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

TY - JOUR

T1 - MANF Promotes Differentiation and Migration of Neural Progenitor Cells with Potential Neural Regenerative Effects in Stroke

AU - Tseng, Kuan-Yin

AU - Anttila, Jenni E

AU - Khodosevich, Konstantin

AU - Tuominen, Raimo K

AU - Lindahl, Maria

AU - Domanskyi, Andrii

AU - Airavaara, Mikko

N1 - Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

PY - 2018/1/3

Y1 - 2018/1/3

N2 - 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. After a stroke, there are endogenous reparative processes in the brain, but they are not sufficient to repair damaged tissue. We demonstrate that MANF is an essential element for regulating migration of neuroprogenitor cells and identified a signaling pathway of STAT3 to mediate MANF's effects of increasing the regenerative capacity.

AB - 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. After a stroke, there are endogenous reparative processes in the brain, but they are not sufficient to repair damaged tissue. We demonstrate that MANF is an essential element for regulating migration of neuroprogenitor cells and identified a signaling pathway of STAT3 to mediate MANF's effects of increasing the regenerative capacity.

KW - Journal Article

U2 - 10.1016/j.ymthe.2017.09.019

DO - 10.1016/j.ymthe.2017.09.019

M3 - Journal article

C2 - 29050872

SN - 1525-0016

VL - 26

SP - 238

EP - 255

JO - Molecular therapy : the journal of the American Society of Gene Therapy

JF - Molecular therapy : the journal of the American Society of Gene Therapy

IS - 1

ER -