title: Focused ultrasound-induced stimulation of microbubbles augments site-targeted engraftment of mesenchymal stem cells after acute myocardial infarction.
abstract: 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.
authors.affiliation: Department of Medicine/Cardiology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany. ghanem@uni-bonn.de
authors.forename: Alexander
authors.initials: A
authors.lastname: Ghanem
authors.forename: Caroline
authors.initials: C
authors.lastname: Steingen
authors.forename: Florian
authors.initials: F
authors.lastname: Brenig
authors.forename: Fabienne
authors.initials: F
authors.lastname: Funcke
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Bai
authors.forename: Christopher
authors.initials: C
authors.lastname: Hall
authors.forename: Chien Ting
authors.initials: CT
authors.lastname: Chin
authors.forename: Georg
authors.initials: G
authors.lastname: Nickenig
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Bloch
authors.forename: Klaus
authors.initials: K
authors.lastname: Tiemann
mesh_terms: 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*
chemical_list: D016207:Cytokines