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Modern anatomical and physiological bases for maintaining the transparency of the corneal stroma

https://doi.org/10.29413/ABS.2023-8.4.21

Abstract

The article presents a literature review of the modern concept of anatomical and physiological structure and functioning of the cornea. The strict morphological structure and corneal tissue homeostasis ensure its transparency. Studying the mechanisms that regulate the constancy of the corneal tissue internal environment allows us to get closer to understanding the prospects forregenerative therapy for the corneal stroma pathology. The article discusses in detail the role and functional potential of corneal stromal cells, which are capable of reverse cytologic differentiation, which primarily ensures the maintenance of tissue homeostasis and corneal transparency. The functional activity of corneal cells can change for a number of reasons, which may be exogenous, iatrogenic (trauma, infection, etc.) or endogenous. Endogenous causes include: cell autoregulation pathologies (for example, enzyme defects); defects in transport systems leading to tissue hypoxia; disorders of the neuro-humoral regulation of trophism. The physical reason forthe violation of the corneal transparency is an increase in the light scattering. The article presents five main causes of increased light scattering in the opaque cornea, and also provides an overview of the main substances – components and products of cellular synthesis of corneal stromal cells: cytokines and growth factors (complex of the signal molecule and the SDF1/CXCR4 receptor, insulin-like growth factor 1, tumor necrosis factor alpha, intercellular adhesion molecule 1, erythropoietin, neurotrophic factors, etc.). Thus, corneal opacity can be caused by a single pathogenic mechanism or be the result of a complex effect of several factors. The main processes of tissue homeostasis regulation are aimed at maintaining the unique morphological structure of the cornea.

About the Authors

K. Yu. Krasner
Novosibirsk Branch of the S. Fyodorov Eye Microsurgery Federal State Institution; Research Institute of Clinical and Experimental Lymphology – Branch of the Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences
Russian Federation

Kristina Yu. Krasner – Ophthalmologist; Junior Research Officer at the Laboratory of Cell Technology 

Kolkhidskaya str. 10, Novosibirsk 630096;
Timakova str. 2, Novosibirsk 630060



O. V. Poveshchenko
Research Institute of Clinical and Experimental Lymphology – Branch of the Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences
Russian Federation

Olga V. Poveshchenko – Dr. Sc. (Med.), Professor, Head of the Laboratory of Cell Technology 

Timakova str. 2, Novosibirsk 630060



M. A. Surovtseva
Research Institute of Clinical and Experimental Lymphology – Branch of the Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences
Russian Federation

Maria A. Surovtseva – Cand. Sc. (Med.), Senior Research Officer at the Laboratory of Cell Technology 

Timakova str. 2, Novosibirsk 630060



A. N. Trunov
Novosibirsk Branch of the S. Fyodorov Eye Microsurgery Federal State Institution
Russian Federation

Aleksandr N. Trunov – Dr. Sc. (Med.), Professor 

Kolkhidskaya str. 10, Novosibirsk 630096



I. I. Kim
Research Institute of Clinical and Experimental Lymphology – Branch of the Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences
Russian Federation

Irina I. Kim – Cand. Sc. (Med.), Research Officer at the Laboratory of Cell Technology 

Timakova str. 2, Novosibirsk 630060



N. A. Bondarenko
Research Institute of Clinical and Experimental Lymphology – Branch of the Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences
Russian Federation

Natalia A. Bondarenko – Cand. Sc. (Med.), Research Officer at the Laboratory of Cell Technology 

Timakova str. 2, Novosibirsk 630060



V. V. Chernykh
Novosibirsk Branch of the S. Fyodorov Eye Microsurgery Federal State Institution
Russian Federation

Valery V. Chernykh – Dr. Sc. (Med.), Professor, Director 

Kolkhidskaya str. 10, Novosibirsk 630096



References

1. Robaei D, Watson S. Corneal blindness: A global problem. Clin Exp Ophthalmol. 2014; 42(3): 213-214. doi: 10.1111/ceo.12330

2. Stramer BM, Zieske JD, Jung JC, Austin JS, Fini ME. Molecular mechanisms controlling the fibrotic repair phenotype in cornea: Implications for surgical outcomes. Invest Ophthalmol Vis Sci. 2003; 44(10): 4237-4246. doi: 10.1167/iovs.02-1188

3. Gain P, Jullienne R, He Z, Aldossary M, Acquart S, Cognasse F, et al. Global survey of corneal transplantation and eye banking. JAMA Ophthalmol. 2016; 134: 167-173. doi: 10.1001/jamaophthalmol.2015.4776

4. Young RD, Knupp C, Pinali C, Png KM, Ralphs JR, Bushby AJ, et al. Three-dimensional aspects of matrix assembly by cells in the developing cornea. Proc Nat Acad Sci U S A. 2014; 111(2): 687-692. doi: 10.1073/pnas.1313561110

5. Remington LE. Clinical anatomy and physiology of the visual system. Moscow: Gorodets; 2020. (In Russ.).

6. Nishida T. Commanding roles of keratocytes in health and disease. Cornea. 2010; 29(1): S3-S6. doi: 10.1097/ICO.0b013e3181f2d578

7. Carlson EC, Liu CY, Chikama T, Hayashi Y, Kao CW, Birk DE, et al. Keratocan a cornea-specific keratan sulfate proteoglycan is regulated by lumican. J Biol Chem. 2005; 280(27): 25541-25547. doi: 10.1074/jbc.M500249200

8. Kao WW, Liu CY. Roles of lumican and keratocan on corneal transparency. Glycoconjugate J. 2002; 19(4–5): 275-285. doi: 10.1023/A:1025396316169

9. Leung BK, Bonanno JA, Radke CJ. Oxygen-deficient metabolism and corneal edema. Prog Retin Eye Res. 2011; 30(6): 471-492. doi: 10.1016/j.preteyeres.2011.07.001

10. Fini ME. Keratocyte and fibroblast phenotypes in the repairing cornea. Prog Retin Eye Res. 1999; 18(4): 529-551. doi: 10.1016/s1350-9462(98)00033-0

11. Fukuda K. Corneal fibroblasts: Function and markers. Exp Eye Res. 2020; 200: 108229. doi: 10.1016/j.exer.2020.108229

12. Jester JV, Petroll WM, Barry PA, Cavanagh HD. Expression of alpha-smooth muscle (alpha-SM) actin during corneal stromal wound healing. Invest Ophthalmol Vis Sci. 1995; 36: 809-819

13. Fini ME. Keratocyte and fibroblast phenotypes in the repairing cornea. Prog Retin Eye Res. 1999; 18(4): 529-551. doi: 10.1016/s1350-9462(98)00033-0

14. Scott SG, Jun AS, Chakravarti S. Sphere formation from corneal keratocytes and phenotype specific markers. Exp Eye Res. 2011; 93(6): 898-905. doi: 10.1016/j.exer.2011.10.004

15. Sherwin T, Green CR. Stromal wound healing. Corneal Surgery: Theory, Technique and Tissue. Mosby Elsevier; 2009: 45-56. doi: 10.1016/B978-0-323-04835-4.50012-4

16. Zieske JD. Extracellular matrix and wound healing. Curr Opin Ophthalmol. 2001; 12: 237-241. doi: 10.1097/00055735-200108000-00001

17. Funderburgh JL, Mann MM, Funderburgh ML. Keratocyte phenotype mediates proteoglycan structure. A role for fibroblasts in corneal fibrosis. J Biol. Chem. 2003; 278(46): 45629-45637. doi: 10.1074/jbc.M303292200

18. Karamichos D, Guo XQ, Hutcheon AE, Zieske JD. Human corneal fibrosis: An in vitro model. Invest Ophthalmol Vis Sci. 2010; 51: 1382-1388. doi: 10.1167/iovs.09-3860

19. Chaurasia SS, Kaur H, de Medeiros FW, Smith SD, Wilson SE. Dynamics of the expression of intermediate filaments vimentin and desmin during myofibroblast differentiation after corneal injury. Exp Eye Res. 2009; 89: 133-139. doi: 10.1016/j.exer.2009.02.022

20. Saikia P, Crabb J, Dibbin L, Madison J, Juszczak BW, GeengFu J, et al. Quantitative proteomic comparison of myofibroblasts derived from bone marrow and cornea. Sci Rep. 2020; 10: 16717. doi: 10.1038/s41598-020-73686-w

21. Sandbo N, Smolyaninova LV, Orlov SN, Dulin NO. Regulation of differentiation and functioning of myofibroblasts by the signaling system of the cytoskeleton. Biological Chemistry Reviews. 2016; 56(13): 259-282. (In Russ.).

22. Cherng S, Jenny Y, Hongbao M. Alpha-smooth muscle actin (α-SMA). J Am Sci. 2008; 4: 7-9. doi: 10.3390/jcm10245804

23. Maltseva O, Folger P, Zekaria D, Petridou S, Masur SK. Fibroblast growth factor reversal of the corneal myofibroblast phenotype. Invest Ophthalmol Vis Sci. 2001; 42: 2490-2495.

24. Kureshi AK, Funderburgh JL, Daniels JT. Human corneal stromal stem cells exhibit survival capacity following isolation from stored organ-culture corneas. Invest Ophthalmol Vis Sci. 2014; 55(11): 7583-7588. doi: 10.1167/iovs.14-14448

25. Nagymihaly RM, Moe MC, Petrovski G. Isolation and culture of corneal stromal stem cells. Methods Mol Biol. 2020; 2145: 1-15. doi: 10.1007/978-1-0716-0599-8_1

26. Lync AP, O’Sullivan F, Ahearne M. The effect of growth factor supplementation on corneal stromal cell phenotype in vitro using a serum-free media. Exp Eye Res. 2016; 151: 26-37. doi: 10.1016/j.exer.2016.07.015

27. Musselmann K, Kane B, Alexandrou B, Hassell JR. Stimulation of collagen synthesis by insulin and proteoglycan accumulation by ascorbate in bovine keratocytes in vitro. Invest Ophthalmol Vis Sci. 2006; 47: 5260-5266. doi: 10.1167/iovs.06-0612

28. Matthyssen S, Van den Bogerd B, Dhubhghaill SN, Koppen C, Zakaria N. Corneal regeneration: A review of stromal replacements. Acta biomaterialia. 2018; 69: 31-41. doi: 10.1016/j.actbio.2018.01.023

29. Adijanto J, Philp N. The SLC16A family of monocarboxylate transporters (MCTs) – physiology and function in cellular metabolism, pH homeostasis, and fluid transport. Curr Topics Membr. 2012; 70: 275-312. doi: 10.1016/B978-0-12-394316-3.00009-0

30. Shemeleva OA, Rozhko AA, Rozhko YuI. Corneal dystrophy: A practical guide for physicians. Gomel; 2020. (In Russ.).

31. Wollensak G, Green WR. Analysis of sex-mismatched human corneal transplants by fluorescence in situ hybridization of the sex-chromosomes. Exp Eye Res. 1999; 68: 341. doi: 10.1006/exer.1998.0611

32. Hassell JR, Birk DE. The molecular basis of corneal transparency. Exp Eye Res. 2010; 91(3): 326-335. doi: 10.1016/j.exer.2010.06.021

33. Lingling Z, Matthew C, Anderson L, Chia-Yang L. The role of corneal stroma: A potential nutritional source for the cornea. J Nat Sci. 2017; 3(8): e428.

34. Meek KM, Knupp C. Corneal structure and transparency. Prog Retin Eye Res. 2015; 49: 1-16. doi: 10.1016/j.preteyeres.2015.07.001

35. Lewis PN, Pinali C, Young RD, Meek KM, Quantock AJ, Knupp C. Structural interactions between collagen and proteoglycans are elucidated by three-dimensional electron tomography of bovine cornea. Structure. 2010; 18: 239-245. doi: 10.1016/j.str.2009.11.013

36. Cheng X, Pinsky PM. Mechanisms of self-organization for the collagen fibril lattice in the human cornea. J R Soc Interface. 2013; 10: 20130512. doi: 10.1098/rsif.2013.0512

37. Jester JV, Budge A, Fisher S, Huang J. Corneal keratocytes: Phenotypic and species differences in abundant protein expression and in vitro light-scattering. Invest Ophthalmol Vis Sci. 2005; 46: 2369e2378. doi: 10.1167/iovs.04-1225

38. Ljubimov AV, Saghizadeh M. Progress in corneal wound healing. Prog Retin Eye Res. 2015; 49: 17-45. doi: 10.1016/j.preteyeres.2015.07.002

39. Kumar A, Kumar Y, Funderburgh M, Du Y. Regenerative therapy for the cornea. Prog Retin Eye Res. 2021; 87: 101011. doi: 10.1016/j.preteyeres.2021.101011

40. Jester JV. Corneal crystallins and the development of cellular transparency. Semin Cell Dev Biol. 2008; 19(2): 82-93. doi: 10.1016/j.semcdb.2007.09.015

41. Pei Y, Reins RY, McDermott AM. Aldehyde dehydrogenase (ALDH) 3A1 expression by the human keratocyte and its repair phenotypes. Exp Eye Res. 2006; 83(5): 1063-1073. doi: 10.1016/j.exer.2006.05.011

42. Stramer BM, Fini ME. Uncoupling keratocyte loss of corneal crystallin from markers of fibrotic repair. Invest Ophthalmol Vis Sci. 2004; 45: 4010e4015. doi: 10.1167/iovs.03-1057

43. Stagos D, Chen Y, Cantore M, Jester JV, Vasiliou V. Corneal aldehyde dehydrogenases: Multiple functions and novel nuclear localization. Brain Res Bull. 2010; 81(2-3): 211-218. doi: 10.1016/j.brainresbull.2009.08.017

44. Stramer BM, Cook JR, Fini ME, Taylor A, Obin M. Induction of the ubiquitin-proteasome pathway during the keratocyte transition to the repair fibroblast phenotype. Invest Ophthalmol Vis Sci. 2001; 42: 1698e1706.

45. Mitchell R, Mellows B, Sheard J, Antonioli M, Kretz O, Chambers D, et al. Secretome of adipose-derived mesenchymal stem cells promotes skeletal muscle regeneration through synergistic action of extracellular vesicle cargo and soluble proteins. Stem Cell Res. 2019; 10: 116. doi: 10.1186/s13287-019-1213-1

46. Cheung MY, McGhee NJ, Sherwin T. A new perspective on the pathobiology of keratoconus: interplay of stromal wound healing and reactive species-associated processes. Clin Exp Optometry. 2013; 96(2): 188-196. doi: 10.1111/cxo.12025

47. Kim WJ, Rabinowitz YS, Meisler DM, Wilson SE. Keratocyte apoptosis associated with keratoconus. Exp Eye Res. 1999; 69(5): 475-481. doi: 10.1006/exer.1999.0719

48. Karamichos D, Hutcheon AE, Rich CB, Trinkaus-Randall V, Asara JM, Zieske JD. In vitro model suggests oxidative stress involved in keratoconus disease. Sci Rep. 2014; 9(4): 4608. doi: 10.1038/srep04608

49. Shetty R, Ghosh A, Lim RR, Subramani M, Mihir K, Reshma AR, et al. Elevated expression of matrix metalloproteinase-9 and inflammatory cytokines in keratoconus patients is inhibited by cyclosporine A. Invest Ophthalmol Vis Sci. 2015; 56: 738-750. doi: 10.1167/iovs.14-14831

50. West-Mays A, Dwivedi J. The keratocyte: Corneal stromal cell with variable repair phenotypes. Int J Biochem Cell Biol. 2006; 38(10): 1627-1631. doi: 10.1016/j.biocel.2006.03.010

51. Meng XM, Nikolic-Paterson DJ, Lan HY. TGF-beta: The master regulator of fibrosis. Nat Rev Nephrol. 2016; 12(6): 325-338. doi: 10.1038/nrneph.2016.48

52. Walton KL, Johnson KE, Harrison CA. Targeting TGF-beta mediated SMAD-signaling for the prevention of fibrosis. Front Pharmacol. 2017; 8: 461. doi: 10.3389/fphar.2017.00461

53. Saika S, Yamanaka O, Okada Y, Tanaka S, Miyamoto T, Sumioka T, et al. TGFβ in fibroproliferative diseases in the eye. Front Biosci (Schol Ed). 2009; 1: 376-390. doi: 10.2741/S32

54. Gilbert RW, Vickaryous MK, Viloria-Petit AM. Signalling by transforming growth factor β isoforms in wound healing and tissue regeneration. JDev Biol. 2016; 4(2): 21. doi: 10.3390/jdb4020021

55. Karamichos D, Hutcheon AE, Zieske JD. Transforming growth factor-β3 regulates assembly of a non-fibrotic matrix in a 3D corneal model. J Tissue Eng Regen Med. 2011; 5(8): e228-e238. doi: 10.1002/term.429

56. de Oliveira RC, Tye G, Sampaio LP, Shiju TM, DeDreu JR, Menko AS, et al. TGF β1 and TGF β2 proteins in corneas with and without stromal fibrosis: Delayed regeneration of apical epithelial growth factor barrier and the epithelial basement membrane in corneas with stromal fibrosis. Exp Eye Res. 2021; 202: 108325. doi: 10.1016/j.exer.2020.108325

57. Weng L, Funderburgh JL, Khandaker I, Geary ML, Yang T, Basu R, et al. The anti-scarring effect of corneal stromal stem cell therapy is mediated by transforming growth factor TGF β3. Eye Vis. 2020; 7(1): 52. doi: 10.1186/s40662-020-00217-z

58. Liu L, Yu Q, Lin J, Lai X, Cao W, Du K, et al. Hypoxia-inducible factor-1α is essential for hypoxia-induced mesenchymal stem cell mobilization into the peripheral blood. Stem Cells Dev. 2011; 20(11): 1961-1971. doi: 10.1089/scd.2010.0453

59. Kim K, Park S, Lee S, Kim J. Upregulated stromal cellderived factor 1 (SDF-1) expression and its interaction with CXCR4 contribute to the pathogenesis of severe pterygia. Invest Opthalmol Vis Sci. 2013; 54(12): 7198. doi: 10.1167/iovs.13-13044

60. Tang Q, Luo C, Lu B, Fu Q, Yin H, Qin Z, et al. Thermosensitive chitosan-based hydrogels releasing stromal cell derived factor-1 alpha recruit MSC for corneal epithelium regeneration. Acta Biomater. 2017; 1(61): 101-113. doi: 10.1016/j.actbio.2017.08.001

61. Eckert F, Schilbach K, Klumpp L, Bardoscia L, Sezgin EC, Schwab M, et al. Potential role of CXCR4 targeting in the context of radiotherapy and immunotherapy of cancer. Front Immunol. 2018; 9: 3018. doi: 10.3389/fimmu.2018.03018

62. Li X, He X, Yin Y, Wu R, Tian B, Chen F. Administration of signalling molecules dictates stem cell homing for in situ regeneration. J Cell Mol Med. 2017; 21(12): 3162-3177. doi: 10.1111/jcmm.13286

63. Miron-Mendoza M, Vazquez D, García-Rámila N, Hikaru R, Matthew Petroll I, Matthew Petroll W. Coupling of fibrin reorganization and fibronectin patterning by corneal fibroblasts in response to PDGF BB and TGFβ1. Bioengineering (Basel). 2020; 7(89): 1-18. doi: 10.3390/bioengineering7030089

64. Chaurasia SS, Kaur H, de Medeiros FW, Smith SD, Wilson SE. Dynamics of the expression of intermediate filaments vimentin and desmin during myofibroblast differentiation after corneal injury. Exp Eye Res. 2009; 89(2): 133-139. doi: 10.1016/j.exer.2009.02.022

65. Nagymihaly R, Vereb Z, Facsko A, Morten C, Petrovski G. Effect of isolation technique and location on the phenotype of human corneal stroma-derived cells. Stem Cells International. 2017; 2017: 1-12. doi: 10.1155/2017/9275248

66. Shyam SC, Rayne RL, Lakshminarayanan R, Mohan RR. Nanomedicine approaches for corneal diseases. J Funct Biomater. 2015: 6: 277-298. doi: 10.3390/jfb6020277

67. Das SK, Gupta I, Cho YK, Zhang X, Uehara H, Muddana SK, et al. Vimentin knockdown decreases corneal opacity. Invest Ophthalmol Vis Sci. 2014; 55(7): 4030-4040. doi: 10.1167/iovs.13-13494

68. Helfand BT, Mendez MG, Murthy SN, Shumaker DK, Grin B, Mahammad S, et al. Vimentin organization modulates the formation of lamellipodia. Mol Biol Cell. 2011; 22(8): 1274-1289. doi: 10.1091/mbc.E10-08-0699

69. Bargagna-Mohan P, Lei L, Thompson A, Shaw C, Kasahara K, Inagaki M, et al. Vimentin phosphorylation underlies myofibroblast sensitivity to withaferin A in vitro and during corneal fibrosis. PLoS One. 2015; 10(7): e0133399. doi: 10.1371/journal.pone.0133399

70. Berthaut A, Mirshahi P, Benabbou N, Elodie D, Aureliou A, Amu T, et al. Insulin growth factor promotes human corneal fibroblast network formation in vitro. Invest Ophthalmol. Vis Sci. 2011; 52: 7647-7653. doi: 10.1167/iovs.10-5625

71. Stuard WL, Titone R, Danielle M, Robertson DM. The IGF/Insulin-IGFBP axis in corneal development, wound healing, and disease. Front Endocrinol. 2020; 11: 24. doi: 10.3389/fendo.2020.00024

72. Sarenac T, Trapecar M, Gradisnik L, Rupnik MS, Pahor D. Single-cell analysis reveals IGF-1 potentiation of inhibition of the TGF-β/Smad pathway of fibrosis in human keratocytes in vitro. Sci Rep. 2016; 6: 34373. doi: 10.1038/srep34373

73. Okada N, Fukagawa K, Takano Y. The implications of the upregulation of ICAM-1/VCAM-1 expression of corneal fibroblasts on the pathogenesis of allergic keratopathy. Invest Ophthalmol Vis Sci. 2005; 46(12): 4512-4518. doi: 10.1167/iovs.04-1494

74. Saika S, Ikeda K, Yamanaka O, Flanders KC, Okada Y, Miyamoto T, et al. Loss of tumor necrosis factor potentiates transforming growth factor-mediated pathogenic tissue response during wound healing. Am J Pathol. 2006; 168(6): 1848-1860. doi: 10.2353/ajpath.2006.050980

75. Luo L, Kaminoh Y, Chen HY, Zhang MN, Zhang K, Ambati BK. Expression of erythropoietin and its receptor in normal and neovascularized murine corneas induced by alkali burns. IntJ Ophthalmol. 2009; 2(1): 30-33.

76. Lingtao Y, Friedrich E, Hans E. Neurotrophic factors in the human cornea. Invest Ophthalmol Vis Sci 2000; 41: 692-702.

77. Nishida T, Chikama T, Morishige N, Yanai R, Yamada N, Saito J. Persistent epithelial defects due to neurotrophic keratopathy treated with a substance p-derived peptide and insulin-like growth factor 1. Jpn J Ophthalmol. 2007; 51: 442-447. doi: 10.1007/s10384-007-0480-z

78. Yanai R, Nishida T, Chikama T, Morishige N, Yamada N, Sonoda KH. Potential new modes of treatment of neurotrophic keratopathy. Cornea. 2015; 34(11): S121-S127. doi: 10.1097/ICO.0000000000000587

79. Mastropasqua L, Massaro-Giordano G, Nubile M, Sacchetti M. Understanding the pathogenesis of neurotrophic keratitis: the role of corneal nerves. J Cell Physiol. 2017; 232: 717-724. doi: 10.1002/jcp.25623

80. Chen H, Zhang J, Dai Y, Xu J. Nerve growth factor inhibits TLR3-induced inflammatory cascades in human corneal epithelial cells. J Inflamm. 2019; 26(16): 27. doi: 10.1186/s12950-019-0232-0


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For citations:


Krasner K.Yu., Poveshchenko O.V., Surovtseva M.A., Trunov A.N., Kim I.I., Bondarenko N.A., Chernykh V.V. Modern anatomical and physiological bases for maintaining the transparency of the corneal stroma. Acta Biomedica Scientifica. 2023;8(4):186-198. https://doi.org/10.29413/ABS.2023-8.4.21

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