Corneal keratocyte

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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.

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 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.[2]

By the end of eye development an interconnected keratocyte network is established in the cornea, with dendrites of neighbouring cells contacting each over.[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 и 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".[11]

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.[12] 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.[13] In a normal course of events, the lack of keratocytes in gradually replenished by the mitosis of the adjacent cells.[2] Apoptosis is observed after eye operations, including keratotomy and laser surgery,[14] and may play a role in the development of post-surgery complications.

Clinical significance

File: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.[15]

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.[16] According to one study, patient's keratocytes have decreased levels of one of the alcohol dehydrogenase subforms,[15] they secrete significantly less superoxide dismutase 3, according to another.[17]

References

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External links

Fibrous tunic (outer)
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Image:Eye-diagram no circles border.svg|275px|1:posterior compartment 2:ora serrata 3:ciliary muscle 4:ciliary zonules 5:canal of Schlemm 6:pupil 7:anterior chamber 8:cornea 9:iris 10:lens cortex 11:lens nucleus 12:ciliary process 13:conjunctiva 14:inferior oblique muscule 15:inferior rectus muscule 16:medial rectus muscle 17:retinal arteries and veins 18:optic disc 19:dura mater 20:central retinal artery 21:central retinal vein 22:optical nerve 23:vorticose vein 24:bulbar sheath 25:macula 26:fovea 27:sclera 28:choroid 29:superior rectus muscle 30:retina

circle 312 128 45 1: posterior compartment circle 238 183 45 2: ora serrata circle 172 250 45 3: ciliary muscle circle 121 327 45 4: ciliary zonules circle 74 410 45 5: canal of Schlemm circle 55 497 45 6: pupil circle 41 592 45 7: anterior chamber circle 44 687 45 8: cornea circle 58 775 45 9: iris circle 93 859 45 10: lens cortex circle 137 940 45 11: lens nucleus circle 186 1011 45 12: ciliary process circle 255 1073 45 13: conjunctiva circle 826 1167 45 14: inferior oblique muscule circle 912 1125 45 15: inferior rectus muscule circle 988 1074 45 16: medial rectus muscle circle 1059 1010 45 17: retinal arteries and veins circle 1114 938 45 18: optic disc circle 1155 861 45 19: dura mater circle 1184 775 45 20: central retinal artery circle 1161 411 45 21: central retinal vein circle 1124 330 45 22: optical nerve circle 1074 252 45 23: vorticose vein circle 1002 188 45 24: bulbar sheath circle 934 134 45 25: macula circle 844 81 45 26: fovea circle 750 52 45 27: sclera circle 661 41 45 28: choroid circle 576 45 45 29: superior rectus muscle circle 486 52 45 30: retina

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Human cell types / list derived primarily from ectoderm
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Neural crest
Corneal keratocyte
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M: EYE

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  1. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  2. ↑ 2.0 2.1 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 Freely accessible. PMID 16675284. 
  3. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  4. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  5. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  6. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  7. ↑ list of the known crystallins in different species - from a review in PMID 17997336
  8. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  9. ↑ MACULAR DYSTROPHY, CORNEAL, 1; MCDC1 - OMIM.
  10. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  11. ↑ Corneal healing process, from a review in PMID 17655845
  12. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  13. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  14. ↑ 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 Freely accessible. PMID 17057788. 
  15. ↑ 15.0 15.1 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 Freely accessible. PMID 19365573. 
  16. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  17. ↑ 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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