title: The cerebral embolism evoked by intra-arterial delivery of allogeneic bone marrow mesenchymal stem cells in rats is related to cell dose and infusion velocity.
abstract: BACKGROUND
  Intra-arterial cell infusion is an efficient delivery route with which to target organs such as the ischemic brain. However, adverse events including microembolisms and decreased cerebral blood flow were recently reported after intra-arterial cell delivery in rodent models, raising safety concerns. We tested the hypothesis that cell dose, infusion volume, and velocity would be related to the severity of complications after intra-arterial cell delivery.
  
  
  METHODS
  In this study, 38 rats were subjected to a sham middle cerebral artery occlusion (sham-MCAO) procedure before being infused with allogeneic bone-marrow mesenchymal stem cells at different cell doses (0 to 1.0 × 10(6)), infusion volumes (0.5 to 1.0 ml), and infusion times (3 to 6 minutes). An additional group (n = 4) was infused with 1.0 × 10(6) cells labeled with iron oxide for in vivo tracking of cells. Cells were infused through the external carotid artery under laser Doppler flowmetry monitoring 48 hours after sham-MCAO. Magnetic resonance imaging (MRI) was performed 24 hours after cell infusion to reveal cerebral embolisms or hemorrhage. Limb placing, cylinder, and open field tests were conducted to assess sensorimotor functions before the rats were perfused for histology.
  
  
  RESULTS
  A cell dose-related reduction in cerebral blood flow was noted, as well as an increase in embolic events and concomitant lesion size, and sensorimotor impairment. In addition, a low infusion velocity (0.5 ml/6 minutes) was associated with high rate of complications. Lesions on MRI were confirmed with histology and corresponded to necrotic cell loss and blood-brain barrier leakage.
  
  
  CONCLUSIONS
  Particularly cell dose but also infusion velocity contribute to complications encountered after intra-arterial cell transplantation. This should be considered before planning efficacy studies in rats and, potentially, in patients with stroke.
authors.affiliation: Institute of Clinical Medicine-Neurology, University of Eastern Finland, Kuopio, 70211, Finland. lili.cui@uef.fi.
authors.forename: Li-li
authors.initials: LL
authors.lastname: Cui
authors.affiliation: Finnish Red Cross Blood Services, Helsinki, 00310, Finland. Erja.Kerkela@veripalvelu.fi.
authors.forename: Erja
authors.initials: E
authors.lastname: Kerkelä
authors.affiliation: Institute of Clinical Medicine-Neurology, University of Eastern Finland, Kuopio, 70211, Finland. abdulb@student.uef.fi.
authors.forename: Abdulhameed
authors.initials: A
authors.lastname: Bakreen
authors.affiliation: Fraunhofer Institute for Cell Therapy and Immunology and Translational Centre for Regenerative Medicine, University of Leipzig, Leipzig, 04103, Germany. franziska.nitzsche@izi.fraunhofer.de.
authors.forename: Franziska
authors.initials: F
authors.lastname: Nitzsche
authors.affiliation: NeuroRepair Department, Mossakowski Medical Research Centre, Warsaw, 02-106, Poland. aandrzejewska_biol@wp.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Andrzejewska
authors.affiliation: NeuroRepair Department, Mossakowski Medical Research Centre, Warsaw, 02-106, Poland. adamnowakowskipl@gmail.com.
authors.forename: Adam
authors.initials: A
authors.lastname: Nowakowski
authors.affiliation: Division of MR Research, Russell H Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. mjanows1@jhmi.edu.
authors.forename: Miroslaw
authors.initials: M
authors.lastname: Janowski
authors.affiliation: Division of MR Research, Russell H Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. pwalczak@mri.jhu.edu.
authors.forename: Piotr
authors.initials: P
authors.lastname: Walczak
authors.affiliation: Fraunhofer Institute for Cell Therapy and Immunology and Translational Centre for Regenerative Medicine, University of Leipzig, Leipzig, 04103, Germany. johannes.boltze@izi.fraunhofer.de.
authors.forename: Johannes
authors.initials: J
authors.lastname: Boltze
authors.affiliation: NeuroRepair Department, Mossakowski Medical Research Centre, Warsaw, 02-106, Poland. barbara.lukomska@imdik.pan.pl.
authors.forename: Barbara
authors.initials: B
authors.lastname: Lukomska
authors.affiliation: Institute of Clinical Medicine-Neurology, University of Eastern Finland, Kuopio, 70211, Finland. jukka.jolkkonen@uef.fi.
authors.forename: Jukka
authors.initials: J
authors.lastname: Jolkkonen
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001783:Blood Flow Velocity; D001854:Bone Marrow Cells / Q000166:cytology*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D048429:Cell Size; D002478:Cells, Cultured; D007261:Infusions, Intra-Arterial; D020766:Intracranial Embolism / Q000628:therapy*; D017078:Laser-Doppler Flowmetry; D008279:Magnetic Resonance Imaging; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014184:Transplantation, Homologous