Dual transplantation of human neural stem cells into cervical and lumbar cord ameliorates motor neuron disease in SOD1 transgenic rats. Neurosci Lett

Department of Pathology, Division of Neuropathology, The Johns Hopkins Medical Institutions (JHMI), Baltimore, MD 21205, USA.
Neuroscience Letters (Impact Factor: 2.03). 03/2011; 494(3):222-6. DOI: 10.1016/j.neulet.2011.03.017
Source: PubMed


Stem cells provide novel sources of cell therapies for motor neuron disease that have recently entered clinical trials. In the present study, we transplanted human neural stem cells (NSCs) into the ventral horn of both the lumbar (L4-L5) and cervical (C4-C5) protuberance of SOD1 G93A rats, in an effort to test the feasibility and general efficacy of a dual grafting paradigm addressing several muscle groups in the front limbs, hind limbs and the respiratory apparatus. Transplantation was done prior to the onset of motor neuron disease. Compared with animals that had received dead NSC grafts (serving as controls), rats with live NSCs grafted at the two spinal levels lived 17 days longer. Disease onset in dually grafted animals was delayed by 10 days compared to control animals. Disease duration in NSC-grafted animals was longer by 7 days compared to controls. Our results support the potential of NSC grafts at multiple levels of spinal cord as future cellular therapy for motor neuron disease.

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Available from: Karl Johe, Jan 26, 2015
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    • "Here, we describe that transplantation of human iPSCderived GRNPs produced astrocytes in vivo and prolonged the survival period of mSOD1 mice. We used hiPSC-GRNPs for testing the efficacy in mSOD1 mice, because replacement therapy using astrocytes from rodent glial-restricted progenitors in the cervical spinal cord of ALS rodent models is already well established (Xu et al., 2011). We showed that glial cells represent a potential target of ALS therapy. "
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    ABSTRACT: Transplantation of glial-rich neural progenitors has been demonstrated to attenuate motor neuron degeneration and disease progression in rodent models of mutant superoxide dismutase 1 (SOD1)-mediated amyotrophic lateral sclerosis (ALS). However, translation of these results into a clinical setting requires a renewable human cell source. Here, we derived glial-rich neural progenitors from human iPSCs and transplanted them into the lumbar spinal cord of ALS mouse models. The transplanted cells differentiated into astrocytes, and the treated mouse group showed prolonged lifespan. Our data suggest a potential therapeutic mechanism via activation of AKT signal. The results demonstrated the efficacy of cell therapy for ALS by the use of human iPSCs as cell source.
    Stem Cell Reports 08/2014; 3(2). DOI:10.1016/j.stemcr.2014.05.017 · 5.37 Impact Factor
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    • "A challenge in comparing cell therapy techniques and optimizing delivery strategy is the variety of approaches that researchers employ with respect to number of injection sites, number of transplantation time points, and cell dose, as shown in Table 1. Some researchers adopt a multiple-transplant approach to improve cell survival, whereas others deliver cells to multiple locations or with multiple delivery routes [12,20,63]. These strategies may allow an increased total cell dose while avoiding safety complications that could result from one large administration to a single location. "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the neuromuscular system and does not have a known singular cause. Genetic mutations, extracellular factors, non-neuronal support cells, and the immune system have all been shown to play varied roles in clinical and pathological disease progression. The therapeutic plasticity of mesenchymal stem cells (MSCs) may be well matched to this complex disease pathology, making MSCs strong candidates for cellular therapy in ALS. In this review, we summarize a variety of explored mechanisms by which MSCs play a role in ALS progression, including neuronal and non-neuronal cell replacement, trophic factor delivery, and modulation of the immune system. Currently relevant techniques for applying MSC therapy in ALS are discussed, focusing in particular on delivery route and cell source. We include examples from in vitro, preclinical, and clinical investigations to elucidate the remaining progress that must be made to understand and apply MSCs as a treatment for ALS.
    Stem Cell Research & Therapy 03/2014; 5(32). DOI:10.1186/scrt421 · 3.37 Impact Factor
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    • "G93A rats of 11 days ( average 149 days ) compared to control animals receiving injection of dead cells ( average 138 days ) . Similar to our study a significantly higher number of persisting lumbar a - motoneurons was found in treated animals . More recently , Xu et al . ( 2011 ) reported a lifespan extension of SOD1 G93A rats by 17 days after dual cervical ( C4 – C5 ) and lumbar ( L4 – L5 ) transplantation of the same human spinal neural stem cell line as used in our current study [ 34 ] . Given the robust graft survival , cell differentiation and migration seen in our study , we speculate that the difference"
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    ABSTRACT: Mutation in the ubiquitously expressed cytoplasmic superoxide dismutase (SOD1) causes an inherited form of Amyotrophic Lateral Sclerosis (ALS). Mutant synthesis in motor neurons drives disease onset and early disease progression. Previous experimental studies have shown that spinal grafting of human fetal spinal neural stem cells (hNSCs) into the lumbar spinal cord of SOD1(G93A) rats leads to a moderate therapeutical effect as evidenced by local α-motoneuron sparing and extension of lifespan. The aim of the present study was to analyze the degree of therapeutical effect of hNSCs once grafted into the lumbar spinal ventral horn in presymptomatic immunosuppressed SOD1(G93A) rats and to assess the presence and functional integrity of the descending motor system in symptomatic SOD1(G93A) animals. Presymptomatic SOD1(G93A) rats (60-65 days old) received spinal lumbar injections of hNSCs. After cell grafting, disease onset, disease progression and lifespan were analyzed. In separate symptomatic SOD1(G93A) rats, the presence and functional conductivity of descending motor tracts (corticospinal and rubrospinal) was analyzed by spinal surface recording electrodes after electrical stimulation of the motor cortex. Silver impregnation of lumbar spinal cord sections and descending motor axon counting in plastic spinal cord sections were used to validate morphologically the integrity of descending motor tracts. Grafting of hNSCs into the lumbar spinal cord of SOD1(G93A) rats protected α-motoneurons in the vicinity of grafted cells, provided transient functional improvement, but offered no protection to α-motoneuron pools distant from grafted lumbar segments. Analysis of motor-evoked potentials recorded from the thoracic spinal cord of symptomatic SOD1(G93A) rats showed a near complete loss of descending motor tract conduction, corresponding to a significant (50-65%) loss of large caliber descending motor axons. These data demonstrate that in order to achieve a more clinically-adequate treatment, cell-replacement/gene therapy strategies will likely require both spinal and supraspinal targets.
    PLoS ONE 08/2012; 7(8):e42614. DOI:10.1371/journal.pone.0042614 · 3.23 Impact Factor
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