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Baraa Noueihed, Jose Carlos Rivera, Sylvain Chemtob; Mesenchymal stromal cells promote vascular regeneration and modulate inflammation in a mouse model of ischemic retinopathy. Invest. Ophthalmol. Vis. Sci. 2018;59(9):550.
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© ARVO (1962-2015); The Authors (2016-present)
Ischemic retinopathies are characterized by vaso-obliteration (VO) of the retinal vascular network, resulting in tissue hypoxia, followed by exaggerated pathological neovascularization (NV) into the vitreous. Current treatment modalities slow down the deregulated proliferation of intravitreal vessels; however, they do not repopulate the damaged vascular bed and may cause adverse side effects. Mesenchymal stromal cells (MSCs) can be an alternative therapeutic approach due to their pro-angiogenic and anti-inflammatory properties. We hypothesize that MSCs can promote vascular repair by modulating the angiogenic and inflammatory microenvironment in ischemic retinas.
Oxygen-induced retinopathy (OIR) mouse model which mimics the hallmarks of ischemic retinopathies was used in this study. Postnatal day 7 (P7) mice were subjected to 75% O2 until P12 to induce VO followed by 5 days of room air leading to NV. MSCs were isolated from the compact bone of adult mice. The supernatant of MSCs (CM) was collected 24 hours later, and injected intravitreally in one eye of P12 OIR mice; whereas the contralateral eye received vehicle (basal media). VO and NV areas were assessed at P17. To determine the effect of CM on inflammation in treated retinas, mRNA levels of various inflammatory mediators (IL1β, TNFα, iNOS, IL10, IL4) were measured by quantitative PCR at P17. Using a microglial cell line (SIM-A9), we investigated the role of CM in modulating its phenotype when treated with lipopolysaccharide (LPS) via quantitative PCR (IL1β, TNFα, iNOS) and flow cytometry (iNOS).
Treatment of OIR retinas with CM significantly reduced VO and NV areas at P17 in comparison to vehicle injection. Gene expression levels of the pro-inflammatory mediators (IL-1β, TNFα, iNOS) were decreased, meanwhile the anti-inflammatory cytokines (IL-10, IL-4) were increased in CM-treated retinas. Exposure of inactivated microglia to CM did not affect cytokine production. However, incubation of LPS-activated microglia with CM significantly reduced IL1β, TNFα, and iNOS levels.
MSC supernatant regenerated the vaso-obliterated areas and inhibited aberrant neovascularization in OIR retinas. This effect is mediated in a paracrine fashion by curtailing the pro-inflammatory response. Our findings suggest that CM may be a preferred therapeutic strategy for ischemic retinopathies.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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