Adrenomedullin enhances therapeutic potency of mesenchymal stem cells after experimental stroke in rats.
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.
Hanabusa
Kenichiro
K
Department of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, Suita, Osaka, Japan.
Nagaya
Noritoshi
N
Iwase
Takashi
T
Itoh
Takefumi
T
Murakami
Shinsuke
S
Shimizu
Yoshito
Y
Taki
Waro
W
Miyatake
Kunio
K
Kangawa
Kenji
K
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
D010455:Peptides; D053607:Adrenomedullin; D019869:Phosphatidylinositol 3-Kinases