Effects of bone marrow stromal cell injection in an experimental glaucoma model

doi:10.1016/j.bbrc.2006.03.231

Biochemical and Biophysical Research Communications

Volume 344, Issue 4, 16 June 2006, Pages 1071-1079

https://doi.org/10.1016/j.bbrc.2006.03.231 Get rights and content

Abstract

We investigated if bone marrow stromal cells (BMSCs) transplanted into the vitreous body of a glaucoma model eye could be integrated in the host retina and also whether they could rescue the retinal ganglion cells (RGCs) from death induced by the elevated intraocular pressure. Glaucoma was induced in the right eye of adult Wistar rats by ligating the episcleral veins. The GFP-expressing BMSCs (GFP-BMSCs) were injected into the vitreous body of both the control and the glaucomatous eyes. After transplantation, GFP-BMSCs were mostly present along with the inner limiting membrane and only a few cells were integrated into the ganglion cell layer. At 2 or 4 weeks after transplantation, GFP-BMSCs were observed to express various trophic factors. The BMSCs injected glaucoma model eyes showed less reduction in the number of RGCs compared to the glaucomatous eyes with PBS injection. This study suggests that BMSC transplantation may be worthy as a neuroprotective tool to treat glaucoma.

Section snippets

Materials and methods

Glaucoma model. The use of animals in this study was in accordance with the Guidelines for Animal Experiments of Kyoto University. All animal experiments in this study were conducted with the approval of the Animal Research Committee, Graduate School of Medicine, Kyoto University. Adult female Wistar rats (9 weeks of age) were obtained from Shimizu Laboratory Supplies (Kyoto, Japan). Rats were maintained on a 14 h light/10 h dark cycle and had access to food and water ad libitum.

Chronic IOP

Elevated IOP

The mean and the peak IOP of glaucomatous eyes were significantly elevated compared to those of the sham-operated control eyes (mean IOP; 26.3 ± 2.2 and 19.5 ± 1.7 mmHg, respectively, peak IOP; 28.2 ± 2.0 and 20.9 ± 1.1 mmHg, respectively) (P < 0.01, Student’s t-test). There was no significant difference in the mean and the peak IOP between BMSCs and PBS injected eyes (P > 0.05; Table 1).

Integration of transplanted BMSCs into the glaucomatous retina

Confocal microscopy revealed the existence of GFP-positive BMSCs, in the glaucomatous retina (glaucoma 2 weeks model)one

Discussion

Glaucoma is one of the major causes of blindness in the world, which is characterized by morphological change of the optic disc and the specific loss of RGCs [2]. The goal of glaucoma treatment is to protect the RGCs; however, there is still no direct way to prevent the death of RGCs. In this study, we attempted the transplantation of BMSCs into the glaucoma model rat eye with the aim of compensating for the loss of the RGCs.

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Citation Excerpt :
Because of this a local administration to target RGC cells is not out of the question and has also been investigated to improve targeted cell delivery, eliminating some of the unwanted side effects from topical administration. Mesenchymal stromal cells (MSC) have been administered using this route and demonstrated neuroprotective capabilities in experimental glaucoma (Johnson et al., 2010; Emre et al., 2015; Yu et al., 2006). MSC cells when compared to other types of cell lines have certain advantages.
Although once daily anti-glaucoma drug therapy is a current clinical reality, most therapies require multiple dosing and there is an unmet need to develop convenient, safe, and effective sustained release drug delivery systems for long-term treatment to improve patient adherence and outcomes. One of the first sustained release drug delivery systems was approved for the reduction of intraocular pressure in glaucoma patients. It is a polymeric reservoir-type insert delivery system, Ocusert™, placed under the eyelid and on the ocular surface for zero-order drug release over one week. The insert, marketed in two strengths, released pilocarpine on the eye surface. While many clinicians appreciated this drug product, it was eventually discontinued. No similar sustained release non-invasive drug delivery system has made it to the market to date for treating glaucoma. Drug delivery systems under development include punctal plugs, ring-type systems, contact lenses, implants, microspheres, nanospheres, gels, and other depot systems placed in the extraocular, periocular, or intraocular regions including intracameral, supraciliary, and intravitreal spaces. This article discusses the advantages and disadvantages of the various routes of administration and delivery systems for sustained glaucoma therapy. It also provides the reader with some examples and discussion of drug delivery systems that could potentially be applied for glaucoma treatment. Interestingly, one intracamerally injected implant, Durysta™, was approved recently for sustained intraocular pressure reduction. However, long-term acceptance of such devices has yet to be established. The ultimate success of the delivery system will depend on efficacy relative to eye drop dosing, safety, reimbursement options, and patient acceptance. Cautious development efforts are warranted considering prior failed approaches for sustained glaucoma drug delivery. Neuroprotective approaches for glaucoma therapy including cell, gene, protein, and drug-combination therapies, mostly administered intravitreally, are also rapidly progressing towards assessment in humans.
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Effects of bone marrow stromal cell injection in an experimental glaucoma model

Abstract

Section snippets

Materials and methods

Elevated IOP

Integration of transplanted BMSCs into the glaucomatous retina

Discussion

Prog. Retin. Eye Res.

Neurosci. Lett.

Neuroscience

Exp. Neurol.

Exp. Eye Res.

Exp. Neurol.

Blood

Am. J. Pathol.

Exp. Eye Res.

Mol. Cell. Neurosci.

Ganglion cell death in glaucoma: pathology recapitulates ontogeny

Aust. N. Z. J. Ophthalmol.

Glaucoma and its treatment: a review

Am. J. Health Syst. Pharm.

Gene therapy with brain-derived neurotrophic factor as a protection: retinal ganglion cells in a rat glaucoma model

Invest. Ophthalmol. Vis. Sci.

CNTF promotes survival of retinal ganglion cells after induction of ocular hypertension in rats: the possible involvement of STAT3 pathway

Eur. J. Neurosci.

Inhibition of nitric-oxide synthase 2 by aminoguanidine provides neuroprotection of retinal ganglion cells in a rat model of chronic glaucoma

Proc. Natl. Acad. Sci. USA

Retinal ganglion cell protection with geranylgeranylacetone, a heat shock protein inducer, in a rat glaucoma model

Invest. Ophthalmol. Vis. Sci.

Clinical potential of lomerizine, a Ca2+ channel blocker as an anti-glaucoma drug: effects on ocular circulation and retinal neuronal damage

Cardiovasc. Drug Rev.

Incorporation and differentiation of hippocampus-derived neural stem cells transplanted in injured adult rat retina

Invest. Ophthalmol. Vis. Sci.

Engraftment of adult neural progenitor cells transplanted to rat retina injured by transient ischemia

Invest. Ophthalmol. Vis. Sci.

Marrow stromal cells, mitosis, and neuronal differentiation: stem cell and precursor functions

Stem Cells

Incorporation of murine brain progenitor cells into the developing mammalian retina

Invest. Ophthalmol. Vis. Sci.