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1. Mutated olfactomedin 1 in the interphotoreceptor matrix of the mouse retina causes functional deficits and vulnerability to light damage.

Author

Koch MA, Rosenhammer B, Paper W, Volz C, Braunger BM, Hausberger J, Jägle H, and Tamm ER

Subjects
Animals, Extracellular Matrix pathology, Mice, Mutation, Photoreceptor Cells metabolism, Retina metabolism, Extracellular Matrix metabolism, Extracellular Matrix radiation effects, Extracellular Matrix Proteins genetics, Extracellular Matrix Proteins metabolism, Glycoproteins genetics, Glycoproteins metabolism, Light adverse effects, Retina pathology, Retina radiation effects
Abstract

Olfactomedin 1 (OLFM1) is a secreted glycoprotein and member of the olfactomedin protein family, which is preferentially expressed in various areas throughout the central nervous system. To learn about the functional properties of OLFM1 in the eye, we investigated its localization in the mouse and pig eye. In addition, we analyzed the ocular phenotype of Olfm1 mutant mice in which 52 amino acids were deleted in the central part (M2 region) of OLFM1. OLFM1 was detected in cornea, sclera, retina, and optic nerve of both wild-type and Olfm1 mutant littermates. By immunohistochemistry and double labeling with the lectin peanut agglutinin, OLFM1 was found in the interphotoreceptor matrix (IPM) of mouse and pig retina where it was directly localized to the inner segments of photoreceptors. Western blotting confirmed the presence of the OLFM1 isoforms pancortin 1 (BMY) and pancortin 2 (BMZ) in the IPM. The retinal phenotype of Olfm1 mutant mice did not obviously differ from that of wild-type littermates. In addition, outer nuclear layer (ONL) and total retinal thickness were not different, and the same was true for the area of the optic nerve in cross sections. Functional changes were observed though by electroretinography, which showed significantly lower a- and b-wave amplitudes in Olfm1 mutant mice when compared to age-matched wild-type mice. When light damage experiments were performed as an experimental paradigm of photoreceptor apoptosis, significantly more TUNEL-positive cells were observed in Olfm1 mutant mice 30 h after light exposure. One week after light exposure, the ONL was significantly thinner in Olfm1 mutant mice than in wild-type littermates indicating increased photoreceptor loss. No differences were observed when rhodopsin turnover or ERK1/2 signaling was investigated. We conclude that OLFM1 is a newly identified IPM molecule that serves an important role for photoreceptor homeostasis, which is significantly compromised in the eyes of Olfm1 mutant mice.

Published
2017
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2. Tuning gelatin-based hydrogel towards bioadhesive ocular tissue engineering applications

Author

Miguel Gonzalez-Andrades, James Chodosh, Sina Sharifi, Tom Eirik Mollnes, Rakibul Islam, Felisa Reyes-Ortega, Per H. Nilsson, David Alba-Molina, Claes H. Dohlman, Mohammad Mirazul Islam, Darrell J. Koza, Hannah Sharifi, [Sharifi,S, Islam,MM, Sharifi,H, Dohlman,CH, Chodosh,J, Gonzalez-Andrades,M] Massachusetts Eye and Ear and Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA. [Islam, Nilsson,PH, Mollnes,TE, ] Department of Immunology, Oslo University Hospital, Rikshospitalet, University of Oslo, Oslo, Norway. [Koza,D] Department of Physical Sciences, Eastern Connecticut State University, Willimantic, CT, USA. [Nilsson,PH] Linnaeus Center for Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden. [Mollnes,TE] Research Laboratory, Nordland Hospital, Bodø, Norway. [Mollnes,TE] Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway. [Reyes-Ortega,F, Alba-Molina,D, Gonzalez-Andrades,M] Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Department of Ophthalmology, Reina Sofia University Hospital and University of Cordoba, Cordoba, Spain. [Mollnes,TE] Faculty of Health Sciences, K.G. Jebsen TREC, University of Tromsø, Norway., and This paper was supported by the Boston-KPro research fund and NIH/NEI P30EY003790 (Core-PA). R.S. was supported in part by the K99 grant from NIH award no. K99 EY030553. This work was performed in part at the Center for Nanoscale Systems (CNS), Harvard University, a member of the National Nanotechnology Coordinated Infrastructure Network (NNCI), which is supported by the National Science Foundation under NSF award no. 1541959. F.R-O and D.A-M were supported by the research project ICI19/00006, funded by Instituto de Salud Carlos III and co-funded by European Union (ERDF/ESF, 'A way to make Europe'/'Investing in your future'). F.R-O additionally acknowledges funding from Plan Andaluz de Investigación, Desarrollo e Innovación (PAIDI2020) Fellowship supported by Consejería de Economía, Conocimiento, Empresas y Universidad, Junta de Andalucía co-funded by Fondo Social Europeo de Andalucía 2014-2020.

Subjects
Biocompatible, Glycidyl methacrylate, Light, Anatomy::Digestive System::Liver [Medical Subject Headings], Anatomy::Urogenital System::Urinary Tract::Kidney [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Equipment and Supplies::Bandages [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Equipment and Supplies::Surgical Equipment::Surgical Fixation Devices::Tissue Adhesives [Medical Subject Headings], 02 engineering and technology, Gelatin, Metacrilatos, Anatomy::Cardiovascular System::Blood Vessels::Arteries::Aorta [Medical Subject Headings], Cornea, Extracellular matrix, chemistry.chemical_compound, Chemicals and Drugs::Organic Chemicals::Ethers::Ethers, Cyclic::Epoxy Compounds [Medical Subject Headings], Materiales biocompatibles, Biology (General), Materials of engineering and construction. Mechanics of materials, Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biotechnology::Biomimetics [Medical Subject Headings], Phenomena and Processes::Physical Phenomena::Optical Phenomena::Light [Medical Subject Headings], Adhesion, 021001 nanoscience & nanotechnology, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Bioprinting [Medical Subject Headings], VDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Scleroproteins::Gelatin [Medical Subject Headings], Anatomy::Sense Organs::Eye::Anterior Eye Segment::Cornea [Medical Subject Headings], Gelatina, Technology and Food and Beverages::Technology, Industry, and Agriculture::Manufactured Materials::Adhesives [Medical Subject Headings], TA401-492, Methacrylates, Biomimetic, 0210 nano-technology, Biotechnology, food.ingredient, Materials science, Biocompatibility, QH301-705.5, Bioadhesive, 0206 medical engineering, Biomedical Engineering, Article, Tissue adhesives, Hidrogeles, Biomaterials, Adhesivos tisulares, Natural-based hydrogel, food, Biomimética, Chemicals and Drugs::Complex Mixtures::Colloids::Gels::Hydrogels [Medical Subject Headings], Anatomy::Tissues::Lymphoid Tissue::Spleen [Medical Subject Headings], VDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710, Luz, 020601 biomedical engineering, Córnea, Transplantation, chemistry, Chemicals and Drugs::Organic Chemicals::Carboxylic Acids::Acids, Acyclic::Acrylates::Methacrylates [Medical Subject Headings], Adhesive, Biomedical engineering
Abstract

Gelatin based adhesives have been used in the last decades in different biomedical applications due to the excellent biocompatibility, easy processability, transparency, non-toxicity, and reasonable mechanical properties to mimic the extracellular matrix (ECM). Gelatin adhesives can be easily tuned to gain different viscoelastic and mechanical properties that facilitate its ocular application. We herein grafted glycidyl methacrylate on the gelatin backbone with a simple chemical modification of the precursor, utilizing epoxide ring-opening reactions and visible light-crosslinking. This chemical modification allows the obtaining of an elastic protein-based hydrogel (GELGYM) with excellent biomimetic properties, approaching those of the native tissue. GELGYM can be modulated to be stretched up to 4 times its initial length and withstand high tensile stresses up to 1.95 MPa with compressive strains as high as 80% compared to Gelatin-methacryloyl (GeIMA), the most studied derivative of gelatin used as a bioadhesive. GELGYM is also highly biocompatible and supports cellular adhesion, proliferation, and migration in both 2 and 3-dimensional cell-cultures. These characteristics along with its super adhesion to biological tissues such as cornea, aorta, heart, muscle, kidney, liver, and spleen suggest widespread applications of this hydrogel in many biomedical areas such as transplantation, tissue adhesive, wound dressing, bioprinting, and drug and cell delivery., Graphical abstract Image 1, Highlights • Gelatin based adhesives have been used in the last decades in different biomedical applications. • Gelatin adhesives can be easily tuned to gain different viscoelastic and mechanical properties that facilitate its ocular application. • We herein grafted glycidyl methacrylate on the gelatin backbone with a simple chemical modification of the precursor. • Epoxide ring-opening reactions and visible light-crosslinking allows the obtaining of an elastic gelatin-based hydrogel (GELGYM). • GELGYM shows excellent biomimetic properties, approaching those of the native tissue.

Published
2021
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