Human Neural Stem Cells Induce Functional Myelination in Mice with Severe Dysmyelination

StemCells Inc., Newark, CA 94560, USA.
Science translational medicine (Impact Factor: 15.84). 10/2012; 4(155):155ra136. DOI: 10.1126/scitranslmed.3004371
Source: PubMed


Shiverer-immunodeficient (Shi-id) mice demonstrate defective myelination in the central nervous system (CNS) and significant ataxia by 2 to 3 weeks of life. Expanded, banked human neural stem cells (HuCNS-SCs) were transplanted into three sites in the brains of neonatal or juvenile Shi-id mice, which were asymptomatic or showed advanced hypomyelination, respectively. In both groups of mice, HuCNS-SCs engrafted and underwent preferential differentiation into oligodendrocytes. These oligodendrocytes generated compact myelin with normalized nodal organization, ultrastructure, and axon conduction velocities. Myelination was equivalent in neonatal and juvenile mice by quantitative histopathology and high-field ex vivo magnetic resonance imaging, which, through fractional anisotropy, revealed CNS myelination 5 to 7 weeks after HuCNS-SC transplantation. Transplanted HuCNS-SCs generated functional myelin in the CNS, even in animals with severe symptomatic hypomyelination, suggesting that this strategy may be useful for treating dysmyelinating diseases.

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    • "There has been growing interest in the use of cell transplantation as therapy for neurological diseases since the first human trials using fetal neural precursors for Parkinson's disease were performed more than 20 years ago (reviewed in Barker et al., 2013). Currently, there are preclinical studies and clinical trials using fibroblastic adult mesenchymal stem cells (reviewed in Neirinckx et al., 2013) and fetal-derived neural cells (Uchida et al., 2012) for transplantation to treat neurological disease. A recent clinical study showed that fetal neural cell transplants promoted myelination in individuals afflicted with Pelizaeus-Merzbacher disease (PMD), a rare hypomyelinating disease (Gupta et al., 2012). "
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    ABSTRACT: Using a viral model of the demyelinating disease multiple sclerosis (MS), we show that intraspinal transplantation of human embryonic stem cell-derived neural precursor cells (hNPCs) results in sustained clinical recovery, although hNPCs were not detectable beyond day 8 posttransplantation. Improved motor skills were associated with a reduction in neuroinflammation, decreased demyelination, and enhanced remyelination. Evidence indicates that the reduced neuroinflammation is correlated with an increased number of CD4+CD25+FOXP3+ regulatory T cells (Tregs) within the spinal cords. Coculture of hNPCs with activated T cells resulted in reduced T cell proliferation and increased Treg numbers. The hNPCs acted, in part, through secretion of TGF-β1 and TGF-β2. These findings indicate that the transient presence of hNPCs transplanted in an animal model of MS has powerful immunomodulatory effects and mediates recovery. Further investigation of the restorative effects of hNPC transplantation may aid in the development of clinically relevant MS treatments.
    Stem Cell Reports 06/2014; 2(6). DOI:10.1016/j.stemcr.2014.04.005 · 5.37 Impact Factor
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    • "Moreover, ex vivo magnetic resonance imaging (MRI) of transplanted Shi-id brains detected changes in water diffusivity consistent with increased myelination. In the rodent brain, robust human MBP expression is observed at approximately 6 weeks after HuCNS-SC transplantation [47]. Thus, while other myelin mutant models of human diseases exist, such as the proteolipid protein (PLP) mutants reflective of Pelizaeus-Merzbacher disease (PMD), their shortened life span precludes assessment of the robustness and longevity of neural stem cell-based therapies. "
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    ABSTRACT: Human neural stem cell transplants have potential as therapeutic candidates to treat a vast number of disorders of the central nervous system (CNS). StemCells, Inc. has purified human neural stem cells and developed culture conditions for expansion and banking that preserve their unique biological properties. The biological activity of these human central nervous system stem cells (HuCNS-SC®) has been analyzed extensively in vitro and in vivo. When formulated for transplantation, the expanded and cryopreserved banked cells maintain their stem cell phenotype, self-renew and generate mature oligodendrocytes, neurons and astrocytes, cells normally found in the CNS. In this overview, the rationale and supporting data for pursuing neuroprotective strategies and clinical translation in the three components of the CNS (brain, spinal cord and eye) are described. A phase I trial for a rare myelin disorder and phase I/II trial for spinal cord injury are providing intriguing data relevant to the biological properties of neural stem cells, and the early clinical outcomes compel further development.
    Stem Cell Research & Therapy 08/2013; 4(4):102. DOI:10.1186/scrt313 · 3.37 Impact Factor
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    • "In recent studies, banked human CNS stem/precursor cells (HuCNS-SC) were successfully transplanted into the brains of hypomyelinated mice and patients with Pelizaeus-Merzbacher Disease (PMD), a rare congenital leukodystrophy in which developmental myelination is never established [63,64]. The HuCNS-SC transplanted into the hypomyelinated brains of neonatal and juvenile shiverer-immunodeficient mice migrated and preferentially differentiated into mature CC1+ oligodendrocytes in white matter, which generated mature, compact myelin with normal node formation and enhanced nerve conduction [63]. "
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