title: Determination of the therapeutic time window for human umbilical cord blood mononuclear cell transplantation following experimental stroke in rats.
abstract: Experimental treatment strategies using human umbilical cord blood mononuclear cells (hUCB MNCs) represent a promising option for alternative stroke therapies. An important point for clinical translation of such treatment approaches is knowledge on the therapeutic time window. Although  expected to be wider than for thrombolysis, the exact time window for hUCB MNC therapy is not known. Our study aimed to determine the time window of intravenous hUCB MNC administration after middle cerebral artery occlusion (MCAO). Male spontaneously hypertensive rats underwent MCAO and were  randomly assigned to hUCB MNC administration at 4, 24, 72, and 120 or 14 days. Influence of cell treatment was observed by magnetic resonance imaging on days 1, 8, and 29 following MCAO and by assessment of functional neurological recovery. On day 30, brains were screened for glial scar development  and presence of hUCB MNCs. Further, influence of hUCB MNCs on necrosis and apoptosis in postischemic neural tissue was investigated in hippocampal slices cultures. Transplantation within a 72-h time window resulted in an early improvement of functional recovery, paralleled by a reduction of  brain atrophy and diminished glial scarring. Cell transplantation 120 h post-MCAO only induced minor functional recovery without changes in the brain atrophy rate and glial reactivity. Later transplantation (14 days) did not show any benefit. No evidence for intracerebrally localized hUCB  MNCs was found in any treatment group. In vitro hUCB MNCs were able to significantly reduce postischemic neural necrosis and apoptosis. Our results for the first time indicate a time window of therapeutic hUCB MNC application of at least 72 h. The time window is limited, but wider than compared  to conventional pharmacological approaches. The data furthermore confirms that differentiation and integration of administered cells is not a prerequisite for poststroke functional improvement and lesion size reduction.
authors.affiliation: Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany. johannes.boltze@izi.fraunhofer.de
authors.forename: Johannes
authors.initials: J
authors.lastname: Boltze
authors.forename: Uwe R
authors.initials: UR
authors.lastname: Schmidt
authors.forename: Doreen M
authors.initials: DM
authors.lastname: Reich
authors.forename: Alexander
authors.initials: A
authors.lastname: Kranz
authors.forename: Klaus G
authors.initials: KG
authors.lastname: Reymann
authors.forename: Maria
authors.initials: M
authors.lastname: Strassburger
authors.forename: Donald
authors.initials: D
authors.lastname: Lobsien
authors.forename: Daniel-Christoph
authors.initials: DC
authors.lastname: Wagner
authors.forename: Annette
authors.initials: A
authors.lastname: Förschler
authors.forename: Wolf-Rüdiger
authors.initials: WR
authors.lastname: Schäbitz
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000000981:diagnostic imaging; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005312:Fetal Blood / Q000166:cytology*; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology* / Q000637:transplantation; D008279:Magnetic Resonance Imaging; D008297:Male; D009457:Neuroglia / Q000502:physiology; D011859:Radiography; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000473:pathology / Q000628:therapy*; D013997:Time Factors; D016896:Treatment Outcome