Long-term accumulation of microglia with proneurogenic phenotype concomitant with persistent neurogenesis in adult subventricular zone after stroke.
Neural stem cells (NSCs) in the adult rat subventricular zone (SVZ) generate new striatal neurons during several months after ischemic stroke. Whether the microglial response associated with ischemic injury extends into SVZ and influences neuroblast production is unknown. Here, we demonstrate increased numbers of activated microglia in ipsilateral SVZ concomitant with neuroblast migration into the striatum at 2, 6, and 16 weeks, with maximum at 6 weeks, following 2 h middle cerebral artery occlusion in rats. In the peri-infarct striatum, numbers of activated microglia peaked already at 2 weeks and declined thereafter. Microglia in SVZ were resident or originated from bone marrow, with maximum proliferation during the first 2 weeks postinsult. In SVZ, microglia exhibited ramified or intermediate morphology, signifying a downregulated inflammatory profile, whereas amoeboid or round phagocytic microglia were frequent in the peri-infarct striatum. Numbers of microglia expressing markers of antigen-presenting cells (MHC-II, CD86) increased in SVZ but very few lymphocytes were detected. Using quantitative PCR, strong short- and long-term increase (at 1 and 6 weeks postinfarct) of insulin-like growth factor-1 (IGF-1) gene expression was detected in SVZ tissue. Elevated numbers of IGF-1-expressing microglia were found in SVZ at 2, 6, and 16 weeks after stroke. At 16 weeks, 5% of microglia but no other cells in SVZ expressed the IGF-1 protein, which mitigates apoptosis and promotes proliferation and differentiation of NSCs. The long-term accumulation of microglia with proneurogenic phenotype in the SVZ implies a supportive role of these cells for the continuous neurogenesis after stroke.
Thored
Pär
P
Laboratory of Neurogenesis and Cell Therapy, Section of Restorative Neurology, Wallenberg Neuroscience Center A11, University Hospital, Lund, Sweden.
Heldmann
Ursula
U
Gomes-Leal
Walace
W
Gisler
Ramiro
R
Darsalia
Vladimer
V
Taneera
Jalal
J
Nygren
Jens M
JM
Jacobsen
Sten-Eirik W
SE
Ekdahl
Christine T
CT
Kokaia
Zaal
Z
Lindvall
Olle
O
D000704:Analysis of Variance; D000818:Animals; D000938:Antigen-Presenting Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000379:methods; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000528:radiation effects; D003342:Corpus Striatum / Q000503:physiopathology; D004195:Disease Models, Animal; D053331:Ectodysplasins / Q000235:genetics / Q000378:metabolism; D007839:Functional Laterality; D049452:Green Fluorescent Proteins / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D020547:Lateral Ventricles / Q000503:physiopathology*; D017493:Leukocyte Common Antigens / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D017628:Microglia / Q000378:metabolism / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology*; D010641:Phenotype; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000473:pathology* / Q000503:physiopathology / Q000601:surgery*; D013997:Time Factors
C100745:Aif1 protein, rat; D002135:Calcium-Binding Proteins; D053331:Ectodysplasins; C506019:Eda protein, mouse; D008840:Microfilament Proteins; D049452:Green Fluorescent Proteins; D007334:Insulin-Like Growth Factor I; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse