Abstract

In demyelinating diseases including multiple sclerosis (MS), neural stem cells (NSCs) can replace damaged oligodendrocytes if the local microenvironment supports the required differentiation process. Although chitinase-like proteins (CLPs) form part of this microenvironment, their function in this differentiation process is unknown. Here, we demonstrate that murine Chitinase 3-like-3 (Chi3l3/Ym1), human Chi3L1 and Chit1 induce oligodendrogenesis. In mice, Chi3l3 is highly expressed in the subventricular zone, a stem cell niche of the adult brain, and in inflammatory brain lesions during experimental autoimmune encephalomyelitis (EAE). We find that silencing Chi3l3 increases severity of EAE. We present evidence that in NSCs Chi3l3 activates the epidermal growth factor receptor (EGFR), thereby inducing Pyk2-and Erk1/2- dependent expression of a pro-oligodendrogenic transcription factor signature. Our results implicate CLP-EGFR-Pyk2-MEK-ERK as a key intrinsic pathway controlling oligodendrogenesis.

Chitinase 3-like-3 (Chi3l3) is expressed in microglia, but its function is not clear. Here the authors show that Chi3l3 is expressed in the subventricular zone in mouse experimental immune encephalitis, which induces oligodendrogenesis.

Details

Title
Chi3l3 induces oligodendrogenesis in an experimental model of autoimmune neuroinflammation
Author
Starossom, Sarah C 1 ; Campo Garcia Juliana 2 ; Woelfle, Tim 2 ; Romero-Suarez, Silvina 2 ; Olah, Marta 3 ; Watanabe Fumihiro 4 ; Cao, Li 5 ; Yeste Ada 5 ; Tukker John J 6   VIAFID ORCID Logo  ; Quintana, Francisco J 3 ; Imitola Jaime 7   VIAFID ORCID Logo  ; Witzel Franziska 8 ; Schmitz, Dietmar 9 ; Morkel, Markus 10   VIAFID ORCID Logo  ; Friedemann, Paul 11 ; Infante-Duarte, Carmen 2 ; Khoury, Samia J 12 

1  Charité – Universitätsmedizin Berlin, Institute for Medical Immunology, Berlin, Germany (GRID:grid.6363.0) (ISNI:0000 0001 2218 4662) ; Max Delbrueck Center for Molecular Medicine and Charité - Universitätsmedizin Berlin, Experimental and Clinical Research Center, Berlin, Germany (GRID:grid.419491.0) (ISNI:0000 0001 1014 0849) ; Charité - Universitätsmedizin Berlin, NeuroCure Clinical Research Center, Berlin, Germany (GRID:grid.6363.0) (ISNI:0000 0001 2218 4662) ; Brigham and Women’s Hospital, Harvard Medical School, Center for Neurologic Diseases, Department of Neurology, Boston, USA (GRID:grid.6363.0) 
2  Charité – Universitätsmedizin Berlin, Institute for Medical Immunology, Berlin, Germany (GRID:grid.6363.0) (ISNI:0000 0001 2218 4662) 
3  Brigham and Women’s Hospital, Harvard Medical School, Center for Neurologic Diseases, Department of Neurology, Boston, USA (GRID:grid.6363.0) 
4  Laboratory of Neural Stem Cells and Functional Neurogenetics, Department of Neurology-The Ohio State University Wexner Medical Center, Columbus, USA (GRID:grid.412332.5) (ISNI:0000 0001 1545 0811) 
5  Brigham and Women’s Hospital, Harvard Medical School, Center for Neurologic Diseases, Department of Neurology, Boston, USA (GRID:grid.412332.5) 
6  Charité – Universitätsmedizin Berlin, Neuroscience Research Center (NWFZ), Berlin, Germany (GRID:grid.6363.0) (ISNI:0000 0001 2218 4662) ; Charité – Universitätsmedizin Berlin, DZNE-German Center for Neurodegenerative Diseases, Berlin, Germany (GRID:grid.6363.0) (ISNI:0000 0001 2218 4662) 
7  Brigham and Women’s Hospital, Harvard Medical School, Center for Neurologic Diseases, Department of Neurology, Boston, USA (GRID:grid.6363.0) ; Laboratory of Neural Stem Cells and Functional Neurogenetics, Department of Neurology-The Ohio State University Wexner Medical Center, Columbus, USA (GRID:grid.412332.5) (ISNI:0000 0001 1545 0811) 
8  Computational Modeling in Medicine, Charité– Universitätsmedizin Berlin, IRI Life Sciences, Institute of Pathology, Berlin, Germany (GRID:grid.6363.0) (ISNI:0000 0001 2218 4662) 
9  Charité - Universitätsmedizin Berlin, NeuroCure Clinical Research Center, Berlin, Germany (GRID:grid.6363.0) (ISNI:0000 0001 2218 4662) ; Charité – Universitätsmedizin Berlin, Neuroscience Research Center (NWFZ), Berlin, Germany (GRID:grid.6363.0) (ISNI:0000 0001 2218 4662) ; Computational Modeling in Medicine, Charité– Universitätsmedizin Berlin, IRI Life Sciences, Institute of Pathology, Berlin, Germany (GRID:grid.6363.0) (ISNI:0000 0001 2218 4662) 
10  Charité – Universitätsmedizin Berlin, Institute of Pathology, Laboratory of Molecular Tumor Pathology and Systems Biology, Berlin, Germany (GRID:grid.6363.0) (ISNI:0000 0001 2218 4662) 
11  Max Delbrueck Center for Molecular Medicine and Charité - Universitätsmedizin Berlin, Experimental and Clinical Research Center, Berlin, Germany (GRID:grid.419491.0) (ISNI:0000 0001 1014 0849) ; Charité - Universitätsmedizin Berlin, NeuroCure Clinical Research Center, Berlin, Germany (GRID:grid.6363.0) (ISNI:0000 0001 2218 4662) ; Charité - Universitätsmedizin Berlin, Department of Neurology, Berlin, Germany (GRID:grid.6363.0) (ISNI:0000 0001 2218 4662) 
12  Brigham and Women’s Hospital, Harvard Medical School, Center for Neurologic Diseases, Department of Neurology, Boston, USA (GRID:grid.6363.0) ; American University of Beirut Medical Center, Abu Haidar Neuroscience Institute, Beirut, Lebanon (GRID:grid.411654.3) (ISNI:0000 0004 0581 3406) 
Publication year
2019
Publication date
Jan 2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-08140-7
ProQuest document ID
1915331059
Copyright
This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.