title: Adrenomedullin enhances therapeutic potency of mesenchymal stem cells after experimental stroke in rats.
abstract: OBJECTIVE
  Adrenomedullin (AM) induces angiogenesis and inhibits cell apoptosis through the phosphatidylinositol 3-kinase/Akt pathway. Transplantation of mesenchymal stem cells (MSCs) has been shown to improve neurological deficits after stroke in rats. We investigated whether AM enhances the therapeutic potency of MSC transplantation.
  
  
  METHODS
  Male Lewis rats (n=100) were subjected to 2-hour middle cerebral artery occlusion. Immediately after reperfusion, rats were assigned randomly to receive intravenous transplantation of MSCs plus subcutaneous infusion of AM for 7 days (MSC+AM group), AM infusion alone (AM group), MSC transplantation alone (MSC group), or vehicle infusion (control group). Neurological and immunohistological assessments were performed to examine the effects of these treatments.
  
  
  RESULTS
  Some engrafted MSCs were positive for neuronal and endothelial cell markers, although the number of differentiated MSCs did not differ significantly between the MSC and MSC+AM groups. The neurological score significantly improved in the MSC, AM, and MSC+AM groups compared with the control group. Importantly, improvement in the MSC+AM group was significantly greater than that in the MSC and AM groups. There was marked induction of angiogenesis in the ischemic penumbra in the MSC+AM group, followed by the AM, MSC, and control groups. AM infusion significantly inhibited apoptosis of transplanted MSCs. As a result, the number of engrafted MSCs in the MSC+AM group was significantly higher than that in the MSC group.
  
  
  CONCLUSIONS
  AM enhanced the therapeutic potency of MSCs, including neurological improvement, possibly through inhibition of MSC apoptosis and induction of angiogenesis.
authors.affiliation: Department of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, Suita, Osaka, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Hanabusa
authors.forename: Noritoshi
authors.initials: N
authors.lastname: Nagaya
authors.forename: Takashi
authors.initials: T
authors.lastname: Iwase
authors.forename: Takefumi
authors.initials: T
authors.lastname: Itoh
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Murakami
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Waro
authors.initials: W
authors.lastname: Taki
authors.forename: Kunio
authors.initials: K
authors.lastname: Miyatake
authors.forename: Kenji
authors.initials: K
authors.lastname: Kangawa
mesh_terms: D053607:Adrenomedullin; D000818:Animals; D017209:Apoptosis; D001835:Body Weight; D017690:Cell Transplantation; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy; D007511:Ischemia; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D009389:Neovascularization, Pathologic; D009474:Neurons / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D013234:Stem Cells / Q000166:cytology; D020521:Stroke / Q000188:drug therapy*; D013997:Time Factors
chemical_list: D010455:Peptides; D053607:Adrenomedullin; D019869:Phosphatidylinositol 3-Kinases