The Notch pathway mediates expansion of a progenitor pool and neuronal differentiation in adult neural progenitor cells after stroke.
Molecular mechanisms by which stroke increases neurogenesis have not been fully investigated. Using neural progenitor cells isolated from the subventricular zone (SVZ) of the adult rat subjected to focal cerebral ischemia, we investigated the Notch pathway in regulating proliferation and differentiation of adult neural progenitor cells after stroke. During proliferation of neural progenitor cells, ischemic neural progenitor cells exhibited substantially increased levels of Notch, Notch intracellular domain (NICD), and hairy enhancer of split (Hes) 1, which was associated with a significant increase of proliferating cells. Blockage of the Notch pathway by short interfering ribonucleic acid (siRNA) against Notch or a gamma secretase inhibitor significantly reduced Notch, NICD and Hes1 expression and cell proliferation induced by stroke. During differentiation of neural progenitor cells, Notch and Hes1 expression was downregulated in ischemic neural progenitor cells, which was coincident with a significant increase of neuronal population. Inhibition of the Notch pathway with a gamma secretase inhibitor further substantially increased neurons, but did not alter astrocyte population in ischemic neural progenitor cells. These data suggest that the Notch signaling pathway mediates adult SVZ neural progenitor cell proliferation and differentiation after stroke.
Wang
L
L
Department of Neurology, Henry Ford Health Sciences Center, Detroit, MI 48202, USA.
Chopp
M
M
Zhang
R L
RL
Zhang
L
L
Letourneau
Y
Y
Feng
Y F
YF
Jiang
A
A
Morris
D C
DC
Zhang
Z G
ZG
D053687:Adult Stem Cells / Q000473:pathology*; D000704:Analysis of Variance; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002552:Cerebral Ventricles / Q000473:pathology*; D015870:Gene Expression / Q000187:drug effects; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology*; D053605:Leukemia Inhibitory Factor / Q000378:metabolism; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D014280:Triglycerides; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives
D053605:Leukemia Inhibitory Factor; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051880:Receptors, Notch; D014280:Triglycerides; D005680:gamma-Aminobutyric Acid; C057077:1,2-dilinolenoyl-3-(4-aminobutyryl)propane-1,2,3-triol; D001973:Bromodeoxyuridine