Focused ultrasound-induced stimulation of microbubbles augments site-targeted engraftment of mesenchymal stem cells after acute myocardial infarction.
Intravascular transplantation of bone marrow-derived mesenchymal stem cells (MSCs) is a promising therapeutic approach after acute myocardial infarction. Efficacy and targeting of myocardial cell engraftment are crucial variables determining the therapeutic value of MSC transplantation. Highly focused ultrasound-mediated stimulation of microbubbles (hf-UMS) allows locoregional pre-treatment of target tissue. In a "proof of concept" study, we investigated augmentation of site-targeted MSC engraftment with hf-UMS. We further evaluated the ability of transplanted MSCs to transmigrate across the endothelial barrier into non-ischemic and post-ischemic myocardium in vivo. After acute myocardial ischemia and reperfusion, rats received hf-UMS focused on the anterior left-ventricular wall followed by intravascular transplantation of MSCs. Global and regional myocardial engraftment of MSCs was quantified by means of confocal laser-scanning microscopy; endothelial adhesion, transendothelial migration and invasion of basement membrane were distinguished. Targeted myocardium exhibited higher amount of transplanted MSCs vs. non-targeted tissue. The rate of transendothelial migration was lowest in non-ischemic (41.2+/-2%) compared to post-ischemic myocardium (53+/-5.7%, p<0.01). Hf-UMS significantly increased the transmigration rate to 50+/-6.1% (p<0.05) and 64+/-8.9% (p<0.05), respectively. Additionally, myocardial segments exposed to hf-UMS revealed an onset of protease activity. Signs of undesired biological effects, such as induction of apoptosis and/or myocardial necrosis were not observed. This study provides the first evidence of the migration of MSCs across the myocardial endothelium in vivo. Hf-UMS not only improves myocardial engraftment of MSCs but also allows locoregional targeting of post-ischemic myocardium.
Ghanem
Alexander
A
Department of Medicine/Cardiology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany. ghanem@uni-bonn.de
Steingen
Caroline
C
Brenig
Florian
F
Funcke
Fabienne
F
Bai
Zhi-Yong
ZY
Hall
Christopher
C
Chin
Chien Ting
CT
Nickenig
Georg
G
Bloch
Wilhelm
W
Tiemann
Klaus
K
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006321:Heart / Q000502:physiology; D007150:Immunohistochemistry / Q000379:methods; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D045423:Microbubbles; D018613:Microscopy, Confocal / Q000379:methods; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology*; D009206:Myocardium / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury; D014463:Ultrasonography / Q000379:methods*
D016207:Cytokines