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Human neural stem cells differentiate and promote locomotor recovery in spinal cord-injured mice.

ABSTRACT: We report that prospectively isolated, human CNS stem cells grown as neurospheres (hCNS-SCns) survive, migrate, and express differentiation markers for neurons and oligodendrocytes after long-term engraftment in spinal cord-injured NOD-scid mice. hCNS-SCns engraftment was associated with locomotor recovery, an observation that was abolished by selective ablation of engrafted cells by diphtheria toxin. Remyelination by hCNS-SCns was found in both the spinal cord injury NOD-scid model and myelin-deficient shiverer mice. Moreover, electron microscopic evidence consistent with synapse formation between hCNS-SCns and mouse host neurons was observed. Glial fibrillary acidic protein-positive astrocytic differentiation was rare, and hCNS-SCns did not appear to contribute to the scar. These data suggest that hCNS-SCns may possess therapeutic potential for CNS injury and disease.

SUBMITTER: Cummings BJ

PROVIDER: S-EPMC1216836 | biostudies-literature | 2005 Sep

REPOSITORIES: biostudies-literature

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Human neural stem cells differentiate and promote locomotor recovery in spinal cord-injured mice.

Cummings Brian J BJ Uchida Nobuko N Tamaki Stanley J SJ Salazar Desirée L DL Hooshmand Mitra M Summers Robert R Gage Fred H FH Anderson Aileen J AJ

Proceedings of the National Academy of Sciences of the United States of America 20050919 39

We report that prospectively isolated, human CNS stem cells grown as neurospheres (hCNS-SCns) survive, migrate, and express differentiation markers for neurons and oligodendrocytes after long-term engraftment in spinal cord-injured NOD-scid mice. hCNS-SCns engraftment was associated with locomotor recovery, an observation that was abolished by selective ablation of engrafted cells by diphtheria toxin. Remyelination by hCNS-SCns was found in both the spinal cord injury NOD-scid model and myelin-d ...[more]

PMID: 16172374

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Project description:Spinal cord injury (SCI) often leads to persistent functional deficits due to severe neuron and glial loss, and to limited axonal regeneration after injury. Here we show that the transplantation of human dental stem cells into the completely transected adult rat spinal cord resulted in a significant recovery of hindlimb locomotor functions. These stem cells exhibited three major neuro-regenerative activities. First, they inhibited the SCI-induced apoptosis of neurons, astrocytes, and oligodendrocytes, improving the preservation of neuronal filaments and myelin sheaths. Second, they promoted the regeneration of transected axons by directly inhibiting multiple axon growth inhibitors, including chondroitin sulfate proteoglycan and myelin-associated glycoprotein, by paracrine mechanisms. Third, they replaced lost cells by differentiating into mature oligodendrocytes under the extreme conditions of SCI. Our data demonstrate that tooth-derived stem cells may provide novel therapeutic benefits for treating SCI through both cell-autonomous and paracrine neuro-regenerative activities. Human dental stem cells were isolated from exfoliated deciduous teeth extracted for clinical purposes were collected at Nagoya University School of Medicine, under approved guidelines set by Nagoya University (H-73, 2003). The ethics committee of Nagoya University approved the experimental protocols (permission number 8-2). Mesenchymal stem cells of human Bone marrow line were obtained from Lonza. Total RNAs were isolated and quantified by spectrophotometer. RNA integrity was checked on 1% agarose gels. RT reactions were carried out with Superscript III reverse transcriptase (Invitrogen) using 1 μg of total RNA in a 50 μl total reaction volume. Microarray experiments were carried out using a CodeLink™ Human Whole Genome Bioarray (Applied Microarrays, Inc. Tempe, AZ) at Filgen, Inc. (Nagoya, Japan). The arrays were scanned using a GenePix4000B Array Scanner (Molecular Devices, Sunnyvale, CA), and the data was analyzed by using MicroArray Data Analysis Tool Ver3.2 (Filgen, Inc.).

Project description:Microtubule stabilization through epothilones is a promising preclinical therapy for functional recovery following spinal cord injury that stimulates axon regeneration, reduces growth-inhibitory molecule deposition and promotes functional improvements. Rehabilitation therapy is the only clinically validated approach to promote functional improvements following spinal cord injury. However, whether microtubule stabilization can augment the beneficial effects of rehabilitation therapy or act in concert with it to further promote repair remains unknown. Here, we investigated the pharmacokinetic, histological and functional efficacies of epothilone D, epothilone B and ixabepilone alone or in combination with rehabilitation following a moderate contusive spinal cord injury. Pharmacokinetic analysis revealed that ixabepilone only weakly crossed the blood-brain barrier and was subsequently excluded from further investigations. In contrast, epothilones B and D rapidly distributed to CNS compartments displaying similar profiles after either subcutaneous or intraperitoneal injections. Following injury and subcutaneous administration of epothilone B or D, rats were subjected to 7 weeks of sequential bipedal and quadrupedal training. For all outcome measures, epothilone B was efficacious compared with epothilone D. Specifically, epothilone B decreased fibrotic scaring which was associated with a retention of fibronectin localized to perivascular cells in sections distal to the lesion. This corresponded to a decreased number of cells present within the intralesional space, resulting in less axons within the lesion. Instead, epothilone B increased serotonergic fibre regeneration and vesicular glutamate transporter 1 expression caudal to the lesion, which was not affected by rehabilitation. Multiparametric behavioural analyses consisting of open-field locomotor scoring, horizontal ladder, catwalk gait analysis and hindlimb kinematics revealed that rehabilitation and epothilone B both improved several aspects of locomotion. Specifically, rehabilitation improved open-field locomotor and ladder scores, as well as improving the gait parameters of limb coupling, limb support, stride length and limb speed; epothilone B improved these same gait parameters but also hindlimb kinematic profiles. Functional improvements by epothilone B and rehabilitation acted complementarily on gait parameters leading to an enhanced recovery in the combination group. As a result, principal component analysis of gait showed the greatest improvement in the epothilone B plus rehabilitation group. Thus, these results support the combination of epothilone B with rehabilitation in a clinical setting.

Dataset Information

Human neural stem cells differentiate and promote locomotor recovery in spinal cord-injured mice.

Publications

Human neural stem cells differentiate and promote locomotor recovery in spinal cord-injured mice.

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