title: Mesenchymal stem cells primed with valproate and lithium robustly migrate to infarcted regions and facilitate recovery in a stroke model.
abstract: OBJECTIVE
  The migratory efficiency of mesenchymal stem cells (MSC) toward cerebral infarct after transplantation is limited. Valproate (VPA) and lithium enhance in vitro migration of MSC by upregulating CXC chemokine receptor 4 and matrix metalloproteinase-9, respectively. Ability of VPA and lithium to promote MSC homing and to improve functional recovery was assessed in a rat model of cerebral ischemia.
  
  
  METHODS
  MSC primed with VPA (2.5 mmol/L, 3 hours) and/or lithium chloride (2.5 mmol/L, 24 hours) were transplanted into rats 24 hours after transient middle cerebral artery occlusion (MCAO). Neurological function was assessed via rotarod test, Neurological Severity Score, and body asymmetry test for 2 weeks. Infarct volume was analyzed by MRI. The number of homing MSC and microvessel density in the infarcted regions were measured 15 days after MCAO using immunohistochemistry.
  
  
  RESULTS
  Priming with VPA or lithium increased the number of MSC homing to the cerebral infarcted regions, and copriming with VPA and lithium further enhanced this effect. MCAO rats receiving VPA-primed and/or lithium-primed MSC showed improved functional recovery, reduced infarct volume, and enhanced angiogenesis in the infarcted penumbra regions. These beneficial effects of VPA or lithium priming were reversed by AMD3100, a CXC chemokine receptor 4 antagonist, and GM6001, a matrix metalloproteinase inhibitor, respectively.
  
  
  CONCLUSIONS
  Priming with VPA and/or lithium promoted the homing and migration ability of MSC, improved functional recovery, reduced brain infarct volume, and enhanced angiogenesis in a rat MCAO model. These effects were likely mediated by VPA-induced CXC chemokine receptor 4 overexpression and lithium-induced matrix metalloproteinase-9 upregulation.
authors.affiliation: Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, 10 Center Dr, MSC 1363, Bethesda, MD 20892-1363, USA.
authors.forename: Li-Kai
authors.initials: LK
authors.lastname: Tsai
authors.forename: Zhifei
authors.initials: Z
authors.lastname: Wang
authors.forename: Jeeva
authors.initials: J
authors.lastname: Munasinghe
authors.forename: Yan
authors.initials: Y
authors.lastname: Leng
authors.forename: Peter
authors.initials: P
authors.lastname: Leeds
authors.forename: De-Maw
authors.initials: DM
authors.lastname: Chuang
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism* / Q000628:therapy; D008094:Lithium / Q000494:pharmacology*; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D020127:Recovery of Function; D020521:Stroke / Q000378:metabolism* / Q000628:therapy; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D014635:Valproic Acid; D008094:Lithium