Adult Spinal Cord Stem/Progenitor Cells Transplanted as Neurospheres Preferentially Differentiate into Oligodendrocytes in the Adult Rat Spinal Cord

Mothe, Andrea J.; Kulbatski, Iris; Parr, Ann M.; Mohareb, Michael; Tator, Charles H.

doi:10.3727/096368908786516756

Cited by 63 publications

(56 citation statements)

References 48 publications

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“…The uninjured rats received LP transplants in the same way. To aid transplant survival and to be consistent with our previous work, 20 all animals received cyclosporine (15 mg kg À1 , Sandimmune, Novartis, Dorval, Quebec, Canada) injected subcutaneously daily from the day of transplant until sacrifice.…”

Section: Compression Sci and Lp Transplantationmentioning

confidence: 86%

“…To quantify the phenotype of the transplanted cells, we used confocal microscopy to count the number of GFP þ double-labeled cells as a proportion of GFP þ transplanted cells, as described previously. 20 All data are presented as mean±s.e. Data were analyzed using SigmaStat v.3.11 software (Systat, Point Richmond, CA, USA).…”

Section: Quantitative and Statistical Analysismentioning

confidence: 99%

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Intrathecal transplantation of stem cells by lumbar puncture for thoracic spinal cord injury in the rat

et al. 2011

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Study design: Experimental investigation of intrathecal transplantation of stem cells by lumbar puncture (LP) in a rat model that simulates human thoracic spinal cord injury (SCI). Objectives: To examine the distribution and phenotype of spinal cord-derived neural stem/progenitor cells (NSPCs) and bone marrow-derived mesenchymal stromal cells (BMSCs) following LP transplantation in SCI rats. Setting: Toronto Western Research Institute, Toronto, Ontario, Canada. Methods: NSPCs or BMSCs were transplanted via LP at level L3-5 1 week after compression SCI at T8. Rats were killed at 3, 17 and 27 days after LP transplantation and the relative distribution of cells at C4, T8 and L3-5 was quantitated. The phenotype of the NSPC and BMSC was assessed with immunocytochemistry in vitro and following LP transplantation. Results: By 4 weeks, more NSPC migrated to the lesion site relative to BMSC and uninjured animals. However, there was no preferential homing of either of these types of cells into the parenchyma of the injury site, and most of the transplanted cells remained in the intrathecal space. In vitro, spinal cord-derived NSPC proliferated and expressed nestin, but after LP transplantation, NSPC became post-mitotic and primarily expressed oligodendrocyte markers. In contrast, BMSC did not express any neural antigens in vivo. Conclusion: LP is a minimally invasive method of cell transplantation that produces wide dissemination of cells in the subarachnoid space of the spinal cord. This is the first study to report and quantify the phenotype and spatial distribution of LP transplanted NSPC and BMSC in the intact and injured spinal cord.

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Section: Compression Sci and Lp Transplantationmentioning

confidence: 86%

Section: Quantitative and Statistical Analysismentioning

confidence: 99%

Intrathecal transplantation of stem cells by lumbar puncture for thoracic spinal cord injury in the rat

et al. 2011

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“…This would seem to match the likely scenario well in treating children with leukodystrophies. However, transplantation of OPCs has also been carried out in adult shi mice [78][79][80] and in the sh pup [52] with successful myelination. This is not always true in all of the myelin mutants, as we and others have had little success in transplanting OPCs into the CNS of the taiep rat.…”

Section: Myelinationmentioning

confidence: 99%

“…The former can give rise to neurons, astrocytes, and OLs on withdrawal of the growth factors basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) [103]. However, few OLs are derived from these cells in vitro, but when transplanted into a dysmyelinated background they can generate large numbers of myelinating OLs [80,107,108]. Hence, it appears that cues in the milieu promote this oligodendrogenic switch and/or factors in the culture inhibit OL differentiation.…”

Section: Cells That Have Been Transplanted In the Myelin Mutantsmentioning

confidence: 99%

The Myelin Mutants as Models to Study Myelin Repair in the Leukodystrophies

2011

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The leukodystrophies are rare and serious genetic disorders of the central nervous system that primarily affect children who frequently die early in life or have significantly delayed motor and mental milestones that result in long-term disability. Although with some of these disorders, early intervention with bone marrow or cord blood transplantation has been proven useful, it has not yet been determined that such therapies promote myelin repair of the central nervous system. Research on experimental therapies aimed at myelin repair is aided by the ability to test cell replacement strategies in genetic models in which the mutations and neuropathology match the human disorder. Thus, models exist of Pelizaeus-Merzbacher disease and the lysosomal storage disorder, Krabbe disease, which reflect the clinical and pathological course of the human disorders. Collectively, animals with mutations in myelin genes are called the myelin mutants, and they include rodent models such as the shiverer mouse that have been extensively used to study myelination by exogenous cell transplantation. These studies have encompassed many permutations of the age of the recipient, type of transplanted cell, site of engraftment, and so forth, and they offer hope that the scaling up of myelin produced by transplanted cells will have clinical significance in treating patients. Here we review these models and discuss their relative importance and use in such translational approaches. We discuss how grafts are identified and functional outcomes are measured. Finally, we briefly discuss the cells that have been successfully transplanted, which may be used in future clinical trials.

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“…Recently, the use of transgenic donor mice or rats stably expressing the reporter gene, GFP, or the human placental alkaline phosphatase, has dramatically improved the tracking of transplanted neural stem cells/progenitors in vivo 9,11 . Third, several studies indicate that in vitro cultured rat NSCs derived from either embryonic or adult CNS exclusively differentiate into glial lineages when transplanted into the milieu of the intact or injured adult spinal cord 7,12,13 , despite the fact that these neural stem cells are capable of differentiating into both neurons and glia in vitro, indicating that local environments may dictate the fate of stem cells. Alternatively, cultured NSCs, especially those derived from adult CNS, may have intrinsic defaulty property to differentiate into glial lineages in vivo .…”

Section: Introductionmentioning

confidence: 99%

Promotion of Survival and Differentiation of Neural Stem Cells with Fibrin and Growth Factor Cocktails after Severe Spinal Cord Injury

Graham

Wang

et al. 2014

JoVE

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Neural stem cells (NSCs) can self-renew and differentiate into neurons and glia. Transplanted NSCs can replace lost neurons and glia after spinal cord injury (SCI), and can form functional relays to re-connect spinal cord segments above and below a lesion. Previous studies grafting neural stem cells have been limited by incomplete graft survival within the spinal cord lesion cavity. Further, tracking of graft cell survival, differentiation, and process extension had not been optimized. Finally, in previous studies, cultured rat NSCs were typically reported to differentiate into glia when grafted to the injured spinal cord, rather than neurons, unless fate was driven to a specific cell type. To address these issues, we developed new methods to improve the survival, integration and differentiation of NSCs to sites of even severe SCI. NSCs were freshly isolated from embryonic day 14 spinal cord (E14) from a stable transgenic Fischer 344 rat line expressing green fluorescent protein (GFP) and were embedded into a fibrin matrix containing growth factors; this formulation aimed to retain grafted cells in the lesion cavity and support cell survival. NSCs in the fibrin/growth factor cocktail were implanted two weeks after thoracic level-3 (T3) complete spinal cord transections, thereby avoiding peak periods of inflammation. Resulting grafts completely filled the lesion cavity and differentiated into both neurons, which extended axons into the host spinal cord over remarkably long distances, and glia. Grafts of cultured human NSCs expressing GFP resulted in similar findings. Thus, methods are defined for improving neural stem cell grafting, survival and analysis of in vivo findings. Video LinkThe video component of this article can be found at

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Adult Spinal Cord Stem/Progenitor Cells Transplanted as Neurospheres Preferentially Differentiate into Oligodendrocytes in the Adult Rat Spinal Cord

Cited by 63 publications

References 48 publications

Intrathecal transplantation of stem cells by lumbar puncture for thoracic spinal cord injury in the rat

Intrathecal transplantation of stem cells by lumbar puncture for thoracic spinal cord injury in the rat

The Myelin Mutants as Models to Study Myelin Repair in the Leukodystrophies

Promotion of Survival and Differentiation of Neural Stem Cells with Fibrin and Growth Factor Cocktails after Severe Spinal Cord Injury

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