title: Efficacy and dose-dependent safety of intra-arterial delivery of mesenchymal stem cells in a rodent stroke model.
abstract: Intra-arterial (IA) delivery of mesenchymal stem cells (MSCs) for acute ischemic stroke is attractive for clinical translation. However, studies using rat model of stroke have demonstrated that IA MSCs delivery can decrease middle cerebral artery (MCA) flow, which may limit its clinical translation. The goal of this study is to identify a dose of IA MSCs (maximum tolerated dose; MTD) that does not compromise MCA flow and evaluate its efficacy and optimal timing in a rat model of reversible middle cerebral artery occlusion (rMCAo). We sought to determine if there is a difference in efficacy of acute (1 h) versus sub-acute (24 h) IA MSCs treatment after rMCAo. Adult female Sprague-Dawley rats underwent rMCAo (90 min) and an hour later a single dose of MSCs (at de-escalating doses 1 × 10(6), 5 × 10(5), 2 × 10(5), 1 × 10(5) and 5 × 10(4)) was given using IA route. MSCs were suspended in phosphate buffered saline (PBS) and PBS alone was used for control experiments. We measured the percent change in mean laser Doppler flow signal over the ipsilateral MCA in de-escalating doses groups to determine MTD. The results demonstrated that the lowering of IA MSC dose to 1 × 10(5) and below did not compromise MCA flow and hence an IA MSC dose of 1 × 10(5) considered as MTD. Subsequently, 1 h and 24 h after rMCAo, rats were treated with IA MSCs or PBS. The 24 h delivery of IA MSCs significantly improved neurodeficit score and reduced the mean infarct volume at one month as compared to control, but not the 1 h delivery. Overall, this study suggests that the IA delivery of MSCs can be performed safely and efficaciously at the MTD of 1 × 10(5) delivered at 24 hours in rodent model of stroke.
authors.affiliation: Cerebral Vascular Disease Research Laboratories, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, United States of America; Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, United States of America; Interdisciplinary Stem Cell Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, United States of America.
authors.forename: Dileep R
authors.initials: DR
authors.lastname: Yavagal
authors.affiliation: Cerebral Vascular Disease Research Laboratories, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, United States of America.
authors.forename: Baowan
authors.initials: B
authors.lastname: Lin
authors.affiliation: Cerebral Vascular Disease Research Laboratories, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, United States of America; Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, United States of America.
authors.forename: Ami P
authors.initials: AP
authors.lastname: Raval
authors.affiliation: Cerebral Vascular Disease Research Laboratories, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, United States of America.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Garza
authors.affiliation: Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, United States of America.
authors.forename: Chuanhui
authors.initials: C
authors.lastname: Dong
authors.affiliation: Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, United States of America.
authors.forename: Weizhao
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Interdisciplinary Stem Cell Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, United States of America.
authors.forename: Erika B
authors.initials: EB
authors.lastname: Rangel
authors.affiliation: Interdisciplinary Stem Cell Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, United States of America.
authors.forename: Ian
authors.initials: I
authors.lastname: McNiece
authors.affiliation: Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, United States of America.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Rundek
authors.affiliation: Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, United States of America.
authors.forename: Ralph L
authors.initials: RL
authors.lastname: Sacco
authors.affiliation: Cerebral Vascular Disease Research Laboratories, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, United States of America; Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, United States of America.
authors.forename: Miguel
authors.initials: M
authors.lastname: Perez-Pinzon
authors.affiliation: Interdisciplinary Stem Cell Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, United States of America; The Department of Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, United States of America.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Hare
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D020244:Infarction, Middle Cerebral Artery / Q000628:therapy; D007261:Infusions, Intra-Arterial; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000628:therapy*