Monocyte-derived pro-angiogenic ocular macrophages identified by spatial transcriptomics are essential for choroidal neovascularization

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Abstract

The human retina and underlying choroid have multiple well-organized vascular layers. However, retinal and choroidal neovascularization can develop in diseases such as diabetic retinopathy or neovascular age-related macular degeneration, which can result in destructive vision loss. Ocular macrophages are implicated in the pathogenesis of such neovascular diseases. To identify a potential pro-angiogenic macrophage subtype, we integrated 13 single-cell RNA sequencing datasets from human and mouse eyes comprising 173 unique samples. From 99,184 mononuclear phagocytes, we identified a single macrophage subtype with high expression of SPP1, FABP5, and IL7R that was over-represented from neovascular disease samples. We fate mapped these cells and specifically depleted them, showing that they are monocyte-derived and necessary for laser-induced choroidal neovascularization in mice. Finally, we performed a high-resolution spatial RNA sequencing experiment on six human donors and found that the pro-angiogenic macrophage subtype localized to human choroidal neovascular membranes. These macrophages and other cells in neovascular membranes expressed MMP14, a potential therapeutic target, and MMP14 inhibition decreased choroidal neovascularization in mice. Collectively, we show that this Monocyte-derived Pro-angiogenic Ocular Macrophage (MoPOM) subtype is upregulated in multiple ocular neovascular diseases across species, necessary for choroidal neovascularization, and is a potential therapeutic target to reduce destructive angiogenesis in the eye.

Authors

Andrew P. Voigt, Joyce Gong, Steven Droho, Kelly Mulfaul, Amrita Rajesh, Greta E. Forbes, Jacob K. Sterling, Miles J. Flamme-Wiese, Robert F. Mullins, Jeremy A. Lavine