Non-Invasive Stem Cell Therapy in a Rat Model for Retinal Degeneration and Vascular Pathology

Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, United States of America.
PLoS ONE (Impact Factor: 3.23). 02/2010; 5(2):e9200. DOI: 10.1371/journal.pone.0009200
Source: PubMed


Retinitis pigmentosa (RP) is characterized by progressive night blindness, visual field loss, altered vascular permeability and loss of central vision. Currently there is no effective treatment available except gene replacement therapy has shown promise in a few patients with specific gene defects. There is an urgent need to develop therapies that offer generic neuro-and vascular-protective effects with non-invasive intervention. Here we explored the potential of systemic administration of pluripotent bone marrow-derived mesenchymal stem cells (MSCs) to rescue vision and associated vascular pathology in the Royal College Surgeons (RCS) rat, a well-established animal model for RP.
Animals received syngeneic MSCs (1x10(6) cells) by tail vein at an age before major photoreceptor loss. Principal results: both rod and cone photoreceptors were preserved (5-6 cells thick) at the time when control animal has a single layer of photoreceptors remained; Visual function was significantly preserved compared with controls as determined by visual acuity and luminance threshold recording from the superior colliculus; The number of pathological vascular complexes (abnormal vessels associated with migrating pigment epithelium cells) and area of vascular leakage that would ordinarily develop were dramatically reduced; Semi-quantitative RT-PCR analysis indicated there was upregulation of growth factors and immunohistochemistry revealed that there was an increase in neurotrophic factors within eyes of animals that received MSCs.
These results underscore the potential application of MSCs in treating retinal degeneration. The advantages of this non-invasive cell-based therapy are: cells are easily isolated and can be expanded in large quantity for autologous graft; hypoimmunogenic nature as allogeneic donors; less controversial in nature than other stem cells; can be readministered with minor discomfort. Therefore, MSCs may prove to be the ideal cell source for auto-cell therapy for retinal degeneration and other ocular vascular diseases.

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    • "It will be interesting to see whether intravenous injection can be a successful route of the cell therapy for the retina. Many works showed that after IV injection MSCs migrated and localized in injured liver, heart, brain and retina, but in this case more cells were required for injection (Xu et al., 2007; Jackson et al., 2010; Wang et al., 2010b). In fact BMSC express main chemokine receptors (CC, CXC, C and CX3C) and can be attracted by their ligands, especially SDF-1 and IL-8 (Ringe et al., 2007; Shi et al., 2007). "
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    ABSTRACT: Retinal degenerations are the main causes of irreversible blindness in developed countries. Up to date the main pathological mechanisms of these diseases are not fully understood and consequently there is no complete treatment option for those diseases. In this aspect stem cells have drawn attention of many researchers and health care professionals. Considering ethical issues, safety and facile isolation Mesenchymal Stem Cells (MSCs) are more preferable for practical use. They have been used for several preclinical and clinical trials. In general the results were promising, however broader practical use should be preceded by resolving many problems and questions. In this review we will describe mesenchymal stem cells, especially those derived from Bone-Marrow (BMSC), their main features, privilege, mechanisms of action and their potential use for the treatment of retinal degenerations. We will also discuss the results of several pre-clinical and clinical trials. © 2014 The Emma Ghazaryan, Shurong Wang, Yan Zhang, Yuxi He and Guanfang Su.
    American Journal of Biochemistry and Biotechnology 04/2014; 10(4):241-250. DOI:10.3844/ajbbsp.2014.241.250
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    • "In particular, secretion of neuroprotective and immuno-modulatory molecules suggest significant therapeutic potential [1]. Most pertinent to the present study, previous reports have already demonstrated a retinal neuroprotective effect with MSCs delivered either by intravenous or intravitreal injection [16], [17]. In addition, ex vivo genetic modification of MSCs could extend the range of therapeutic benefits of MSC therapy [18]. "
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    ABSTRACT: Mesenchymal stem cells (MSCs) have well-established paracrine effects that are proving to be therapeutically useful. This potential is based on the ability of MSCs to secrete a range of neuroprotective and anti-inflammatory molecules. Previous work in our laboratory has demonstrated that intravenous injection of MSCs, treated with superparamagnetic iron oxide nanoparticle fluidMAG-D resulted in enhanced levels of glial-derived neurotrophic factor, ciliary neurotrophic factor, hepatocyte growth factor and interleukin-10 in the dystrophic rat retina. In this present study we investigated whether the concentration of fluidMAG-D in cell culture media affects the secretion of these four molecules in vitro. In addition, we assessed the effect of fluidMAG-D concentration on retinoschisin secretion from genetically modified MSCs. ELISA-assayed secretion of these molecules was measured using escalating concentrations of fluidMAG-D which resulted in MSC iron loads of 0, 7, 120, or 274 pg iron oxide per cell respectively. Our results demonstrated glial-derived neurotrophic factor and hepatocyte growth factor secretion was significantly decreased but only at the 96 hour's time-point whereas no statistically significant effect was seen with ciliary neurotrophic factor secretion. Whereas no effect was observed on culture media concentrations of retinoschisin with increasing iron oxide load, a statistically significant increase in cell lysate retinoschisin concentration $({rm p}=0.01)$ was observed suggesting that increasing fluidMAG-D concentration did increase retinoschisin production but this did not lead to greater secretion. We hypothesize that higher concentrations of iron-oxide nanoparticle fluidMAG-D have an effect on the innate ability of MSCs to secrete therapeutically useful molecules and also on secretion from genetically modified cells. Further work is required to verify these in vitro finding using - in vivo model systems.
    IEEE Transactions on Magnetics 01/2013; 49(1):389-393. DOI:10.1109/TMAG.2012.2225829 · 1.39 Impact Factor
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    • "The recruitment of microglia recruited to lesion sites in the CNS, including the retina, is regulated by several molecules, among which chemokines and their cognate receptors are key players. The CC-chemokine ligand (CCL2) is the most potent microglia chemoattractant that binds CC-chemokine receptor 2 (CCR2) on microglia cell surfaces [17-23] and mediates the accumulation of these cells at sites of pathology [11-13]. This work represents the first to overexpress CCR2 in primary microglia via lentiviral transduction to enhance recruitment in response to CCL2. "
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    ABSTRACT: Retinal microglia can be activated and recruited by chemokines and play a protective role in early retinal degeneration. CC-chemokine ligand 2 (CCL2) and its receptor, CC-chemokine receptor 2 (CCR2), have been implicated as key mediators for the trafficking and accumulation of microglial cells in lesioned tissue. The current study investigates whether the overexpression of CCR2 allows microglia to migrate toward CCL2 more efficiently. Primary microglial cells were transduced with lentivirus carrying green fluorescent protein (GFP)-tagged CCR2 (CCR2-GFP). Overexpression of CCR2 was assessed by western blot analysis and fluorescence-assisted cell sorting. The chemotaxis of primary microglia transduced with lentivirus carrying CCR2-GFP was compared to either those transduced with GFP alone or those not transduced, using a chemotaxis chamber assay. Primary microglia showed a high transduction rate following lentivirus application and maintained normal microglial morphology and a significant overexpression of CCR2 protein. We found that CCL2-mediated chemotaxis is concentration and time dependent in microglia. The chemotactic response of microglia cells overexpressing CCR2-GFP was significantly increased compared to that of nontransduced and GFP-expressing microglia. These findings suggest that microglia can be efficiently transduced with CCR2-GFP lentiviral vectors and that the overexpression of CCR2 in retinal microglia promotes their chemotaxis in response to chemokines, suggesting that these cells may be promising targets for cell-based therapeutic manipulation in retinal disease.
    Molecular vision 12/2012; 18:2982-92. · 1.99 Impact Factor
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