title: Development of a new therapeutic technique to direct stem cells to the infarcted heart using targeted microbubbles: StemBells.
abstract: Successful stem cell therapy after acute myocardial infarction (AMI) is hindered by lack of engraftment of sufficient stem cells at the site of injury. We designed a novel technique to overcome this problem by assembling stem cell-microbubble complexes, named 'StemBells'. StemBells were assembled through binding of dual-targeted microbubbles (~3μm) to adipose-derived stem cells (ASCs) via a CD90 antibody. StemBells were targeted to the infarct area via an ICAM-1 antibody on the microbubbles. StemBells were characterized microscopically and by flow cytometry. The effect of ultrasound on directing StemBells towards the vessel wall was demonstrated in an in vitro flow model. In a rat AMI-reperfusion model, StemBells or ASCs were injected one week post-infarction. A pilot study demonstrated feasibility of intravenous StemBell injection, resulting in localization in ICAM-1-positive infarct area three hours post-injection. In a functional study five weeks after injection of StemBells cardiac function was significantly improved compared with controls, as monitored by 2D-echocardiography. This functional improvement neither coincided with a reduction in infarct size as determined by histochemical analysis, nor with a change in anti- and pro-inflammatory macrophages. In conclusion, the StemBell technique is a novel and feasible method, able to improve cardiac function post-AMI in rats.
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands; Institute of Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Woudstra
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands; Institute of Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: P A J
authors.initials: PA
authors.lastname: Krijnen
authors.affiliation: Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands; Institute of Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: S J P
authors.initials: SJ
authors.lastname: Bogaards
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Meinster
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands; Institute of Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: R W
authors.initials: RW
authors.lastname: Emmens
authors.affiliation: Interuniversity Cardiology Institute of the Netherlands (ICIN), Utrecht, The Netherlands; Department of Biomedical Engineering, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: T J A
authors.initials: TJ
authors.lastname: Kokhuis
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands; Institute of Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: I A E
authors.initials: IA
authors.lastname: Bollen
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Baltzer
authors.affiliation: Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: S M T
authors.initials: SM
authors.lastname: Baart
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Parbhudayal
authors.affiliation: Department of Orthopedics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: M N
authors.initials: MN
authors.lastname: Helder
authors.affiliation: Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands; Institute of Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: V W M
authors.initials: VW
authors.lastname: van Hinsbergh
authors.affiliation: Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands; Institute of Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: R J P
authors.initials: RJ
authors.lastname: Musters
authors.affiliation: Interuniversity Cardiology Institute of the Netherlands (ICIN), Utrecht, The Netherlands; Department of Biomedical Engineering, Erasmus MC, Rotterdam, The Netherlands; Department of Acoustical Wavefield Imaging, Technical University of Delft, Delft, The Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: de Jong
authors.affiliation: Department of Cardiology, VU University Medical Center, Amsterdam, The Netherlands; Institute of Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands; Interuniversity Cardiology Institute of the Netherlands (ICIN), Utrecht, The Netherlands.
authors.forename: O
authors.initials: O
authors.lastname: Kamp
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands; Department of Cardiac Surgery, VU University Medical Center, Amsterdam, The Netherlands; Institute of Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: H W M
authors.initials: HW
authors.lastname: Niessen
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands; Institute of Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: van Dijk
authors.affiliation: Department of Cardiology, VU University Medical Center, Amsterdam, The Netherlands; Institute of Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands; Interuniversity Cardiology Institute of the Netherlands (ICIN), Utrecht, The Netherlands. Electronic address: ljm.juffermans@vumc.nl.
authors.forename: L J M
authors.initials: LJ
authors.lastname: Juffermans
mesh_terms: D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D061605:Administration, Intravenous; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004452:Echocardiography; D006321:Heart / Q000000981:diagnostic imaging / Q000503:physiopathology; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D045423:Microbubbles; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D010865:Pilot Projects; D051381:Rats; D017208:Rats, Wistar; D013010:Sonication; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; C067980:CD68 antigen, human; D000097382:CD68 Molecule
keywords: Acoustic radiation force; Acute myocardial infarction; Adipose tissue-derived stem cells; Microbubbles; StemBells; Targeting