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

Centre for Neuroscience, University of Melbourne, Parkville, VIC, Australia.
Frontiers in Cellular Neuroscience (Impact Factor: 4.29). 03/2012; 6(5):11. DOI: 10.3389/fncel.2012.00011
Source: PubMed


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.

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Available from: Lachlan Thompson
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    • "In theory, human iPSC-derived neural tissue or ESCs could also be transplanted into neonatal animals to generate humanized models without the need for continual suppression. While there are numerous studies injecting human cells into both neonatal and adult rats (Denham et al., 2012; Englund et al., 2002; Jablonska et al., 2010; Kallur et al., 2006; Kopen et al., 1999; Lundberg et al., 2002; Rachubinski et al., 2012; Windrem et al., 2004), there are far fewer that have used neonatal or adult mice (Windrem et al., 2004, 2008). Neonatal desensitization is a new strategy for long-term immune protection of human neural cells transplanted into the adult brain, without the need for immunosuppression (Kelly et al., 2009; Peiguo et al., 2012; Zhang et al., 2013). "
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    • "ES-NPCs possesses the ability to differentiate into dorsal forebrain neurons based on their gene expression profile (Ideguchi et al., 2010). Some reports demonstrated that pluripotent stem cell-derived neurons grew and developed neuronal connectivity with either adult athymic, immunosuppressed, damaged, or normal neonatal rodent brain (Gaillard et al., 2007; Thompson et al., 2009; Gaillard and Jaber, 2011; Denham et al., 2012; Steinbeck et al., 2012). Daadi et al. demonstrated that human neural stem cells which engrafted into the ischemic-injured adult brain had enhanced axonal sprouting into subcortical target areas, and increased expression of genes related to neurogenesis, resulting in motor functional recovery of the animals (Daadi et al., 2010). "
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