Chi3l3 induces oligodendrogenesis in an experimental model of autoimmune neuroinflammation

Sarah C. Starossom (), Juliana Campo Garcia, Tim Woelfle, Silvina Romero-Suarez, Marta Olah, Fumihiro Watanabe, Li Cao, Ada Yeste, John J. Tukker, Francisco J. Quintana, Jaime Imitola, Franziska Witzel, Dietmar Schmitz, Markus Morkel, Friedemann Paul, Carmen Infante-Duarte and Samia J. Khoury
Additional contact information
Sarah C. Starossom: Charité – Universitätsmedizin Berlin
Juliana Campo Garcia: Charité – Universitätsmedizin Berlin
Tim Woelfle: Charité – Universitätsmedizin Berlin
Silvina Romero-Suarez: Charité – Universitätsmedizin Berlin
Marta Olah: Brigham and Women’s Hospital, Harvard Medical School
Fumihiro Watanabe: Laboratory of Neural Stem Cells and Functional Neurogenetics, Department of Neurology-The Ohio State University Wexner Medical Center
Li Cao: Brigham and Women’s Hospital, Harvard Medical School
Ada Yeste: Brigham and Women’s Hospital, Harvard Medical School
John J. Tukker: Charité – Universitätsmedizin Berlin
Francisco J. Quintana: Brigham and Women’s Hospital, Harvard Medical School
Jaime Imitola: Brigham and Women’s Hospital, Harvard Medical School
Franziska Witzel: Computational Modeling in Medicine, Charité– Universitätsmedizin Berlin
Dietmar Schmitz: Charité - Universitätsmedizin Berlin
Markus Morkel: Charité – Universitätsmedizin Berlin
Friedemann Paul: Max Delbrueck Center for Molecular Medicine and Charité - Universitätsmedizin Berlin
Carmen Infante-Duarte: Charité – Universitätsmedizin Berlin
Samia J. Khoury: Brigham and Women’s Hospital, Harvard Medical School

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-08140-7

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