Neurons derived from human embryonic stem cells extend long-distance axonal projections through growth along host white matter tracts after intra-cerebral transplantation.

Centre for Neuroscience, University of Melbourne, Parkville, VIC, Australia.
Frontiers in Cellular Neuroscience (Impact Factor: 4.47). 01/2012; 6:11. DOI: 10.3389/fncel.2012.00011
Source: PubMed

ABSTRACT Human pluripotent stem cells have the capacity for directed differentiation into a wide variety of neuronal subtypes that may be useful for brain repair. While a substantial body of research has lead to a detailed understanding of the ability of neurons in fetal tissue grafts to structurally and functionally integrate after intra-cerebral transplantation, we are only just beginning to understand the in vivo properties of neurons derived from human pluripotent stem cells. Here we have utilized the human embryonic stem (ES) cell line Envy, which constitutively expresses green fluorescent protein (GFP), in order to study the in vivo properties of neurons derived from human ES cells. Rapid and efficient neural induction, followed by differentiation as neurospheres resulted in a GFP+ neural precursor population with traits of neuroepithelial and dorsal forebrain identity. Ten weeks after transplantation into neonatal rats, GFP+ fiber patterns revealed extensive axonal growth in the host brain, particularly along host white matter tracts, although innervation of adjacent nuclei was limited. The grafts were composed of a mix of neural cell types including differentiated neurons and glia, but also dividing neural progenitors and migrating neuroblasts, indicating an incomplete state of maturation at 10 weeks. This was reflected in patch-clamp recordings showing stereotypical properties appropriate for mature functional neurons, including the ability to generate action potentials, as well profiles consistent for more immature neurons. These findings illustrate the intrinsic capacity for neurons derived from human ES cells to integrate at a structural and functional level following transplantation.

1 Bookmark
  • [Show abstract] [Hide abstract]
    ABSTRACT: This study aimed to investigate the roles of bone marrow stromal cells (BMSCs) in promoting axonal regeneration after complete transection of spinal cord in adult rats. Transplantation was done 9 days after injury. Only a few BMSCs were detected at the injury site 8 weeks after transplantation, yet there was robust growth of axons. The scarcity of surviving BMSCs may attribute to the adverse conditions in their ambient environment. In this connection, the immediate accumulation of a large number of macrophages/reactive microglia following BMSCs transplantation and subsequent cavitation of tissues may be detrimental to their survival. An unexpected finding following BMSCs transplantation was the marked increase in the nestin, GFAP, NF200, olig 3 and CNP positive cells at the injury site. Immunoelectron microscopy showed CNP cells were oval or fibroblast-like and had multiple perineurial-like compartments with long extending filopodia. The spatial relationship between regenerating axons and CNP-positive cells was also confirmed by double immunofluorescence staining. Our results suggest that transplantation of BMSCs elicits the influx and survival of local cells including CNP positive cells and Schwann cells into injury site, which provide structural support for the axon regeneration and remyelination after spinal cord injury.
    American Journal of Translational Research 01/2014; 6(3):224-35.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Assessing the efficacy of human stem cell transplantation in rodent models is complicated by the significant immune rejection that occurs. Two recent reports have shown conflicting results using neonatal tolerance to xenografts in rats. Here we extend this approach to mice and assess whether neonatal tolerance can prevent the rapid rejection of xenografts. In three strains of neonatal immune-intact mice, using two different brain transplant regimes and three independent stem cell types, we conclusively show that there is rapid rejection of the implanted cells. We also address specific challenges associated with the generation of humanized mouse models of disease.
    Experimental Neurology 01/2014; · 4.65 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Spinal cord injury (SCI) is a devastating condition that causes substantial morbidity and mortality and for which no treatments are available. Stem cells offer some promise in the restoration of neurological function. We used systematic review, meta-analysis, and meta-regression to study the impact of stem cell biology and experimental design on motor and sensory outcomes following stem cell treatments in animal models of SCI. One hundred and fifty-six publications using 45 different stem cell preparations met our prespecified inclusion criteria. Only one publication used autologous stem cells. Overall, allogeneic stem cell treatment appears to improve both motor (effect size, 27.2%; 95% Confidence Interval [CI], 25.0%-29.4%; 312 comparisons in 5,628 animals) and sensory (effect size, 26.3%; 95% CI, 7.9%-44.7%; 23 comparisons in 473 animals) outcome. For sensory outcome, most heterogeneity between experiments was accounted for by facets of stem cell biology. Differentiation before implantation and intravenous route of delivery favoured better outcome. Stem cell implantation did not appear to improve sensory outcome in female animals and appeared to be enhanced by isoflurane anaesthesia. Biological plausibility was supported by the presence of a dose-response relationship. For motor outcome, facets of stem cell biology had little detectable effect. Instead most heterogeneity could be explained by the experimental modelling and the outcome measure used. The location of injury, method of injury induction, and presence of immunosuppression all had an impact. Reporting of measures to reduce bias was higher than has been seen in other neuroscience domains but were still suboptimal. Motor outcomes studies that did not report the blinded assessment of outcome gave inflated estimates of efficacy. Extensive recent preclinical literature suggests that stem-cell-based therapies may offer promise, however the impact of compromised internal validity and publication bias mean that efficacy is likely to be somewhat lower than reported here.
    PLoS Biology 12/2013; 11(12):e1001738. · 12.69 Impact Factor

Full-text (3 Sources)

Available from
May 28, 2014