Proliferation, migration, and differentiation of human neural stem/progenitor cells after transplantation into a rat model of traumatic brain injury

Wennersten, André; Meier, Xia; Holmin, Staffan; Wahlberg, Lars U.; Mathiesen, Tiit

doi:10.3171/jns.2004.100.1.0088

Cited by 124 publications

(91 citation statements)

References 50 publications

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“…Modo et al (11) obtained similar results with conditionally immortalized mouse neuroepithelial cells transplanted into the striatum of the ischemic brain. None of our cells expressed the oligodendrocyte marker NG2 at this time point; this finding is consistent with the results of Wennersten et al (36), who transplanted human neural progenitors into a rat model of cortical trauma. However, we (N.U., unpublished data) and others (37) have shown that hCNS-derived neurospheres or other neural progenitors can become oligodendrocytes that myelinate axons of the myelin-deficient shiverer mouse.…”

Section: Discussionsupporting

confidence: 82%

Transplanted human fetal neural stem cells survive, migrate, and differentiate in ischemic rat cerebral cortex

Kelly

Bliss

Shah

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

568

446

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We characterize the survival, migration, and differentiation of human neurospheres derived from CNS stem cells transplanted into the ischemic cortex of rats 7 days after distal middle cerebral artery occlusion. Transplanted neurospheres survived robustly in naive and ischemic brains 4 wk posttransplant. Survival was influenced by proximity of the graft to the stroke lesion and was negatively correlated with the number of IB4-positive inflammatory cells. Targeted migration of the human cells was seen in ischemic animals, with many human cells migrating long distances (Ϸ1.2 mm) predominantly toward the lesion; in naive rats, cells migrated radially from the injection site in smaller number and over shorter distances (0.2 mm). The majority of migrating cells in ischemic rats had a neuronal phenotype. Migrating cells between the graft and the lesion expressed the neuroblast marker doublecortin, whereas human cells at the lesion border expressed the immature neuronal marker ␤-tubulin, although a small percentage of cells at the lesion border also expressed glial fibrillary acid protein (GFAP). Thus, transplanted human CNS (hCNS)-derived neurospheres survived robustly in naive and ischemic brains, and the microenvironment influenced their migration and fate.

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Section: Discussionsupporting

confidence: 82%

Transplanted human fetal neural stem cells survive, migrate, and differentiate in ischemic rat cerebral cortex

Kelly

Bliss

Shah

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

568

446

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“…Cryopreservation of NPCs has not been studied in detail, except as a part of transplantation studies [6,[21][22][23]. The present study demonstrates that deep-freezing (-70°C) may allow banking of murine neurospheres, with preserved functionality yielding a minimum of 50% NPC recovery.…”

Section: Discussionmentioning

confidence: 94%

Cryopreservation Does Not Affect Proliferation and Multipotency of Murine Neural Precursor Cells

2005

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Stem cell research offers unique opportunities for developing new medical therapies for devastating diseases and a new way to explore fundamental questions of biology. Establishing an efficient freezing protocol for neural precursor cells (NPCs) is of great importance for advances in cell-based therapies. We used fluorescence-activated cell sorter-based cell death/survival analysis and Western blot analysis of proliferation markers (proliferating cell nuclear antigen) and prosurvival proteins (Bcl-2) to study the effect of a variety of cryoprotective agents on fetal mouse forebrain NPCs. Neurospheres frozen at -70ºC or in liquid nitrogen in a ratecontrolled manner and thawed after 5 days retained viability of 60%-70% measured 24 hours after thawing. However, 1 week after thawing, viability dropped to 50%-60%. Using a clonogenic sphere formation assay, we showed that recovery rate of frozen NPCs was approximately 26% and did not significantly differ between dimethyl sulfoxide (DMSO)-and glycerol-supplemented samples. Application of the caspase inhibitor zVAD-fmk during freezing or in the first week after thawing resulted in protection of cryopreserved neurospheres after thawing but not during the freezing process, indicating that apoptosis limits recovery of NPCs. Cell survival was not reduced in cells that were enzymatically separated before cryopreservation. Optimal protection of NPCs was achieved when 10% DMSO alone or in a combination with 10% fetal calf serum (FCS) was used. However, 10% glycerol alone was equally effective. Using these protocols, NPCs retained their multipotency and differentiated into both glial (GFAP-positive) and neuronal (Tuj1-positive) cells. Percentage of Tuj1-positive cells in 5% and 10% DMSO, in 10% DMSO + 10% FCS, and in 10% glycerol remained at the same level as before freezing and varied from 5%-7%. We conclude that cryopreservation (up to 1 month at -70°C and up to 1 year in liquid nitrogen) does not markedly alter the rate of proliferation and multipotency of murine neural precursor cells. Stem Cells

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“…16 Since the Suicide gene therapy using neural stem cells S Li et al discovery and characterization of neural stem/progenitor cells, many studies have been performed on neuronal restoration by transplantation after ischemic and traumatic injuries of the central nervous system. 8 It has been shown that neural stem/progenitor cells migrate to the regions where neurogenesis is required such as ischemic and traumatic lesions. Aboody et al 6 have also demonstrated the exceptional migratory ability of NSCs to brain tumors.…”

Section: Discussionmentioning

confidence: 99%

“…In the present study, we isolated neural stem cells (NSCs) from Sprague-Dawley rat embryos and expanded them using neural stem cell expansion kit/Neurosphere system (R&D Systems) and tested the use of NSCs, which recently have been shown to possess the ability to proliferate, migrate and then differentiate along the neuronal and glial lines, [6][7][8] as TK-expressing cells.…”

mentioning

confidence: 99%

Bystander effect-mediated gene therapy of gliomas using genetically engineered neural stem cells

Tokuyama

Yamamoto

et al. 2005

Cancer Gene Ther

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Since neural stem cells (NSCs) have the ability to migrate toward a tumor mass, genetically engineered NSCs were used for the treatment of gliomas. We first evaluated the ''bystander effect'' between NSCs transduced with the herpes simplex virus-thymidine kinase (HSVtk) gene (NSCtk) and C6 rat glioma cells under both in vitro and in vivo conditions. A potent bystander effect was observed in co-culture experiments of NSCtk and C6 cells. In the intracranial co-implantation experiments in athymic nude mice and Sprague-Dawley rats, the animals co-implanted with NSCtk and C6 cells and treated with ganciclovir (GCV) showed no intracranial tumors and survived more than 100 days, while those treated with physiological saline (PS) died of tumor progression. We next injected NSCtk cells into the pre-existing C6 tumor in rats and treated them with GCV or PS. The tumor volume was serially measured by magnetic resonance imaging. The tumor disappeared in six out of nine rats in the NSCtk/GCV group, while all the rats treated with PS died of tumor progression by day 21. The results indicate the feasibility of a novel gene therapy strategy for gliomas through a bystander effect generated by intratumoral injection of NSCtk cells and systemic GCV administration.

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Proliferation, migration, and differentiation of human neural stem/progenitor cells after transplantation into a rat model of traumatic brain injury

Abstract: This study shows that expandable human neural stem/progenitor cells survive transplantation, and migrate, differentiate, and proliferate in the injured brain. These cells could potentially be developed for transplantation therapy in cases of traumatic brain injury.

Cited by 124 publications

References 50 publications

Transplanted human fetal neural stem cells survive, migrate, and differentiate in ischemic rat cerebral cortex

Transplanted human fetal neural stem cells survive, migrate, and differentiate in ischemic rat cerebral cortex

Cryopreservation Does Not Affect Proliferation and Multipotency of Murine Neural Precursor Cells

Bystander effect-mediated gene therapy of gliomas using genetically engineered neural stem cells

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