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Laminins and alpha11 integrin in the human eye: importance in development and disease
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The extracellular matrix (ECM) offers a protective shelter for cells and provides signaling paths important for cell to cell communication. ECM consists of basement membranes (BM) and interstitial matrix. BMs provide mechanical support for parenchymal cells, influence cell proliferation, survival, migration and differentiation. They are also important for tissue integrity. Laminins (LM) are the major non-collagenous component of BMs. Cell-ECM interactions, mediated by receptors, are indispensable during embryonic development, wound healing, remodeling and homeostasis of tissues. The integrins are the major cell-adhesion receptors. The expression of alpha11 integrin chain in the cornea is of great interest, as it is part of the alpha11beta1 integrin receptor for collagen type I, the predominant component of the corneal stroma.

The aims were to thoroughly characterize the ECM in the developing and adult human eye, with particular focus on the cornea, LM and alpha11 integrin chains, and to examine alpha11 integrin chain in an animal model of corneal wound healing and remodeling. Human fetal eyes, 9-20 weeks of gestation (wg), and adult human corneas with different diagnosis were treated for immunohistochemistry with specific antibodies against LM and alpha11 integrin chains. Normal and knockout (ko) mice were treated with laser surgery to create a deep wound in the corneal stroma. The wound healing process was followed at different time points. The cellular source of alpha11 integrin chain was studied in cell cultures.

In the fetal eyes, the BM of the corneal epithelium, the Descemet’s membrane (DM) and the Bruch’s membrane each had their specific combinations of LM chains and time line of development, whereas the lens capsule and the internal limiting membrane showed constant LM chain patterns.

The epithelial BMs of normal and diseased adult corneas contained similar LM chains. The normal morphology of the epithelial BM was altered in the different diseases, particularly when scarring was present. In the scarred keratoconus corneas there were excessive LM chains. The majority of keratoconus corneas also expressed extra LM chains in the DM.

At 10-17 wg alpha11 integrin chain was present in the human corneal stroma, especially in the anterior portion, but it was scarce at 20 wg, in normal adult corneas and in Fuchs’ endothelial dystrophy. In contrast, it was increased in the anterior portion of the stroma in keratoconus corneas with scarring. Alpha11 integrin ko mice had a defective healing with subsequent thinner corneas. Alpha11 integrin expression correlated to the presence of alpha-smooth muscle actin in vivo as well as in vitro.

The distinct spatial and temporal patterns of distribution for alpha11 integrin and each of the LM chains suggest that they play an important role in human ocular differentiation. The selectively affected LM composition and the novel expression of alpha11 integrin chain in scarred keratoconus corneas as well as the pathologic healing in ko mice, indicate that alpha11 integrin and LM chains also play an important role in the process of corneal healing, remodeling and scarring and might participate in the pathogenesis of corneal disease. This knowledge is of practical importance for future topical therapeutic agents capable of modulating the corneal wound healing processes.

Place, publisher, year, edition, pages
Umeå: Oftalmiatrik , 2008. , 53 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1229
Keyword [en]
basement membranes, extracellular matrix, laminin, integrin, cornea, development, keratoconus, wound healing, remodeling, immunohistochemistry
National Category
Ophthalmology
Identifiers
URN: urn:nbn:se:umu:diva-1950ISBN: 978-91-7264-696-4 (print)OAI: oai:DiVA.org:umu-1950DiVA: diva2:142546
Public defence
2009-01-23, Betula, Bottenvåningen, Norrlands UniversitetsSjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2008-12-19 Created: 2008-12-19 Last updated: 2016-10-27Bibliographically approved
List of papers
1. Distribution of laminins in the developing human eye
Open this publication in new window or tab >>Distribution of laminins in the developing human eye
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2006 (English)In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, Vol. 47, no 3, 777-785 p.Article in journal (Refereed) Published
Abstract [en]

PURPOSE: To examine the distribution of laminin (Ln) chains in basement membranes (BMs) of the human cornea, lens, and retina in fetal development. METHODS: Ten fetal eyes (9-20 weeks of gestation [wg]) were serially sectioned and treated with specific antibodies against the Ln-alpha1, -alpha2, -alpha3, -alpha4, -alpha5, -beta1, -beta2, -beta3, and -gamma1 chains. RESULTS: The BM of the corneal epithelium was reactive for Ln-alpha3, -alpha5, -beta1, and beta3 chains through all ages, whereas the Ln-alpha1 chain was present at 9 to 12 wg and the Ln-alpha4 chain from 10 wg. The Descemet's membrane (DM) was labeled with the Ln-alpha1 and -alpha4 chains at 10 to 17 wg, the Ln-alpha5 chain from 10 wg, the Ln-beta1 chain at 11 to 17 wg, and the Ln-beta3 chain from 17 wg. The Ln-alpha1, alpha5, -beta1, and -beta2 chains were present in the lens capsule and the internal limiting membrane (ILM) through all ages. The Bruch's membrane (BrM) was immunoreactive for the Ln-alpha3, alpha4, -alpha5, -beta1, and -beta2 chains through all ages, whereas the Ln-alpha1 chain was absent from 20 wg onward. The Ln-alpha2 chain was not detected in the eye, but it was present in the extraocular muscles. CONCLUSIONS: BMs play an important role during morphogenesis, in that they influence cell proliferation, migration, and tissue differentiation. Lns are the major noncollagenous component of BMs. The presence of four different alpha chains, three beta chains, and one gamma chain of Ln in the eye reveals a high degree of complexity from the early stages of development and suggests an important role for the different Ln chains in human ocular differentiation.

Place, publisher, year, edition, pages
Association for Research in Vision and Ophthalmology, 2006
Keyword
Basement Membrane/embryology/metabolism, Cornea/*embryology/metabolism, Eye Proteins/*metabolism, Fetal Development, Fluorescent Antibody Technique; Indirect, Gestational Age, Humans, Laminin/*metabolism, Lens; Crystalline/*embryology/metabolism, Microscopy; Fluorescence, Morphogenesis, Protein Isoforms/metabolism, Retina/*embryology
National Category
Ophthalmology
Identifiers
urn:nbn:se:umu:diva-12671 (URN)10.1167/iovs.05-0367 (DOI)16505007 (PubMedID)
Available from: 2007-12-27 Created: 2007-12-27 Last updated: 2013-12-12Bibliographically approved
2. Laminins in normal, keratoconus, bullous keratopathy and scarred human corneas
Open this publication in new window or tab >>Laminins in normal, keratoconus, bullous keratopathy and scarred human corneas
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2007 (English)In: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 127, no 6, 657-667 p.Article in journal (Refereed) Published
Abstract [en]

The laminin composition (LMalpha1-alpha5, beta1-beta3, gamma1 and gamma2 chains) of normal corneas and corneal buttons from keratoconus, bullous keratopathy (BKP), Fuchs' dystrophy + BKP, Fuchs' dystrophy without BKP and scar after deep lamellar keratoplasty (DLKP) was investigated with immunohistochemistry. The epithelial basement membranes (BMs) of both normal and diseased corneas contained LMalpha3, alpha5, beta1, beta3, gamma1 and gamma2 chains. The epithelial BM morphology was altered in the different diseases. Scarring was associated with irregular BM and ectopic stromal localization of different laminin chains. The Descemet's membrane (DM) contained LMalpha5, beta1 and gamma1 chains in all cases and additionally LMbeta3 and gamma2 chains in the majority of keratoconus corneas. The interface in the DLKP cornea had patches of LMalpha3, alpha4, alpha5, beta1 and beta2 chains, and an extra BM-like structure under the Bowman's membrane. These results suggest that laminin chains participate in the process of corneal scarring and in the pathogenesis of some corneal diseases. The novel finding of LMalpha3, beta3 and gamma2 in the DM of keratoconus buttons indicates that this membrane is also involved in the disease and that some cases of keratoconus may have a congenital origin, without normal downregulation of the LMbeta3 chain.

Keyword
Laminin - Cornea - Human - Keratoconus - Basement membrane
Identifiers
urn:nbn:se:umu:diva-3717 (URN)10.1007/s00418-007-0288-4 (DOI)17492460 (PubMedID)744 (Local ID)744 (Archive number)744 (OAI)
Available from: 2008-12-19 Created: 2008-12-19 Last updated: 2011-08-26Bibliographically approved
3. Alpha11 integrin in the human cornea: importance in development and disease.
Open this publication in new window or tab >>Alpha11 integrin in the human cornea: importance in development and disease.
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2009 (English)In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, Vol. 50, no 11, 5044-5053 p.Article in journal (Refereed) Published
Abstract [en]

PURPOSE: To examine the distribution of the alpha11 integrin chain in the human cornea during fetal development and in normal and diseased adult human corneas.

METHODS: Six fetal corneas, 10 to 20 weeks of gestation (wg), and 18 adult corneas including 3 normal, 7 with keratoconus, 5 with pseudophakic bullous keratopathy (PBK), 2 with Fuchs' corneal dystrophy, and 1 with a scar after deep lamellar keratoplasty (DLKP) were processed for immunohistochemistry with specific antibodies against the alpha11 integrin chain; collagen I, IV, and V; and alpha-smooth muscle actin (alpha-SMA). The cellular source of alpha11 integrin chain was further investigated in cell cultures.

RESULTS: At 10 to 17 wg, the alpha11 integrin chain was predominantly present in the anterior corneal stroma. At 20 wg, in normal adult corneas and in Fuchs' dystrophy corneas there was weak staining in the stroma. The PBK corneas showed variable and weak staining, generally accentuated in the posterior stroma near Descemet's membrane. In contrast, the anterior portion of the stroma in the keratoconus corneas was strongly stained in an irregular streaky pattern. Human corneal fibroblasts/myofibroblasts produced alpha11 integrin chain in culture. Cultures treated with TGF-beta showed higher content of both alpha-SMA and the alpha11 integrin chain.

CONCLUSIONS: The presence of the alpha11 integrin chain during early corneal development and the enhanced expression in scarred keratoconus corneas indicates that this integrin chain is likely to play an important role in collagen deposition during corneal development and in keratoconus with a scarring component and compromised basement membrane integrity.

Place, publisher, year, edition, pages
Association for Research in Vision and Ophthalmology (ARVO), 2009
Keyword
Alpha11 integrin, cornea
National Category
Ophthalmology
Research subject
Ophtalmology
Identifiers
urn:nbn:se:umu:diva-32003 (URN)10.1167/iovs.08-3261 (DOI)19516006 (PubMedID)744 (Local ID)744 (Archive number)744 (OAI)
Available from: 2010-03-03 Created: 2010-02-26 Last updated: 2013-12-12Bibliographically approved
4. Alpha11 integrin in an animal model of corneal wound healing/remodeling
Open this publication in new window or tab >>Alpha11 integrin in an animal model of corneal wound healing/remodeling
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Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-3719 (URN)
Available from: 2008-12-19 Created: 2008-12-19 Last updated: 2010-01-13Bibliographically approved

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