Focal cerebral ischemia induces a multilineage cytogenic response from adult subventricular zone that is predominantly gliogenic.
The purpose of this study was to ascertain the relative contribution of neural stem/progenitor cells (NSPCs) of the subventricular zone (SVZ) to lineages that repopulate the injured striatum following focal ischemia. We utilized a tamoxifen-inducible Cre/loxP system under control of the nestin promoter, which provides permanent YFP labeling of multipotent nestin(+) SVZ-NSPCs prior to ischemic injury and continued YFP expression in all subsequent progeny following stroke. YFP reporter expression was induced in adult male nestin-CreER(T2):R26R-YFP mice by tamoxifen administration (180 mg kg(-1), daily for 5 days). Fourteen days later, mice were subjected to 60-min transient middle cerebral artery occlusion (MCAO) and sacrificed at 2 days, 2 weeks, or 6 weeks post-MCAO for phenotypic fate mapping of YFP(+) cells using lineage-specific markers. Migration of YFP(+) cells from SVZ into the injured striatal parenchyma was apparent at 2 and 6 weeks, but not 2 days, post-MCAO. At 2 weeks post-MCAO, the average percent distribution of YFP(+) cells within the injured striatal parenchyma was as follows: 10% Dcx(+) neuroblasts, 15-20% oligodendrocyte progenitors, 59% GFAP(+) astrocytes, and only rare NeuN(+) postmitotic neurons. A similar phenotypic distribution was observed at 6 weeks, except for an increased average percentage of YFP(+) cells that expressed Dcx(+) (20%) or NeuN (5%). YFP(+) cells did not express endothelial markers, but displayed unique anatomical relationships with striatal vasculature. These results indicate that nestin(+) NSPCs within the SVZ mount a multilineage response to stroke that includes a gliogenic component more predominant than previously appreciated.
Li
Lu
L
Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, NM 87131-0001, USA.
Harms
Kate M
KM
Ventura
P Britten
PB
Lagace
Diane C
DC
Eisch
Amelia J
AJ
Cunningham
Lee Anna
LA
D053687:Adult Stem Cells / Q000502:physiology*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D002552:Cerebral Ventricles / Q000473:pathology*; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D004965:Estrogen Antagonists / Q000627:therapeutic use; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000473:pathology*; D007381:Intermediate Filament Proteins / Q000235:genetics; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D064231:Nestin; D009474:Neurons / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000378:metabolism*; D013629:Tamoxifen / Q000627:therapeutic use
D051792:Basic Helix-Loop-Helix Proteins; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D004965:Estrogen Antagonists; D007381:Intermediate Filament Proteins; D008164:Luminescent Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D064231:Nestin; D009479:Neuropeptides; D000076104:Oligodendrocyte Transcription Factor 2; D013629:Tamoxifen; C000714847:Dcx protein, mouse; C577485:Nes protein, mouse; C512773:Olig2 protein, mouse