Central nervous system entry of peripherally injected umbilical cord blood cells is not required for neuroprotection in stroke.
OBJECTIVE
To date, stem cell graft-mediated neuroprotection is equated with graft survival and secretion of neurotrophic factors in the brain. Here, we examined whether neuroprotection by systemically delivered human umbilical cord blood (HUCB) cells was dependent on their entry into the central nervous system in a rodent model of acute stroke.


METHODS
Adult male Sprague-Dawley rats were subjected to right middle cerebral artery occlusion for 60 minutes. During the 1-hour occlusion, animals were randomly assigned to 1 of the following treatments: intravenous injection of HUCB (a subtherapeutic dose of 200,000 cells in 10 microL) with blood-brain barrier (BBB) permeabilizer (1.1 mol/L mannitol at 4 degrees C) or vehicle, intravenous vehicle alone, or intravenous mannitol alone. Behavioral tests, using elevated body swing test and passive avoidance test, were conducted at day 3 poststroke, and thereafter, animals were euthanized for: (1) immunohistochemical examination of HUCB, which were lentivirally labeled with green fluorescent protein; (2) cerebral infarction analysis using 2,3,5-triphenyl-tetrazolium chloride; and (3) enzyme-linked immunosorbent assay of trophic factors within the striatal region.


RESULTS
We did not detect intravenously administered low dose of HUCB cells in the brains of animals at day 3 after stroke even when cells were coinfused with a BBB permeabilizer (mannitol). However, HUCB-mannitol treatment significantly increased brain levels of neurotrophic factors, which correlated positively with reduced cerebral infarcts and improved behavioral functions.


CONCLUSIONS
Our data show that central nervous system availability of grafted cells is not a prerequisite for acute neuroprotection provided that therapeutic molecules secreted by these cells could cross the BBB.
Borlongan
Cesar V
CV
Department of Neurology, Medical College of Georgia, Augusta, GA 30912-3200, USA. cborlongan@mail.mcg.edu
Hadman
Martin
M
Sanberg
Cyndy Davis
CD
Sanberg
Paul R
PR
D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D036101:Cord Blood Stem Cell Transplantation; D004195:Disease Models, Animal; D004234:Diuretics, Osmotic / Q000627:therapeutic use; D020244:Infarction, Middle Cerebral Artery / Q000628:therapy*; D008297:Male; D008353:Mannitol / Q000627:therapeutic use; D009414:Nerve Growth Factors / Q000096:biosynthesis*; D018696:Neuroprotective Agents / Q000627:therapeutic use; D011597:Psychomotor Performance; D051381:Rats; D017207:Rats, Sprague-Dawley
D004234:Diuretics, Osmotic; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D008353:Mannitol