Identification of Barriers to Retinal Engraftment of Transplanted Stem Cells

Intraocular stem cell transplantation may be therapeutic for retinal neurodegenerative diseases such as glaucoma via neuronal replacement and/or neuroprotection. However, efficacy is hindered by extremely poor retinal graft integration. The purpose was to identify the major barrier to retinal integr...

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Bibliographic Details
Published in:Investigative ophthalmology & visual science 2010-02, Vol.51 (2), p.960-970
Main Authors: Johnson, Thomas V, Bull, Natalie D, Martin, Keith R
Format: Article
Language:English
Subjects:
2-Aminoadipic Acid - pharmacology
Animals
Basement Membrane - physiology
Cell Movement - physiology
Cell Survival - physiology
Coculture Techniques
Excitatory Amino Acid Antagonists - pharmacology
Extracellular Matrix - physiology
Fluorescent Antibody Technique, Indirect
Intraocular Pressure
Male
Mesenchymal Stem Cell Transplantation
Mesenchymal Stromal Cells - cytology
Mesenchymal Stromal Cells - physiology
Neuroglia - cytology
Ocular Hypertension - surgery
Rats
Rats, Sprague-Dawley
Rats, Transgenic
Retinal Neurons - cytology
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Summary:Intraocular stem cell transplantation may be therapeutic for retinal neurodegenerative diseases such as glaucoma via neuronal replacement and/or neuroprotection. However, efficacy is hindered by extremely poor retinal graft integration. The purpose was to identify the major barrier to retinal integration of intravitreally transplanted stem cells, which was hypothesized to include the cellular and/or extracellular matrix (ECM) components of the inner limiting membrane (ILM). Mesenchymal stem cells (MSCs) were cocultured on the vitreal surface of retinal explants. Retinal MSC migration was compared between control explants and explants in which portions of the ILM were removed by mechanical peeling; the inner basal lamina was digested with collagenase; and glial cell reactivity was selectively modulated with alpha-aminoadipic acid (AAA). In vivo, the MSCs were transplanted after intravitreal AAA or saline injection into glaucomatous rat eyes. Retinal MSC migration correlated positively with the amount of peeled ILM, whereas enzymatic digestion of the basal lamina was robust but did not enhance MSC entry. In contrast, AAA treatment suppressed glial cell reactivity and facilitated a >50-fold increase in MSC migration into retinal explants. In vivo analysis showed that AAA treatment led to a more than fourfold increase in retinal engraftment. The results demonstrated that the ECM of the inner basal lamina is neither necessary nor sufficient to prevent migration of transplanted cells into the neural retina. In contrast, glial reactivity was associated with poor graft migration. Targeted disruption of glial reactivity dramatically improved the structural integration of intravitreally transplanted cells.
ISSN:0146-0404
1552-5783
1552-5783
DOI:10.1167/iovs.09-3884