title: Therapeutic time window and dose response of autologous bone marrow mononuclear cells for ischemic stroke.
abstract: Although mononuclear cells (MNCs) from bone marrow are being investigated in phase I clinical trials in stroke patients, dose response, therapeutic time window, and biodistribiton have not been well-characterized in animal stroke models. Long Evans rats underwent common carotid artery/middle cerebral artery occlusion (CCA/MCAo) and 24 hr later were randomized to receive saline IV or a bone marrow aspiration followed by an IV infusion of autologous separated MNCs (1 million, 10 million, or 30 million cells/kg). In another experiment, rats underwent CCAo/MCAo and were randomized at 24 hr, 72 hr, or 7 days after stroke to receive a saline injection or 10 million/kg MNCs. All animals were evaluated on the cylinder and corner tests up to 28 days. MNCs were tracked using Q-dot nanocrystals to monitor biodistribution. Animals treated with MNCs at 10 million and 30 million cells/kg at 24 hr after stroke had significant reductions in neurological deficits and lesion size compared with saline controls or animals treated with 1 million cells/kg. There was no difference in neurological deficits in the 10 and 30 million cell/kg groups at 28 days. Animals treated with MNCs at 72 hr but not at 7 days showed a significant reduction in neurological deficits by 28 days. Labeled MNCs were found in the brain, spleen, lung, liver, and kidney at 1 hr and exponentially decreased over the ensuing week. In conclusion, we found a maximum reduction in neurological deficits at 10 and 30 million cells/kg and a therapeutic time window up to 72 hr after stroke. © 2011 Wiley-Liss, Inc.
authors.affiliation: Department of Neurology, University of Texas Medical School at Houston, Houston, TX 77030, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Yang
authors.forename: Roger
authors.initials: R
authors.lastname: Strong
authors.forename: Sushil
authors.initials: S
authors.lastname: Sharma
authors.forename: Miranda
authors.initials: M
authors.lastname: Brenneman
authors.forename: Kasam
authors.initials: K
authors.lastname: Mallikarjunarao
authors.forename: Xiaopei
authors.initials: X
authors.lastname: Xi
authors.forename: James C
authors.initials: JC
authors.lastname: Grotta
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Aronowski
authors.forename: Sean I
authors.initials: SI
authors.lastname: Savitz
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology*; D016026:Bone Marrow Transplantation / Q000379:methods*; D020520:Brain Infarction / Q000209:etiology / Q000473:pathology; D004195:Disease Models, Animal; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000601:surgery*; D007275:Injections, Intravenous / Q000379:methods; D008297:Male; D009069:Movement Disorders / Q000209:etiology; D051381:Rats; D020318:Rats, Long-Evans; D013997:Time Factors; D014182:Transplantation, Autologous