Folic acid stimulates proliferation of transplanted neural stem cells after focal cerebral ischemia in rats.

Folic acid (FA) stimulates neural stem cell (NSC) proliferation in vitro and enhances hippocampal neurogenesis in rats after middle cerebral artery occlusion (MCAO). The effect of FA supplementation on exogenous NSCs transplanted in MCAO rats was observed to determine if FA can stimulate NSC replacement after focal cerebral ischemia. Rats were randomly assigned to 3 groups: MCAO; MCAO and exogenous NSC transplantation (MCAO+NSCs); and MCAO, NSC transplantation and FA (MCAO+NSCs+FA). FA (0.8 mg/kg) or vehicle was administered by gavage daily for 28 days before MCAO and 23 days afterward. NSCs were labeled with superparamagnetic iron oxide (SPIO) and bromodeoxyuridine (BrdU) prior to transplantation into the striatum, contralateral to the ischemic zone, at 2 days post-MCAO. Magnetic resonance imaging tracking and fluorescent immunohistochemistry, as well as measurement of serum folate concentration, were performed at intervals up to 21 days after transplantation. FA supplementation caused sustained increases of 400-600% in serum folate concentration. Magnetic resonance images indicated that SPIO-labeled NSCs were more abundant at the transplantation and ischemic brain sites in MCAO+NSCs+FA rats than in MCAO+NSCs rats. Similarly, immunohistochemistry showed that the numbers of Sox-2/BrdU double positive cells at the transplantation and ischemic sites were higher in the rats that received FA. In conclusion, after focal cerebral ischemia, FA supplementation stimulates transplanted NSCs to proliferate and migrate to ischemic sites.

[1]  Charles Tator,et al.  Effects of Dibutyryl Cyclic-AMP on Survival and Neuronal Differentiation of Neural Stem/Progenitor Cells Transplanted into Spinal Cord Injured Rats , 2011, PloS one.

[2]  O. Lindvall,et al.  Stem Cell Research in Stroke: How Far From the Clinic? , 2011, Stroke.

[3]  Huan Liu,et al.  Folic Acid Supplementation Stimulates Notch Signaling and Cell Proliferation in Embryonic Neural Stem Cells , 2010, Journal of clinical biochemistry and nutrition.

[4]  Xiping Xu,et al.  EFFICACY OF FOLIC ACID SUPPLEMENTATION IN STROKE PREVENTION: NEW INSIGHT FROM A META-ANALYSIS , 2012, Heart.

[5]  D. Xavier,et al.  Antiplatelet therapy and the effects of B vitamins in patients with previous stroke or transient ischaemic attack: a post-hoc subanalysis of VITATOPS, a randomised, placebo-controlled trial , 2012, The Lancet Neurology.

[6]  R. Moats,et al.  Iron Labeling and Pre-Clinical MRI Visualization of Therapeutic Human Neural Stem Cells in a Murine Glioma Model , 2009, PloS one.

[7]  Youngju Kim,et al.  MRI tracking of intravenously transplanted human neural stem cells in rat focal ischemia model , 2009, Neuroscience Research.

[8]  Yu Tian Wang,et al.  Neural progenitor cells attenuate inflammatory reactivity and neuronal loss in an animal model of inflamed AD brain , 2009, Journal of Neuroinflammation.

[9]  Michael Chopp,et al.  Longitudinal Magnetic Resonance Imaging of Sildenafil Treatment of Embolic Stroke in Aged Rats , 2011, Stroke.

[10]  Lin Xie,et al.  Transplantation of Human Neural Precursor Cells in Matrigel Scaffolding Improves Outcome from Focal Cerebral Ischemia after Delayed Postischemic Treatment in Rats , 2010, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[11]  J. Bulte,et al.  Long‐term MR cell tracking of neural stem cells grafted in immunocompetent versus immunodeficient mice reveals distinct differences in contrast between live and dead cells , 2011, Magnetic resonance in medicine.

[12]  M. Palkovits,et al.  Bone marrow-derived nonreactive astrocytes in the mouse brain after permanent middle cerebral artery occlusion. , 2011, Stem cells and development.

[13]  T. Bliss,et al.  Optimizing the success of cell transplantation therapy for stroke , 2010, Neurobiology of Disease.

[14]  Guowei Huang,et al.  Folic acid enhances Notch signaling, hippocampal neurogenesis, and cognitive function in a rat model of cerebral ischemia , 2012, Nutritional neuroscience.

[15]  M. Neri,et al.  Efficient In Vitro Labeling of Human Neural Precursor Cells with Superparamagnetic Iron Oxide Particles: Relevance for In Vivo Cell Tracking , 2008, Stem cells.

[16]  R. Finnell,et al.  Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation. , 2010, The Journal of clinical investigation.

[17]  Xiping Xu,et al.  EFFICACY OF FOLIC ACID SUPPLEMENTATION IN STROKE PREVENTION: NEW INSIGHT FROM A META-ANALYSIS , 2012, Heart.

[18]  D. Resnick,et al.  Folic acid supplementation enhances repair of the adult central nervous system , 2004, Annals of neurology.

[19]  R. Traystman.  Stem Cell Research in Stroke How Far From the Clinic ? , 2011 .