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Mol Ther. 2018 Jan 3;26(1):238-255. doi: 10.1016/j.ymthe.2017.09.019. Epub 2017 Sep 21.

MANF Promotes Differentiation and Migration of Neural Progenitor Cells with Potential Neural Regenerative Effects in Stroke.

Author information

1
Institute of Biotechnology, HiLIFE Unit, University of Helsinki, Helsinki, Finland; Department of Neurological Surgery, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan.
2
Institute of Biotechnology, HiLIFE Unit, University of Helsinki, Helsinki, Finland.
3
Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
4
Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
5
Institute of Biotechnology, HiLIFE Unit, University of Helsinki, Helsinki, Finland. Electronic address: mikko.airavaara@helsinki.fi.

Abstract

Cerebral ischemia activates endogenous reparative processes, such as increased proliferation of neural stem cells (NSCs) in the subventricular zone (SVZ) and migration of neural progenitor cells (NPCs) toward the ischemic area. However, this reparative process is limited because most of the NPCs die shortly after injury or are unable to arrive at the infarct boundary. In this study, we demonstrate for the first time that endogenous mesencephalic astrocyte-derived neurotrophic factor (MANF) protects NSCs against oxygen-glucose-deprivation-induced injury and has a crucial role in regulating NPC migration. In NSC cultures, MANF protein administration did not affect growth of cells but triggered neuronal and glial differentiation, followed by activation of STAT3. In SVZ explants, MANF overexpression facilitated cell migration and activated the STAT3 and ERK1/2 pathway. Using a rat model of cortical stroke, intracerebroventricular injections of MANF did not affect cell proliferation in the SVZ, but promoted migration of doublecortin (DCX)+ cells toward the corpus callosum and infarct boundary on day 14 post-stroke. Long-term infusion of MANF into the peri-infarct zone increased the recruitment of DCX+ cells in the infarct area. In conclusion, our data demonstrate a neuroregenerative activity of MANF that facilitates differentiation and migration of NPCs, thereby increasing recruitment of neuroblasts in stroke cortex.

KEYWORDS:

Armet; Armetl1; cdnf; cerebral dopamine-derived neurotrophic factor; manf; mesencephalic astrocyte-derived neurotrophic factor; neuroblast; neurogenesis; neuronal migration

PMID:
29050872
PMCID:
PMC5763030
[Available on 2019-01-03]
DOI:
10.1016/j.ymthe.2017.09.019
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