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Jose Carlos Rivera, Baraa Noueihed, Sylvain Chemtob; Mesenchymal stromal cells promote retinal vascular regeneration by modulating Sema3E and IL-17A in a mouse model of ischemic retinopathy. Invest. Ophthalmol. Vis. Sci. 2019;60(9):1664.
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© ARVO (1962-2015); The Authors (2016-present)
Ischemic retinopathies (IRs) are characterized by an initial phase of vaso-obliteration (VO) that results in retinal ischemia, followed by exaggerated pathological neovascularization (NV). Sema3E, originally implicated in axon guidance, has been shown to suppress disoriented angiogenesis in the retina; however, its production during IRs is decreased. On the other hand, microglia-derived IL-17A, a pro-inflammatory cytokine highly secreted during IRs, has been implicated in pathologic NV. Mesenchymal stromal cells (MSCs) have potent pro-angiogenic and anti-inflammatory properties; however, the mechanisms underlying these functions remain largely unknown. Here, we investigated whether MSCs can promote vascular repair by modulating Sema3E and IL-17A in the ischemic retina.
An oxygen-induced retinopathy (OIR) mouse model was used. Briefly, mice were subjected to 75% O2 from postnatal day 7 (P7) until P12, to induce VO, followed by 5 days of room air leading to NV. MSCs were isolated from bone marrow and cultured. The supernatant of MSCs (CM) was collected 24 hours later and injected intravitreally at P12. VO and NV areas were assessed in retinas at P17. mRNA levels of some inflammatory and angiogenic mediators were quantified by qPCR in retinas treated with CM or vehicle. We investigated whether CM modulates Sema3E expression in retinal ganglion cells (RGC) and whether recombinant Sema3E (rSema3E) could regulate IL-17A expression in macrophages.
CM significantly reduced VO and NV in OIR retinas in comparison to vehicle at P17. Gene expression levels of the pro-inflammatory mediators (IL-1β and TNFα) were decreased, while the anti-inflammatory cytokines (IL-10, IL-4) were increased in CM-treated retinas. Interestingly, the CM re-established Sema3E levels in the OIR retinas and significantly (p<0.05) downregulated IL-17A expression. Intravitreal injection of rSema3E during OIR resulted in retinal vascular repair associated to a significant decrease in IL-17A, similar to CM. RGC cells exposed to the CM showed an increase in Sema3E production, while rSema3E was able to inhibit IL-17A expression in macrophages.
Our findings suggest that MSC supernatant promotes retinal vascular repair and inhibits aberrant neovascularization in OIR retinas, at least in part, by restoring Sema3E levels and reducing pathological levels of IL-17A.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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