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M. R. Ritter, S. H. Moreno, A. Dorsey, M. El-Kalay, M. Friedlander; CC Chemokines Recruit Microglia Progenitors to the Retina and Promote Vascular Repair in a Model of Ischemic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3340.
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Current treatments for ischemic retinopathies, such as diabetic retinopathy, seek to halt the growth of the pathological vessels but do not address the underlying ischemia that drives their growth. We have recently suggested an alternative approach to the treatment of ischemic retinopathy that promotes vessel repair by intravitreal injection of bone marrow-derived microglia progenitors. We report here a direct and clinically translatable approach to this same concept where a compound is used to recruit microglia progenitors from the circulation into the retina where they mediate vascular repair.
Selected CC chemokines were administered intravitreally at P12 in the mouse OIR model. Whole mount preparations were used to evaluate recruitment and areas of obliteration and neovascularization.
Injection of 50ng/ml CCL2 resulted in a dramatic increase in the number of CD45+, CD11b+, isolectin positive microglia/macrophages in the retina when quantified one day later at P13. Time course studies showed a relatively rapid recruitment with early activity observed at 12 hrs post-injection and evidence of differentiation toward microglia at 72 hrs. After labeling circulating cells with an intracardiac infusion of a non-specific dye, we observed the presence of labeled cells in the retina after intravitreal chemokine injections, confirming that these cells were recruited, and not simply proliferating local cells. The functional consequence of this recruitment was shown in the OIR models where a single P12 intravitreal injection of 0.5ng CCL2 reduced retinal vascular obliteration by approximately 30% and retinal neovascularization by approximately 60% (n=34).
The finding that other members of the CC chemokine family have similar activity demonstrates that the observed effects are not specific to CCL2 and are likely to be mediated by any agent that can recruit microglia progenitors into the retina. We believe this concept represents a novel approach to the treatment of retinal vascular disease where the patient’s cells are manipulated in situ to bring about tissue repair.
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