{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:08:06Z","timestamp":1790813286502,"version":"4.1.0"},"reference-count":45,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,3,19]],"date-time":"2019-03-19T00:00:00Z","timestamp":1552953600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,3,19]],"date-time":"2019-03-19T00:00:00Z","timestamp":1552953600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000002","name":"U.S. Department of Health &amp; Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["R01-EY24320"],"award-info":[{"award-number":["R01-EY24320"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health &amp; Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["T32-GM007377"],"award-info":[{"award-number":["T32-GM007377"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health &amp; Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["T32-EY105387"],"award-info":[{"award-number":["T32-EY105387"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health &amp; Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["R01-EY24320"],"award-info":[{"award-number":["R01-EY24320"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health &amp; Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["R01-EY24320"],"award-info":[{"award-number":["R01-EY24320"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health &amp; Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["T32-GM007377"],"award-info":[{"award-number":["T32-GM007377"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health &amp; Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["T32-EY105387"],"award-info":[{"award-number":["T32-EY105387"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health &amp; Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["R01-EY24320"],"award-info":[{"award-number":["R01-EY24320"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health &amp; Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["P30-EY012576"],"award-info":[{"award-number":["P30-EY012576"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health &amp; Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["P30-CA093373"],"award-info":[{"award-number":["P30-CA093373"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health &amp; Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["S10-OD0100786"],"award-info":[{"award-number":["S10-OD0100786"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health &amp; Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["S10-OD018223"],"award-info":[{"award-number":["S10-OD018223"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Bright Focus Foundation"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Neuroinflammation commonly accompanies neurodegeneration, but the specific roles of resident and infiltrating immune cells during degeneration remains controversial. Much of the difficulty in assessing myeloid cell-specific functions during disease progression arises from the inability to clearly distinguish between activated microglia and bone\u00a0marrow-derived monocytes and macrophages in various stages of differentiation and activation within the central nervous system. Using an inducible model of photoreceptor cell death, we investigated the prevalence of infiltrating monocytes and macrophage subpopulations after the initiation of degeneration in the mouse retina. <jats:italic>In vivo<\/jats:italic> retinal imaging revealed infiltration of CCR2<jats:sup>+<\/jats:sup> leukocytes across retinal vessels and into the parenchyma within 48\u2009hours of photoreceptor degeneration. Immunohistochemistry and flow cytometry confirmed and characterized these leukocytes as CD11b<jats:sup>+<\/jats:sup>CD45<jats:sup>+<\/jats:sup> cells. Single-cell mRNA sequencing of the entire CD11b<jats:sup>+<\/jats:sup>CD45<jats:sup>+<\/jats:sup> population revealed the presence of resting microglia, activated microglia, monocytes, and macrophages as well as 12 distinct subpopulations within these four major cell classes. Our results demonstrate a previously immeasurable degree of molecular heterogeneity in the innate immune response to cell-autonomous degeneration within the central nervous system and highlight the necessity of unbiased high-throughput and high-dimensional molecular techniques like scRNAseq to understand the complex and changing landscape of immune responders during disease progression.<\/jats:p>","DOI":"10.1038\/s41598-019-41141-0","type":"journal-article","created":{"date-parts":[[2019,3,19]],"date-time":"2019-03-19T21:35:28Z","timestamp":1553031328000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":81,"title":["Molecular profiling of resident and infiltrating mononuclear phagocytes during rapid adult retinal degeneration using single-cell RNA sequencing"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6727-5776","authenticated-orcid":false,"given":"Kaitryn E.","family":"Ronning","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah J.","family":"Karlen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric B.","family":"Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie E.","family":"Burns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,3,19]]},"reference":[{"key":"41141_CR1","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1016\/j.immuni.2017.06.007","volume":"46","author":"J Herz","year":"2017","unstructured":"Herz, J., Filiano, A. J., Smith, A., Yogev, N. & Kipnis, J. Myeloid Cells in the Central Nervous System. Immunity 46, 943\u2013956, https:\/\/doi.org\/10.1016\/j.immuni.2017.06.007 (2017).","journal-title":"Immunity"},{"key":"41141_CR2","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1146\/annurev-physiol-022516-034406","volume":"79","author":"SA Wolf","year":"2017","unstructured":"Wolf, S. A., Boddeke, H. W. & Kettenmann, H. Microglia in Physiology and Disease. Annu Rev Physiol 79, 619\u2013643, https:\/\/doi.org\/10.1146\/annurev-physiol-022516-034406 (2017).","journal-title":"Annu Rev Physiol"},{"key":"41141_CR3","doi-asserted-by":"publisher","first-page":"1096","DOI":"10.1038\/nn.3161","volume":"15","author":"SS Ousman","year":"2012","unstructured":"Ousman, S. S. & Kubes, P. Immune surveillance in the central nervous system. Nat Neurosci 15, 1096\u20131101, https:\/\/doi.org\/10.1038\/nn.3161 (2012).","journal-title":"Nat Neurosci"},{"key":"41141_CR4","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1007\/s00702-017-1795-7","volume":"125","author":"C Baufeld","year":"2018","unstructured":"Baufeld, C., O\u2019Loughlin, E., Calcagno, N., Madore, C. & Butovsky, O. Differential contribution of microglia and monocytes in neurodegenerative diseases. J Neural Transm (Vienna) 125, 809\u2013826, https:\/\/doi.org\/10.1007\/s00702-017-1795-7 (2018).","journal-title":"J Neural Transm (Vienna)"},{"key":"41141_CR5","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.preteyeres.2017.06.002","volume":"61","author":"X Guillonneau","year":"2017","unstructured":"Guillonneau, X. et al. On phagocytes and macular degeneration. Prog Retin Eye Res 61, 98\u2013128, https:\/\/doi.org\/10.1016\/j.preteyeres.2017.06.002 (2017).","journal-title":"Prog Retin Eye Res"},{"key":"41141_CR6","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-08702-7","volume":"7","author":"W Ma","year":"2017","unstructured":"Ma, W. et al. Monocyte infiltration and proliferation reestablish myeloid cell homeostasis in the mouse retina following retinal pigment epithelial cell injury. Sci Rep 7, 8433, https:\/\/doi.org\/10.1038\/s41598-017-08702-7 (2017).","journal-title":"Sci Rep"},{"key":"41141_CR7","doi-asserted-by":"publisher","first-page":"1775","DOI":"10.1002\/emmm.201302692","volume":"5","author":"F Sennlaub","year":"2013","unstructured":"Sennlaub, F. et al. CCR2(+) monocytes infiltrate atrophic lesions in age-related macular disease and mediate photoreceptor degeneration in experimental subretinal inflammation in Cx3cr1 deficient mice. EMBO Mol Med 5, 1775\u20131793, https:\/\/doi.org\/10.1002\/emmm.201302692 (2013).","journal-title":"EMBO Mol Med"},{"key":"41141_CR8","doi-asserted-by":"publisher","DOI":"10.1038\/srep20636","volume":"6","author":"EG O\u2019Koren","year":"2016","unstructured":"O\u2019Koren, E. G., Mathew, R. & Saban, D. R. Fate mapping reveals that microglia and recruited monocyte-derived macrophages are definitively distinguishable by phenotype in the retina. Sci Rep 6, 20636, https:\/\/doi.org\/10.1038\/srep20636 (2016).","journal-title":"Sci Rep"},{"key":"41141_CR9","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1038\/nri.2017.13","volume":"17","author":"NJ Reyes","year":"2017","unstructured":"Reyes, N. J., O\u2019Koren, E. G. & Saban, D. R. New insights into mononuclear phagocyte biology from the visual system. Nat Rev Immunol 17, 322\u2013332, https:\/\/doi.org\/10.1038\/nri.2017.13 (2017).","journal-title":"Nat Rev Immunol"},{"key":"41141_CR10","doi-asserted-by":"publisher","unstructured":"McMenamin, P. G., Saban, D. & Dando, S. J. Immune cells in the retina and choroid: Two different tissue environments that require different defenses and surveillance. Prog Retin Eye Res, https:\/\/doi.org\/10.1016\/j.preteyeres.2018.12.002 (2018).","DOI":"10.1016\/j.preteyeres.2018.12.002"},{"key":"41141_CR11","doi-asserted-by":"publisher","first-page":"1896","DOI":"10.1038\/nn.3554","volume":"16","author":"SE Hickman","year":"2013","unstructured":"Hickman, S. E. et al. The microglial sensome revealed by direct RNA sequencing. Nat Neurosci 16, 1896\u20131905, https:\/\/doi.org\/10.1038\/nn.3554 (2013).","journal-title":"Nat Neurosci"},{"key":"41141_CR12","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1038\/39068","volume":"389","author":"J Xu","year":"1997","unstructured":"Xu, J. et al. Prolonged photoresponses in transgenic mouse rods lacking arrestin. Nature 389, 505\u2013509, https:\/\/doi.org\/10.1038\/39068 (1997).","journal-title":"Nature"},{"key":"41141_CR13","doi-asserted-by":"publisher","first-page":"3014","DOI":"10.1021\/bi00541a032","volume":"21","author":"U Wilden","year":"1982","unstructured":"Wilden, U. & Kuhn, H. Light-dependent phosphorylation of rhodopsin: number of phosphorylation sites. Biochemistry 21, 3014\u20133022 (1982).","journal-title":"Biochemistry"},{"key":"41141_CR14","first-page":"2978","volume":"40","author":"J Chen","year":"1999","unstructured":"Chen, J., Simon, M. I., Matthes, M. T., Yasumura, D. & LaVail, M. M. Increased susceptibility to light damage in an arrestin knockout mouse model of Oguchi disease (stationary night blindness). Invest Ophthalmol Vis Sci 40, 2978\u20132982 (1999).","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"41141_CR15","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1038\/ng984","volume":"32","author":"W Hao","year":"2002","unstructured":"Hao, W. et al. Evidence for two apoptotic pathways in light-induced retinal degeneration. Nat Genet 32, 254\u2013260, https:\/\/doi.org\/10.1038\/ng984 (2002).","journal-title":"Nat Genet"},{"key":"41141_CR16","doi-asserted-by":"publisher","first-page":"29310","DOI":"10.1074\/jbc.M114.595207","volume":"289","author":"T Wang","year":"2014","unstructured":"Wang, T. & Chen, J. Induction of the unfolded protein response by constitutive G-protein signaling in rod photoreceptor cells. J Biol Chem 289, 29310\u201329321, https:\/\/doi.org\/10.1074\/jbc.M114.595207 (2014).","journal-title":"J Biol Chem"},{"key":"41141_CR17","doi-asserted-by":"publisher","unstructured":"Karlen, S. J. Miller, E. B., Wang, X., Levine, E. S., Zawadzki, R. J. & Burns, M.E. Monocyte infiltration rather than microglia proliferation dominates the early immune response to rapid photoreceptor degeneration. Journal of Neuroinflammation\u00a015, 344, https:\/\/doi.org\/10.1186\/s12974-018-1365-4\u00a0(2018).","DOI":"10.1186\/s12974-018-1365-4"},{"key":"41141_CR18","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.visres.2014.07.011","volume":"102","author":"ES Levine","year":"2014","unstructured":"Levine, E. S. et al. Rapid light-induced activation of retinal microglia in mice lacking Arrestin-1. Vision Res 102, 71\u201379, https:\/\/doi.org\/10.1016\/j.visres.2014.07.011 (2014).","journal-title":"Vision Res"},{"key":"41141_CR19","doi-asserted-by":"publisher","first-page":"1276","DOI":"10.1016\/j.cell.2017.05.018","volume":"169","author":"H Keren-Shaul","year":"2017","unstructured":"Keren-Shaul, H. et al. A Unique Microglia Type Associated with Restricting Development of Alzheimer\u2019s Disease. Cell 169, 1276\u20131290 e1217, https:\/\/doi.org\/10.1016\/j.cell.2017.05.018 (2017).","journal-title":"Cell"},{"key":"41141_CR20","doi-asserted-by":"publisher","unstructured":"Hammond, T. R. et al. Single-Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes. Immunity, https:\/\/doi.org\/10.1016\/j.immuni.2018.11.004 (2018).","DOI":"10.1016\/j.immuni.2018.11.004"},{"key":"41141_CR21","doi-asserted-by":"publisher","first-page":"e0150606","DOI":"10.1371\/journal.pone.0150606","volume":"11","author":"YR Yu","year":"2016","unstructured":"Yu, Y. R. et al. A Protocol for the Comprehensive Flow Cytometric Analysis of Immune Cells in Normal and Inflamed Murine Non-Lymphoid Tissues. PLoS One 11, e0150606, https:\/\/doi.org\/10.1371\/journal.pone.0150606 (2016).","journal-title":"PLoS One"},{"key":"41141_CR22","doi-asserted-by":"publisher","first-page":"1202","DOI":"10.1016\/j.cell.2015.05.002","volume":"161","author":"EZ Macosko","year":"2015","unstructured":"Macosko, E. Z. et al. Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets. Cell 161, 1202\u20131214, https:\/\/doi.org\/10.1016\/j.cell.2015.05.002 (2015).","journal-title":"Cell"},{"key":"41141_CR23","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.molimm.2015.02.032","volume":"67","author":"S McHarg","year":"2015","unstructured":"McHarg, S., Clark, S. J., Day, A. J. & Bishop, P. N. Age-related macular degeneration and the role of the complement system. Mol Immunol 67, 43\u201350, https:\/\/doi.org\/10.1016\/j.molimm.2015.02.032 (2015).","journal-title":"Mol Immunol"},{"key":"41141_CR24","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1016\/j.immuni.2017.01.006","volume":"46","author":"B Calippe","year":"2017","unstructured":"Calippe, B. et al. Complement Factor H Inhibits CD47-Mediated Resolution of Inflammation. Immunity 46, 261\u2013272, https:\/\/doi.org\/10.1016\/j.immuni.2017.01.006 (2017).","journal-title":"Immunity"},{"key":"41141_CR25","doi-asserted-by":"publisher","DOI":"10.1186\/2050-7771-2-1","volume":"2","author":"J Yang","year":"2014","unstructured":"Yang, J., Zhang, L., Yu, C., Yang, X. F. & Wang, H. Monocyte and macrophage differentiation: circulation inflammatory monocyte as biomarker for inflammatory diseases. Biomark Res 2, 1, https:\/\/doi.org\/10.1186\/2050-7771-2-1 (2014).","journal-title":"Biomark Res"},{"key":"41141_CR26","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1146\/annurev-vision-111815-114407","volume":"2","author":"PD Kiser","year":"2016","unstructured":"Kiser, P. D. & Palczewski, K. Retinoids and Retinal Diseases. Annu Rev Vis Sci 2, 197\u2013234, https:\/\/doi.org\/10.1146\/annurev-vision-111815-114407 (2016).","journal-title":"Annu Rev Vis Sci"},{"key":"41141_CR27","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1016\/S0042-6989(01)00146-8","volume":"42","author":"B Chang","year":"2002","unstructured":"Chang, B. et al. Retinal degeneration mutants in the mouse. Vision Res 42, 517\u2013525 (2002).","journal-title":"Vision Res"},{"key":"41141_CR28","doi-asserted-by":"publisher","first-page":"13568","DOI":"10.1523\/JNEUROSCI.2468-15.2015","volume":"35","author":"O Levy","year":"2015","unstructured":"Levy, O. et al. APOE Isoforms Control Pathogenic Subretinal Inflammation in Age-Related Macular Degeneration. J Neurosci 35, 13568\u201313576, https:\/\/doi.org\/10.1523\/JNEUROSCI.2468-15.2015 (2015).","journal-title":"J Neurosci"},{"key":"41141_CR29","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1016\/j.it.2013.03.004","volume":"34","author":"T Shay","year":"2013","unstructured":"Shay, T. & Kang, J. Immunological Genome Project and systems immunology. Trends Immunol 34, 602\u2013609, https:\/\/doi.org\/10.1016\/j.it.2013.03.004 (2013).","journal-title":"Trends Immunol"},{"key":"41141_CR30","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1038\/ni1008-1091","volume":"9","author":"TS Heng","year":"2008","unstructured":"Heng, T. S. & Painter, M. W. & Immunological Genome Project, C. The Immunological Genome Project: networks of gene expression in immune cells. Nat Immunol 9, 1091\u20131094, https:\/\/doi.org\/10.1038\/ni1008-1091 (2008).","journal-title":"Nat Immunol"},{"issue":"487-495","key":"41141_CR31","doi-asserted-by":"publisher","first-page":"S481","DOI":"10.1038\/nn.3032","volume":"15","author":"S Siegert","year":"2012","unstructured":"Siegert, S. et al. Transcriptional code and disease map for adult retinal cell types. Nat Neurosci 15(487-495), S481\u2013482, https:\/\/doi.org\/10.1038\/nn.3032 (2012).","journal-title":"Nat Neurosci"},{"key":"41141_CR32","doi-asserted-by":"publisher","first-page":"1174","DOI":"10.1073\/pnas.83.5.1174","volume":"83","author":"U Wilden","year":"1986","unstructured":"Wilden, U., Hall, S. W. & Kuhn, H. Phosphodiesterase activation by photoexcited rhodopsin is quenched when rhodopsin is phosphorylated and binds the intrinsic 48-kDa protein of rod outer segments. Proc Natl Acad Sci USA 83, 1174\u20131178 (1986).","journal-title":"Proc Natl Acad Sci USA"},{"key":"41141_CR33","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1126\/science.aaf2403","volume":"353","author":"PL Stahl","year":"2016","unstructured":"Stahl, P. L. et al. Visualization and analysis of gene expression in tissue sections by spatial transcriptomics. Science 353, 78\u201382, https:\/\/doi.org\/10.1126\/science.aaf2403 (2016).","journal-title":"Science"},{"key":"41141_CR34","doi-asserted-by":"publisher","unstructured":"Strell, C. et al. Placing RNA in context and space - methods for spatially resolved transcriptomics. FEBS J, https:\/\/doi.org\/10.1111\/febs.14435 (2018).","DOI":"10.1111\/febs.14435"},{"key":"41141_CR35","doi-asserted-by":"publisher","first-page":"4106","DOI":"10.1128\/MCB.20.11.4106-4114.2000","volume":"20","author":"S Jung","year":"2000","unstructured":"Jung, S. et al. Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol Cell Biol 20, 4106\u20134114 (2000).","journal-title":"Mol Cell Biol"},{"key":"41141_CR36","doi-asserted-by":"publisher","first-page":"e13693","DOI":"10.1371\/journal.pone.0013693","volume":"5","author":"N Saederup","year":"2010","unstructured":"Saederup, N. et al. Selective chemokine receptor usage by central nervous system myeloid cells in CCR2-red fluorescent protein knock-in mice. PLoS One 5, e13693, https:\/\/doi.org\/10.1371\/journal.pone.0013693 (2010).","journal-title":"PLoS One"},{"key":"41141_CR37","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1177\/1073858414536468","volume":"21","author":"KM Lenz","year":"2015","unstructured":"Lenz, K. M. & McCarthy, M. M. A starring role for microglia in brain sex differences. Neuroscientist 21, 306\u2013321, https:\/\/doi.org\/10.1177\/1073858414536468 (2015).","journal-title":"Neuroscientist"},{"key":"41141_CR38","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1016\/j.molcel.2017.01.023","volume":"65","author":"C Ziegenhain","year":"2017","unstructured":"Ziegenhain, C. et al. Comparative Analysis of Single-Cell RNA Sequencing Methods. Mol Cell 65, 631\u2013643 e634, https:\/\/doi.org\/10.1016\/j.molcel.2017.01.023 (2017).","journal-title":"Mol Cell"},{"key":"41141_CR39","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.exer.2018.02.024","volume":"171","author":"KE Ronning","year":"2018","unstructured":"Ronning, K. E. et al. Loss of cone function without degeneration in a novel Gnat2 knock-out mouse. Exp Eye Res 171, 111\u2013118, https:\/\/doi.org\/10.1016\/j.exer.2018.02.024 (2018).","journal-title":"Exp Eye Res"},{"key":"41141_CR40","doi-asserted-by":"publisher","first-page":"126005","DOI":"10.1117\/1.JBO.20.12.126005","volume":"20","author":"P Zhang","year":"2015","unstructured":"Zhang, P. et al. In vivo wide-field multispectral scanning laser ophthalmoscopy-optical coherence tomography mouse retinal imager: longitudinal imaging of ganglion cells, microglia, and Muller glia, and mapping of the mouse retinal and choroidal vasculature. J Biomed Opt 20, 126005, https:\/\/doi.org\/10.1117\/1.JBO.20.12.126005 (2015).","journal-title":"J Biomed Opt"},{"key":"41141_CR41","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1038\/nmeth.2019","volume":"9","author":"J Schindelin","year":"2012","unstructured":"Schindelin, J. et al. Fiji: an open-source platform for biological-image analysis. Nat Methods 9, 676\u2013682, https:\/\/doi.org\/10.1038\/nmeth.2019 (2012).","journal-title":"Nat Methods"},{"key":"41141_CR42","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1109\/83.650848","volume":"7","author":"P Thevenaz","year":"1998","unstructured":"Thevenaz, P., Ruttimann, U. E. & Unser, M. A pyramid approach to subpixel registration based on intensity. IEEE Trans Image Process 7, 27\u201341, https:\/\/doi.org\/10.1109\/83.650848 (1998).","journal-title":"IEEE Trans Image Process"},{"key":"41141_CR43","unstructured":"R: A language and environment for statistical computing (R Foundation for Statistical Computing, Vienna, Austria, 2008)."},{"key":"41141_CR44","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1038\/nbt.3192","volume":"33","author":"R Satija","year":"2015","unstructured":"Satija, R., Farrell, J. A., Gennert, D., Schier, A. F. & Regev, A. Spatial reconstruction of single-cell gene expression data. Nat Biotechnol 33, 495\u2013502, https:\/\/doi.org\/10.1038\/nbt.3192 (2015).","journal-title":"Nat Biotechnol"},{"key":"41141_CR45","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1038\/nbt.4096","volume":"36","author":"A Butler","year":"2018","unstructured":"Butler, A., Hoffman, P., Smibert, P., Papalexi, E. & Satija, R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol 36, 411\u2013420, https:\/\/doi.org\/10.1038\/nbt.4096 (2018).","journal-title":"Nat Biotechnol"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-41141-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-41141-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-41141-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T07:45:52Z","timestamp":1671263152000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-41141-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,19]]},"references-count":45,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["41141"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-41141-0","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,3,19]]},"assertion":[{"value":"15 October 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 February 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 March 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"4858"}}