". Mol. Vis. 13: 1285–90. PMID   17679946.
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