Human neural stem cells differentiate and promote locomotor recovery in spinal cord-injured mice. Proc Natl Acad Sci USA

Department of Physical Medicine and Rehabilitation, Reeve-Irvine Research Center, University of California, Irvine, CA 92697, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 10/2005; 102(39):14069-74. DOI: 10.1073/pnas.0507063102
Source: PubMed


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.

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    • "These data therefore suggest that hCNS-SCns loss was likely to occur shortly after or during the transplantation process, likely as a result of mechanical shear forces during injection (Aguado et al., 2012). In our previous studies, hCNS-SCns transplanted at a dose of 75,000 cells exhibited an average of 250% expansion over the initial transplantation dose in this immunodeficient mouse SCI model by 12–16 WPT (Cummings et al., 2005; Hooshmand et al., 2009; Salazar et al., 2010; Sontag et al., 2013, 2014). To test the effect of dose on donor cell survival/expansion, we normalized the stereologically quantified number of human cells present to the initial transplantation dose to obtain the proportion of surviving cells at 2 and 16 WPT. "
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    ABSTRACT: The effect of transplantation dose on the spatiotemporal dynamics of human neural stem cell (hNSC) engraftment has not been quantitatively evaluated in the central nervous system.We investigated changes over time in engraftment/survival, proliferation, andmigration ofmultipotent human central nervous system-derived neural stem cells (hCNS-SCns) transplanted at doses ranging from 10,000 to 500,000 cells in spinal cord injured immunodeficient mice. Transplant dose was inversely correlated with measures of donor cell proliferation at 2 weeks post-transplant (WPT) and dose-normalized engraftment at 16 WPT. Critically, mice receiving the highest cell dose exhibited an engraftment plateau, in which the total number of engrafted human cells never exceeded the initial dose. These data suggest that donor cell expansion was inversely regulated by target niche parameters and/or transplantation density. Investigation of the response of donor cells to the host microenvironment should be a key variable in defining target cell dose in pre-clinical models of CNS disease and injury.
    Stem Cell Research 07/2015; 15(2):341-353. · 3.69 Impact Factor
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    • "Equally, although not immunosuppressive, iPSC derived from the somatic cells of the recipient carry the same histocompatibility antigens and do not require immunosuppression after transplantation. By contrast, ESC//NSC require immunosuppression when transplanted into the CNS in animals and, since autologous transplantation is not possible, immunosuppression is required in NSC-based treatment(Cummings et al., 2005, Lu et al., 2012, Schwartz et al., 2012, Lu et al., 2013). "
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    ABSTRACT: Stem cell therapies are being explored extensively as treatments for degenerative eye disease, either for replacing lost neurons, restoring neural circuits or, based on more recent evidence, as paracrine-mediated therapies in which stem cell-derived trophic factors protect compromised endogenous retinal neurons from death and induce the growth of new connections. Retinal progenitor phenotypes induced from embryonic stem cells/induced pluripotent stem cells (ESCs/iPSCs) and endogenous retinal stem cells may replace lost photoreceptors and retinal pigment epithelial (RPE) cells and restore vision in the diseased eye, whereas treatment of injured retinal ganglion cells (RGCs) has so far been reliant on mesenchymal stem cells (MSC). Here, we review the properties of non-retinal-derived adult stem cells, in particular neural stem cells (NSCs), MSC derived from bone marrow (BMSC), adipose tissues (ADSC) and dental pulp (DPSC), together with ESC/iPSC and discuss and compare their potential advantages as therapies designed to provide trophic support, repair and replacement of retinal neurons, RPE and glia in degenerative retinal diseases. We conclude that ESCs/iPSCs have the potential to replace lost retinal cells, whereas MSC may be a useful source of paracrine factors that protect RGC and stimulate regeneration of their axons in the optic nerve in degenerate eye disease. NSC may have potential as both a source of replacement cells and also as mediators of paracrine treatment. Copyright © 2015. Published by Elsevier B.V.
    Stem Cell Research 02/2015; 2(3). DOI:10.1016/j.scr.2015.02.003 · 3.69 Impact Factor
    • "These favourable effects are present at chronic stages (Salazar et al., 2010), but are less readily seen without degradation of gliotic scar (Karimi-Abdolrezaee et al., 2010). Specifi c ablation of cell grafts following transplantation has been shown to abolish behavioural recovery (Cummings et al., 2005), lending strength to myelination as mechanism. Furthermore, NSPCs unable to produce compact myelin demonstrate no functional recovery and reduced white matter sparing (Yasuda et al., 2011) despite near identical growth factor secretion (unpublished data). "
    Jared T Wilcox · RV · MGF ·
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    ABSTRACT: Stem cell transplantation offers an attractive potential therapy for neurological and neurodegenerative disorders such as spinal cord injury (SCI). Given the demand and expectations for the success of regenerative medicines, newly developed cellular therapeutics must be carefully designed and executed, informed by strong preclinical rationale available. This chapter will address the current state of preclinical scientific research for translation into clinical use of stem cell therapy. Focus will be given to current advances in cell transplantation strategies, with specific attention paid to critical assessment of mechanism and efficacy. Specific cell types will be discussed with respect to pathophysiological processes of SCI and their proposed targets. These therapeutics targets include: 1) trophic support and reducing cell loss, 2) remyelination and neuroprotection, 3) tissue modification, and 4) regeneration through neuroplasticity. Combinatorial strategies consisting of co-administering cell types, neurotrophins and tissue modification will also be addressed. Pressing considerations and challenges of translating preclinical findings into clinical therapy exist, and ought to be critically assessed with respect to the best current animal model data. Clinical trials of cell transplantation in human participants with spinal injuries are of significant importance, and will be critically appraised. Taken as a whole—while expectations must be measured—the current status of knowledge on stem cell transplantation for SCI has evolved substantially over the past decade. While translational knowledge gaps continue to exist with regard to cervical and chronic SCI, carefully conducted early phase clinical trials with cellular therapies are warranted, but must be complemented by a robust preclinical research strategy.
    Stem Cells and Neurological Disorders, Edited by L Lescaundron, 01/2015: chapter 3: pages 61-92; Science Publishers.
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