期刊
SCIENCE
卷 372, 期 6540, 页码 360-+出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abf1230
关键词
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资金
- NIH [NS102807, ES02530, ES029136, AI126880, 1K99NS114111, F30AG063463, F32NS101790, 5T32AG000222, R21AG061678]
- National Multiple Sclerosis Society [RG4111A1, JF2161-A-5]
- American Cancer Society [RSG-14198-01-LIB]
- International Progressive MS Alliance [PA-160408459]
- DFG [CRC/TRR167]
- Alfonso Martin Escudero Foundation
- European Molecular Biology Organization [ALTF 610-2017]
- Dana-Farber Cancer Institute [T32CA207201]
- Program in Interdisciplinary Neuroscience at Brigham and Women's Hospital
- Women's Brain Initiative at Brigham and Women's Hospital
- Mallinkrodt Pharmaceuticals [A219074]
- German Research Foundation [DFG RO4866 1/1]
- joint FRQS-EndMS postdoctoral fellowship
- Ministry of Science and Technology, Taiwan [104-2917-I-564024]
- FAPESP BEPE [2019/13731-0]
- senior Canada Research Chair in Multiple Sclerosis
- NCI Cancer Center support grant [2P30CA006516-48]
The study identified microglia-astrocyte interactions and candidate therapeutic targets using RABID-seq, providing new insights into CNS pathology.
Cell-cell interactions control the physiology and pathology of the central nervous system (CNS). To study astrocyte cell interactions in vivo, we developed rabies barcode interaction detection followed by sequencing (RABID-seq), which combines barcoded viral tracing and single-cell RNA sequencing (scRNA-seq). Using RABID-seq, we identified axon guidance molecules as candidate mediators of microgliaastrocyte interactions that promote CNS pathology in experimental autoimmune encephalomyelitis (EAE) and, potentially, multiple sclerosis (MS). In vivo cell- specific genetic perturbation EAE studies, in vitro systems, and the analysis of MS scRNA-seq datasets and CNS tissue established that Sema4D and Ephrin-B3 expressed in microglia control astrocyte responses via PlexinB2 and EphB3, respectively. Furthermore, a CNS-penetrant EphB3 inhibitor suppressed astrocyte and microglia proinflammatory responses and ameliorated EAE. In summary, RABID-seq identified microgliaastrocyte interactions and candidate therapeutic targets.
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