The Internal Limiting Membrane: Roles in Retinal Development and Implications for Emerging Ocular Therapies

Overview

Journal Exp Eye Res

Specialty Ophthalmology

Date 2021 Mar 23

PMID 33753089

Citations 15

Authors

Kevin Y Zhang

Thomas V Johnson

Affiliations

Soon will be listed here.

Abstract

Basement membranes help to establish, maintain, and separate their associated tissues. They also provide growth and signaling substrates for nearby resident cells. The internal limiting membrane (ILM) is the basement membrane at the ocular vitreoretinal interface. While the ILM is essential for normal retinal development, it is dispensable in adulthood. Moreover, the ILM may constitute a significant barrier to emerging ocular therapeutics, such as viral gene therapy or stem cell transplantation. Here we take a neurodevelopmental perspective in examining how retinal neurons, glia, and vasculature interact with individual extracellular matrix constituents at the ILM. In addition, we review evidence that the ILM may impede novel ocular therapies and discuss approaches for achieving retinal parenchymal targeting of gene vectors and cell transplants delivered into the vitreous cavity by manipulating interactions with the ILM.

Citing Articles

Cell-penetrating peptide-grafted AAV2 capsids for improved retinal delivery via intravitreal injection.

Wang J, Cui M, Liu H, Guo P, McGowan J, Cheng S Mol Ther Methods Clin Dev. 2025; 33(1):101426.

PMID: 40027263 PMC: 11872077. DOI: 10.1016/j.omtm.2025.101426.

Recent advances in photothermal nanomaterials for ophthalmic applications.

Zhuang J, Jia L, Li C, Yang R, Wang J, Wang W Beilstein J Nanotechnol. 2025; 16:195-215.

PMID: 39995756 PMC: 11849557. DOI: 10.3762/bjnano.16.16.

Fibrotic Changes in Rhegmatogenous Retinal Detachment.

Harju N, Kauppinen A, Loukovaara S Int J Mol Sci. 2025; 26(3).

PMID: 39940795 PMC: 11817287. DOI: 10.3390/ijms26031025.

Challenges in AAV-Based Retinal Gene Therapies and the Role of Magnetic Nanoparticle Platforms.

Siontas O, Ahn S J Clin Med. 2024; 13(23).

PMID: 39685843 PMC: 11642484. DOI: 10.3390/jcm13237385.

Intravitreal AAV2 gene delivery to feline retinal ganglion cells.

Oikawa K, Eaton J, Kiland J, Torne O, Mathu V, Nickells R Vision Res. 2024; 226:108519.

PMID: 39549467 PMC: 11658774. DOI: 10.1016/j.visres.2024.108519.

References

Edwards M, McLeod D, Grebe R, Heng C, Lefebvre O, Lutty G . Lama1 mutations lead to vitreoretinal blood vessel formation, persistence of fetal vasculature, and epiretinal membrane formation in mice. BMC Dev Biol. 2011; 11:60. PMC: 3215647. DOI: 10.1186/1471-213X-11-60. View

Balasubramani M, Schreiber E, Candiello J, Balasubramani G, Kurtz J, Halfter W . Molecular interactions in the retinal basement membrane system: a proteomic approach. Matrix Biol. 2010; 29(6):471-83. DOI: 10.1016/j.matbio.2010.04.002. View

Halfter W, Dong S, Dong A, Eller A, Nischt R . Origin and turnover of ECM proteins from the inner limiting membrane and vitreous body. Eye (Lond). 2008; 22(10):1207-13. DOI: 10.1038/eye.2008.19. View

Bull N, Limb G, Martin K . Human Müller stem cell (MIO-M1) transplantation in a rat model of glaucoma: survival, differentiation, and integration. Invest Ophthalmol Vis Sci. 2008; 49(8):3449-56. DOI: 10.1167/iovs.08-1770. View

Mets M . Childhood blindness and visual loss: an assessment at two institutions including a "new" cause. Trans Am Ophthalmol Soc. 2000; 97:653-96. PMC: 1298279. View

Halfter W, Candiello J, Hu H, Zhang P, Schreiber E, Balasubramani M . Protein composition and biomechanical properties of in vivo-derived basement membranes. Cell Adh Migr. 2012; 7(1):64-71. PMC: 3544788. DOI: 10.4161/cam.22479. View

Das A, Mallya K, Zhao X, Ahmad F, Bhattacharya S, Thoreson W . Neural stem cell properties of Müller glia in the mammalian retina: regulation by Notch and Wnt signaling. Dev Biol. 2006; 299(1):283-302. DOI: 10.1016/j.ydbio.2006.07.029. View

Clark S, Keenan T, Fielder H, Collinson L, Holley R, Merry C . Mapping the differential distribution of glycosaminoglycans in the adult human retina, choroid, and sclera. Invest Ophthalmol Vis Sci. 2011; 52(9):6511-21. PMC: 3175996. DOI: 10.1167/iovs.11-7909. View

Cehajic-Kapetanovic J, Le Goff M, Allen A, Lucas R, Bishop P . Glycosidic enzymes enhance retinal transduction following intravitreal delivery of AAV2. Mol Vis. 2011; 17:1771-83. PMC: 3133842. View

10.

Colognato H, Yurchenco P . Form and function: the laminin family of heterotrimers. Dev Dyn. 2000; 218(2):213-34. DOI: 10.1002/(SICI)1097-0177(200006)218:2<213::AID-DVDY1>3.0.CO;2-R. View

11.

Henry M, Campbell K . A role for dystroglycan in basement membrane assembly. Cell. 1998; 95(6):859-70. DOI: 10.1016/s0092-8674(00)81708-0. View

12.

Zhou M, Wang H, Ren H, Jiang R, Zhang C, Wu X . is required for normal astrocyte migration and retinal vasculature development. Cell Biosci. 2017; 7:18. PMC: 5392960. DOI: 10.1186/s13578-017-0143-9. View

13.

Takahashi K, Igarashi T, Miyake K, Kobayashi M, Yaguchi C, Iijima O . Improved Intravitreal AAV-Mediated Inner Retinal Gene Transduction after Surgical Internal Limiting Membrane Peeling in Cynomolgus Monkeys. Mol Ther. 2017; 25(1):296-302. PMC: 5363307. DOI: 10.1016/j.ymthe.2016.10.008. View

14.

Park T, Wu Z, Kjellstrom S, Zeng Y, Bush R, Sieving P . Intravitreal delivery of AAV8 retinoschisin results in cell type-specific gene expression and retinal rescue in the Rs1-KO mouse. Gene Ther. 2009; 16(7):916-26. PMC: 2774250. DOI: 10.1038/gt.2009.61. View

15.

Fassler R, Meyer M . Consequences of lack of beta 1 integrin gene expression in mice. Genes Dev. 1995; 9(15):1896-908. DOI: 10.1101/gad.9.15.1896. View

16.

Welsbie D, Ziogas N, Xu L, Kim B, Ge Y, Patel A . Targeted disruption of dual leucine zipper kinase and leucine zipper kinase promotes neuronal survival in a model of diffuse traumatic brain injury. Mol Neurodegener. 2019; 14(1):44. PMC: 6882250. DOI: 10.1186/s13024-019-0345-1. View

17.

Johnson T, Martin K . Development and characterization of an adult retinal explant organotypic tissue culture system as an in vitro intraocular stem cell transplantation model. Invest Ophthalmol Vis Sci. 2008; 49(8):3503-12. DOI: 10.1167/iovs.07-1601. View

18.

Riccomagno M, Sun L, M Brady C, Alexandropoulos K, Seo S, Kurokawa M . Cas adaptor proteins organize the retinal ganglion cell layer downstream of integrin signaling. Neuron. 2014; 81(4):779-86. PMC: 3988023. DOI: 10.1016/j.neuron.2014.01.036. View

19.

Lei W, Xing S, Deng C, Ju X, Jiang X, Luo Z . Laminin/β1 integrin signal triggers axon formation by promoting microtubule assembly and stabilization. Cell Res. 2012; 22(6):954-72. PMC: 3367525. DOI: 10.1038/cr.2012.40. View

20.

Stenzel D, Franco C, Estrach S, Mettouchi A, Sauvaget D, Rosewell I . Endothelial basement membrane limits tip cell formation by inducing Dll4/Notch signalling in vivo. EMBO Rep. 2011; 12(11):1135-43. PMC: 3207109. DOI: 10.1038/embor.2011.194. View