PMID- 29424466 OWN - NLM STAT- MEDLINE DCOM- 20181025 LR - 20210109 IS - 1098-1136 (Electronic) IS - 0894-1491 (Print) IS - 0894-1491 (Linking) VI - 66 IP - 5 DP - 2018 May TI - Differential local tissue permissiveness influences the final fate of GPR17-expressing oligodendrocyte precursors in two distinct models of demyelination. PG - 1118-1130 LID - 10.1002/glia.23305 [doi] AB - Promoting remyelination is recognized as a novel strategy to foster repair in neurodegenerative demyelinating diseases, such as multiple sclerosis. In this respect, the receptor GPR17, recently emerged as a new target for remyelination, is expressed by early oligodendrocyte precursors (OPCs) and after a certain differentiation stage it has to be downregulated to allow progression to mature myelinating oligodendrocytes. Here, we took advantage of the first inducible GPR17 reporter mouse line (GPR17-iCreER(T2) xCAG-eGFP mice) allowing to follow the final fate of GPR17(+) cells by tamoxifen-induced GFP-labeling to unveil the destiny of these cells in two demyelination models: experimental autoimmune encephalomyelitis (EAE), characterized by marked immune cell activation and inflammation, and cuprizone induced demyelination, where myelin dysfunction is achieved by a toxic insult. In both models, demyelination induced a strong increase of fluorescent GFP(+) cells at damaged areas. However, only in the cuprizone model reacting GFP(+) cells terminally differentiated to mature oligodendrocytes, thus contributing to remyelination. In EAE, GFP(+) cells were blocked at immature stages and never became myelinating oligodendrocytes. We suggest these strikingly distinct fates be due to different permissiveness of the local CNS environment. Based on previously reported GPR17 activation by emergency signals (e.g., Stromal Derived Factor-1), we propose that a marked inflammatory milieu, such as that reproduced in EAE, induces GPR17 overactivation resulting in impaired downregulation, untimely and prolonged permanence in OPCs, leading, in turn, to differentiation blockade. Combined treatments with remyelinating agents and anti-inflammatory drugs may represent new potential adequate strategies to halt neurodegeneration and foster recovery. CI - (c) 2018 The Authors GLIA Published by Wiley Periodicals, Inc. FAU - Coppolino, Giusy T AU - Coppolino GT AD - Laboratory of Molecular and Cellular Pharmacology of the Purinergic Transmission, Dipartimento di Scienze Farmacologiche e Biomolecolari, Universita degli Studi di Milano, Via Balzaretti 9, Milan, 20133, Italy. FAU - Marangon, Davide AU - Marangon D AD - Laboratory of Molecular and Cellular Pharmacology of the Purinergic Transmission, Dipartimento di Scienze Farmacologiche e Biomolecolari, Universita degli Studi di Milano, Via Balzaretti 9, Milan, 20133, Italy. FAU - Negri, Camilla AU - Negri C AD - Laboratory of Molecular and Cellular Pharmacology of the Purinergic Transmission, Dipartimento di Scienze Farmacologiche e Biomolecolari, Universita degli Studi di Milano, Via Balzaretti 9, Milan, 20133, Italy. FAU - Menichetti, Gianluca AU - Menichetti G AD - Laboratory of Molecular and Cellular Pharmacology of the Purinergic Transmission, Dipartimento di Scienze Farmacologiche e Biomolecolari, Universita degli Studi di Milano, Via Balzaretti 9, Milan, 20133, Italy. FAU - Fumagalli, Marta AU - Fumagalli M AD - Laboratory of Molecular and Cellular Pharmacology of the Purinergic Transmission, Dipartimento di Scienze Farmacologiche e Biomolecolari, Universita degli Studi di Milano, Via Balzaretti 9, Milan, 20133, Italy. FAU - Gelosa, Paolo AU - Gelosa P AD - Centro Cardiologico Monzino, Via Parea, 4, Milano, 20138, Italy. FAU - Dimou, Leda AU - Dimou L AD - Molecular and Translational Neuroscience, University of Ulm, Albert-Einstein-Allee 11, Ulm, D - 89081, Germany. FAU - Furlan, Roberto AU - Furlan R AD - Institute of Experimental Neurology, S. Raffaele Scientific Institute, Via Olgettina, 58, Milano, 20132, Italy. FAU - Lecca, Davide AU - Lecca D AD - Laboratory of Molecular and Cellular Pharmacology of the Purinergic Transmission, Dipartimento di Scienze Farmacologiche e Biomolecolari, Universita degli Studi di Milano, Via Balzaretti 9, Milan, 20133, Italy. FAU - Abbracchio, Maria P AU - Abbracchio MP AUID- ORCID: 0000-0002-7833-3388 AD - Laboratory of Molecular and Cellular Pharmacology of the Purinergic Transmission, Dipartimento di Scienze Farmacologiche e Biomolecolari, Universita degli Studi di Milano, Via Balzaretti 9, Milan, 20133, Italy. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180209 PL - United States TA - Glia JT - Glia JID - 8806785 RN - 0 (GPR17 protein, mouse) RN - 0 (Myelin-Oligodendrocyte Glycoprotein) RN - 0 (Nerve Tissue Proteins) RN - 0 (Peptide Fragments) RN - 0 (Receptors, G-Protein-Coupled) RN - 0 (enhanced green fluorescent protein) RN - 0 (myelin oligodendrocyte glycoprotein (35-55)) RN - 147336-22-9 (Green Fluorescent Proteins) RN - 5N16U7E0AO (Cuprizone) SB - IM MH - Animals MH - Cuprizone MH - Demyelinating Diseases/*metabolism/pathology MH - Disease Models, Animal MH - Female MH - Green Fluorescent Proteins/genetics/metabolism MH - Male MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Myelin-Oligodendrocyte Glycoprotein MH - Nerve Tissue Proteins/*metabolism MH - Oligodendrocyte Precursor Cells/*metabolism/pathology MH - Peptide Fragments MH - Receptors, G-Protein-Coupled/*metabolism MH - Remyelination/physiology MH - Spinal Cord/metabolism/pathology PMC - PMC5900886 OTO - NOTNLM OT - G protein-coupled receptor OT - animal models OT - differentiation OT - multiple sclerosis OT - oligodendrocyte precursor cells EDAT- 2018/02/10 06:00 MHDA- 2018/10/26 06:00 PMCR- 2018/04/16 CRDT- 2018/02/10 06:00 PHST- 2017/09/22 00:00 [received] PHST- 2018/01/13 00:00 [revised] PHST- 2018/01/29 00:00 [accepted] PHST- 2018/02/10 06:00 [pubmed] PHST- 2018/10/26 06:00 [medline] PHST- 2018/02/10 06:00 [entrez] PHST- 2018/04/16 00:00 [pmc-release] AID - GLIA23305 [pii] AID - 10.1002/glia.23305 [doi] PST - ppublish SO - Glia. 2018 May;66(5):1118-1130. doi: 10.1002/glia.23305. Epub 2018 Feb 9.