Intracerebral, but not intravenous, transplantation of bone marrow stromal cells enhances functional recovery in rat cerebral infarct: An optical imaging study

Abstract

Recent studies have indicated that bone marrow stromal cells (BMSC) may improve neurological function when transplanted into an animal model of CNS disorders, including cerebral infarct. However, there are few studies that evaluate the therapeutic benefits of intracerebral and intravenous BMSC transplantation for cerebral infarct. This study was aimed to clarify the favorable route of cell delivery for cerebral infarct in rats. The rats were subjected to permanent middle cerebral artery occlusion. The BMSC were labeled with near infrared (NIR)-emitting quantum dots and were transplanted stereotactically (1 × 10⁶ cells) or intravenously (3 × 10⁶ cells) at 7 days after the insult. Using in vivo NIR fluorescence imaging technique, the behaviors of BMSC were serially visualized during 4 weeks after transplantation. Motor function was also assessed. Immunohistochemistry was performed to evaluate the fate of the engrafted BMSC. Intracerebral, but not intravenous, transplantation of BMSC significantly enhanced functional recovery. In vivo NIR fluorescence imaging could clearly visualize their migration toward the cerebral infarct during 4 weeks after transplantation in the intracerebral group, but not in the intravenous, group. The BMSC were widely distributed in the ischemic brain and some of them expressed neural cell markers in the intracerebral group, but not in the intravenous group. These findings strongly suggest that intravenous administration of BMSC has limited effectiveness at clinically relevant timing and intracerebral administration should be chosen for patients with ischemic stroke, although further studies would be warranted to establish the treatment protocol.

Bone Marrow Stromal Cell Transplantation Enhances Recovery of Local Glucose Metabolism After Cerebral Infarction in Rats: A Serial 18F-FDG PET Study

“…The BMSCs were isolated under sterile conditions from male 8-wk-old transgenic rats expressing enhanced green fluorescent protein (GFP) (Japan SLC Inc.) and were cultured as previously reported (14,18,22,23). The cells were passed 3 times for subsequent experiments.…”

“…Permanent MCA occlusion was induced, as described previously (14,18,22,23). Briefly, anesthesia was induced by 4.0% isoflurane in N 2 O/O 2 (70:30) and was maintained with 2.0% isoflurane in N 2 O/O 2 (70:30).…”

“…The GFP-expressing BMSC or vehicle was stereotactically transplanted into the ipsilateral striatum at 7 d after ischemia (n 5 9 in each group), as reported previously (14,18,20,22,23,25). Briefly, a burr hole was made 3 mm to the right of the bregma.…”

“…All animals were trained for 3 d before the study. The maximum time that the animal stayed on the rotarod was recorded for each performance, as described previously (22,23).…”

“…The brain was removed, and 4-mm-thick coronal sections were prepared for subsequent analysis. Double fluorescence immunohistochemistry was performed, as reported previously (14,18,22,23). Briefly, each section was treated with primary antibody against glial fibrillary acidic protein (GFAP) (mouse monoclonal, 1:500 dilution; BD Pharmingen) or NeuN (mouse monoclonal, 1:100 dilution; Millipore) and labeled with Alexa Fluor 594 (Molecular Probes Inc.).…”