title: Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat.
abstract: The present study investigates the induction of neurogenesis, reduction of apoptosis, and promotion of basic fibroblast growth factor (bFGF) expression as possible mechanisms by which treatment of stroke with bone marrow stromal cells (MSCs) improves neurological functional recovery. Additionally, for the first time, we treated cerebral ischemia in female rats with intraveneous administration of MSCs. Female rats were subjected to 2 hr of middle cerebral artery occlusion (MCAo), followed by an injection of 3 x 10(6) male (for Y chromosome labeling) rat MSCs or phosphate-buffered saline (PBS) into the tail vein 24 hr after MCAo. All animals received daily injection of bromodeoxyuridine (BrdU; 50 mg/kg, i.p.) for 13 days after treatment for identification of newly synthesized DNA. Animals were sacrificed at 14 days after MCAo. Behavioral tests (rotarod and adhesive-removal tests) were performed. In situ hybridization, immunohistochemistry, and terminal deoxynucleotidyltransferase (TdT)-mediated dUTP-biotin nick-end labeling (TUNEL) were performed to identify transplanted MSCs (Y chromosome), BrdU, bFGF, and apoptotic cells in the brain. Significant recovery of behavior was found in MSC-treated rats at 7 days in the somatosensory test and at 14 days in the motor test after MCAo compared with control, PBS-treated animals (P<.05). MSCs were found to survive and preferentially localize to the ipsilateral ischemic hemisphere. Significantly more BrdU-positive cells were located in the subventricular zone (P<.05), and significantly fewer apoptotic cells and more bFGF immunoreactive cell were found in the ischemic boundary area (P<.05) of MSC-treated rats than in PBS-treated animals. Here we demonstrate that intravenously administered male MSCs increase bFGF expression, reduce apoptosis, promote endogenous cellular proliferation, and improve functional recovery after stroke in female rats.
authors.affiliation: Department of Neurology, Henry Ford Health Sciences Center, Detroit, Michigan 48202, USA.
authors.forename: Jieli
authors.initials: J
authors.lastname: Chen
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Mark
authors.initials: M
authors.lastname: Katakowski
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Chen
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Dunyue
authors.initials: D
authors.lastname: Lu
authors.forename: Mei
authors.initials: M
authors.lastname: Lu
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Gautam
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
mesh_terms: D000818:Animals; D017209:Apoptosis; D001522:Behavior, Animal; D016026:Bone Marrow Transplantation; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count; D002455:Cell Division; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D020244:Infarction, Middle Cerebral Artery / Q000503:physiopathology / Q000628:therapy*; D009043:Motor Activity; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D011597:Psychomotor Performance / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time; D020127:Recovery of Function; D017154:Stromal Cells / Q000378:metabolism / Q000637:transplantation*; D013997:Time Factors; D014180:Transplantation; D014404:Tubulin / Q000378:metabolism*; D014998:Y Chromosome / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D014404:Tubulin; C462941:beta3 tubulin, mouse; C418606:neugrin; D014841:von Willebrand Factor; D016222:Fibroblast Growth Factor 2; D001973:Bromodeoxyuridine