Subretinal Transplantation of Rat MSCs and Erythropoietin Gene Modified Rat MSCs for Protecting and Rescuing Degenerative Retina in Rats

Abstract

For degenerative retinal diseases, like the acquired form exemplified by age-related macular degeneration (AMD), there is currently no cure. This study was to explore a stem cell therapy and a stem cell based gene therapy for sodium iodate (SI)-induced retinal degeneration in rats. Three cell types, i.e., rat mesenchymal stem cells (rMSCs) alone, erythropoietin (EPO) gene modified rMSCs (EPO-rMSCs) or doxycycline (DOX) inducible EPO expression rMSCs (Tet-on EPO-rMSCs), were transplanted into the subretinal spaces of SI-treated rats. The rMSCs were prepared for transplantation after 3 to 5 passages or modified with EPO gene. During the 8 weeks after the transplantation, the rats treated with rMSCs alone or with two types of EPO-rMSCs were all monitored with fundus examination, fundus fluorescein angiography (FFA) and electroretinogram. The transplantation efficiency of donor cells was examined for their survival, integration and differentiation. Following the transplantation, labeled donor cells were observed in subretinal space and adopted RPE morphology. EPO concentration in vitreous and retina of SI-treated rats which were transplanted with EPO-rMSCs or Tet-on EPO-rMSCs was markedly increased, in parallel with the improvement of retinal morphology and function. These findings suggest that rMSCs transplantation could be a new therapy for degenerative retinal diseases since it can protect and rescue RPE and retinal neurons, while EPO gene modification to rMSCs could be an even better option.

Revisiting the role of erythropoietin for treatment of ocular disorders

“…Local treatments that include eye drops, subconjunctival, intracameral, intravitreal, subretinal, subtenon, peribulbar, and retrobulbar injections are usually preferred to avoid systemic side effects. Local administration routes that have been studied for EPO include intravitreal, 35 subretinal, 76 subconjunctival, 77 eye drops administration (patent: EP2590666A1), and retrobulbar injections. 78 Among the local administration, subconjunctival approach has been tested pre-clinically for ocular penetration, for retinal neuroprotection, and for potential systemic side effect of hematocrit elevation in rats.…”

“…They found that the improvement in the retinal morphology and function was greater in the rats transplanted with EPO gene-modified MSCs. 76 Thus, incorporating this therapeutic gene with a better controlled regulation and safe system will potentially magnify the beneficial effect of stem cell therapy 136,137 for ocular disorders in the future.…”

Subretinal Injection: A Review on the Novel Route of Therapeutic Delivery for Vitreoretinal Diseases

“…In rats, photoreceptor degeneration can be prevented by subretinal transplantation of human fetal lung fibroblasts expressing the ciliary neurotrophic factor gene [66] , and laser-induced choroidal neovascularization can be inhibited by subretinal transplantation of RPE overexpressing fibulin-5 [67] . Of all of the cell types, progenitor cells and stem cells, such as human neural progenitor cells [68] , human retinal progenitor cells [69] , progenitor cells from the porcine neural retina [70] , forebrain progenitor cells [71] , brain-derived precursor cells [72] , human embryonic stem cell-derived retinal progenitors [73] , human RPE stem cells [74] , human bone marrow mesenchymal stem cells [75] , and rat mesenchymal stem cells [76] , are the most popular when given subretinally for cell replacement therapy for retinal degeneration. All these cells are considered to have the capability to survive and migrate into retinal layers and restore retina function or induce cell regeneration in different types of retinal cells when delivered via the subretinal route.…”

The Protective Effect of Erythropoietin on the Retina

“…However, there is currently no cure for degenerative retinal diseases. Recent studies [29] have presented a feasible treatment in an animal model of retinal degeneration induced by sodium iodate, by subretinal transplantation of Epo gene-modified mesenchymal stem cells, which compared to normal rat mesenchymal stem cells can significantly enhance the survival, distribution and differentiation of retinal cells. Moreover, an intravitreal injection of soluble Epo-R, which can neutralize endogenous Epo, will exacerbate photoreceptor cell apoptosis in a rat model of retinal detachment [30].…”