Temporospatial distribution and transcriptional profile of retinal microglia in the oxygen-induced retinopathy mouse model

被引:51
作者
Boeck, Myriam [1 ]
Thien, Adrian [1 ]
Wolf, Julian [1 ]
Hagemeyer, Nora [2 ]
Laich, Yannik [1 ]
Yusuf, Dilmurat [3 ]
Backofen, Rolf [3 ]
Zhang, Peipei [1 ]
Boneva, Stefaniya [1 ]
Stahl, Andreas [4 ]
Hilgendorf, Ingo [5 ]
Agostini, Hansjuergen [1 ]
Prinz, Marco [2 ,6 ,7 ]
Wieghofer, Peter [8 ]
Schlunck, Guenther [1 ]
Schlecht, Anja [1 ]
Lange, Clemens [1 ]
机构
[1] Univ Freiburg, Fac Med, Eye Ctr, Med Ctr, Freiburg, Germany
[2] Univ Freiburg, Inst Neuropathol, Fac Med, Freiburg, Germany
[3] Univ Freiburg, Dept Bioinformat, Freiburg, Germany
[4] Univ Med Ctr Greifswald, Dept Ophthalmol, Greifswald, Germany
[5] Univ Freiburg, Univ Heart Ctr, Cardiol & Angiol, Freiburg, Germany
[6] Univ Freiburg, Signalling Res Ctr BIOSS & CIBSS, Freiburg, Germany
[7] Univ Freiburg, Fac Med, Ctr Basics NeuroModulat NeuroModulBasics, Freiburg, Germany
[8] Univ Leipzig, Inst Anat, Freiburg, Germany
关键词
Cx3cr1(CreERT2); microglia; oxygen-induced retinopathy; retinal neovascularization; RNA sequencing; MACROPHAGES; NEOVASCULARIZATION; ANGIOGENESIS; EXPRESSION; REVEALS;
D O I
10.1002/glia.23810
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Myeloid cells such as resident retinal microglia (MG) or infiltrating blood-derived macrophages (M phi) accumulate in areas of retinal ischemia and neovascularization (RNV) and modulate neovascular eye disease. Their temporospatial distribution and biological function in this process, however, remain unclarified. Using state-of-the-art methods, including cell-specific reporter mice and high-throughput RNA sequencing (RNA Seq), this study determined the extent of MG proliferation and M phi infiltration in areas with retinal ischemia and RNV inCx3cr1(CreERT2):Rosa26-tdTomatomice and examined the transcriptional profile of MG in the mouse model of oxygen-induced retinopathy (OIR). For RNA Seq, tdTomato-positive retinal MG were sorted by flow cytometry followed by Gene ontology (GO) cluster analysis. Furthermore, intraperitoneal injections of the cell proliferation marker 5-ethynyl-2 '-deoxyuridine (EdU) were performed from postnatal day (p) 12 to p16. We found that MG is the predominant myeloid cell population while M phi rarely appears in areas of RNV. Thirty percent of retinal MG in areas of RNV were EdU-positive indicating a considerable local MG cell expansion. GO cluster analysis revealed an enrichment of clusters related to cell division, tubulin binding, ATPase activity, protein kinase regulatory activity, and chemokine receptor binding in MG in the OIR model compared to untreated controls. In conclusion, activated retinal MG alter their transcriptional profile, exhibit considerable proliferative ability and are by far the most frequent myeloid cell population in areas of ischemia and RNV in the OIR model thus presenting a potential target for future therapeutic approaches.
引用
收藏
页码:1859 / 1873
页数:15
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