Suppression of stroke-induced progenitor proliferation in adult subventricular zone by tumor necrosis factor receptor 1.
Stroke induced by middle cerebral artery occlusion leads to transiently increased progenitor proliferation in the subventricular zone (SVZ) and long-lasting striatal neurogenesis in adult rodents. Tumor necrosis factor-alpha (TNF-alpha) is upregulated in stroke-damaged brain. Whether TNF-alpha and its receptors influence SVZ progenitor proliferation after stroke is unclear. Here we show that the increased proliferation 1 week after stroke occurred concomitantly with elevated microglia numbers and TNF-alpha and TNF receptor-1 (TNF-R1) gene expression in the SVZ of wild-type mice. TNF receptor-1 was expressed on sorted SVZ progenitor cells from nestin-green fluorescent protein reporter mice. In animals lacking TNF-R1, stroke-induced SVZ cell proliferation and neuroblast formation were enhanced. In contrast, deletion of TNF-R1 did not alter basal or status epilepticus-stimulated cell proliferation in SVZ. Addition of TNF-alpha reduced the size and numbers of SVZ neurospheres through a TNF-R1-dependent mechanism without affecting cell survival. Our results provide the first evidence that TNF-R1 is a negative regulator of stroke-induced SVZ progenitor proliferation. Blockade of TNF-R1 signaling might be a novel strategy to promote the proliferative response in SVZ after stroke.
Iosif
Robert E
RE
Laboratory of Neurogenesis and Cell Therapy, Section of Restorative Neurology, Wallenberg Neuroscience Center, University Hospital, Lund, Sweden.
Ahlenius
Henrik
H
Ekdahl
Christine T
CT
Darsalia
Vladimer
V
Thored
Pär
P
Jovinge
Stefan
S
Kokaia
Zaal
Z
Lindvall
Olle
O
D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival; D020244:Infarction, Middle Cerebral Artery; D020547:Lateral Ventricles; D051379:Mice; D018345:Mice, Knockout; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology*; D020521:Stroke / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha