Chi3l3 induces oligodendrogenesis in an experimental model of autoimmune neuroinflammation.
Sarah C StarossomJuliana Campo GarciaTim WoelfleSilvina Romero-SuarezMarta OlahFumihiro WatanabeLi CaoAda YesteJohn J TukkerFrancisco J QuintanaJaime ImitolaFranziska WitzelDietmar SchmitzMarkus MorkelFriedemann PaulCarmen Infante-DuarteSamia J KhouryPublished in: Nature communications (2019)
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.
Keyphrases
- epidermal growth factor receptor
- multiple sclerosis
- stem cells
- tyrosine kinase
- small cell lung cancer
- transcription factor
- white matter
- advanced non small cell lung cancer
- signaling pathway
- neural stem cells
- pi k akt
- endothelial cells
- resting state
- traumatic brain injury
- cerebral ischemia
- poor prognosis
- oxidative stress
- type diabetes
- ms ms
- functional connectivity
- skeletal muscle
- lps induced
- high fat diet induced
- drug induced