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  • Human embryonic stem cell neural differentiation and enhanced cell survival promoted by hypoxic preconditioning. 21364630

    Transplantation of neural progenitors derived from human embryonic stem cells (hESCs) provides a potential therapy for ischemic stroke. However, poor graft survival within the host environment has hampered the benefits and applications of cell-based therapies. The present investigation tested a preconditioning strategy to enhance hESC tolerance, thereby improving graft survival and the therapeutic potential of hESC transplantation. UC06 hESCs underwent neural induction and terminal differentiation for up to 30 days, becoming neural lineage cells, exhibiting extensive neurites and axonal projections, generating synapses and action potentials. To induce a cytoprotective phenotype, hESC-derived neurospheres were cultured at 0.1% oxygen for 12 h, dissociated and plated for terminal differentiation under 21% oxygen. Immunocytochemistry and electrophysiology demonstrated the 'hypoxic preconditioning' promoted neuronal differentiation. Western blotting revealed significantly upregulated oxygen-sensitive transcription factors hypoxia-inducible factor (HIF)-1α and HIF-2α, while producing a biphasic response within HIF targets, including erythropoietin, vascular endothelial growth factor and Bcl-2 family members, during hypoxia and subsequent reoxygenation. This cytoprotective phenotype resulted in a 50% increase in both total and neural precursor cell survival after either hydrogen peroxide insult or oxygen-glucose deprivation. Cellular protection was maintained for at least 5 days and corresponded to upregulation of neuroprotective proteins. These results suggest that hypoxic preconditioning could be used to improve the effectiveness of human neural precursor transplantation therapies.
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  • Human Embryonic Stem Cell-Derived Progenitors Assist Functional Sensory Axon Regeneration after Dorsal Root Avulsion Injury. 26053681

    Dorsal root avulsion results in permanent impairment of sensory functions due to disconnection between the peripheral and central nervous system. Improved strategies are therefore needed to reconnect injured sensory neurons with their spinal cord targets in order to achieve functional repair after brachial and lumbosacral plexus avulsion injuries. Here, we show that sensory functions can be restored in the adult mouse if avulsed sensory fibers are bridged with the spinal cord by human neural progenitor (hNP) transplants. Responses to peripheral mechanical sensory stimulation were significantly improved in transplanted animals. Transganglionic tracing showed host sensory axons only in the spinal cord dorsal horn of treated animals. Immunohistochemical analysis confirmed that sensory fibers had grown through the bridge and showed robust survival and differentiation of the transplants. Section of the repaired dorsal roots distal to the transplant completely abolished the behavioral improvement. This demonstrates that hNP transplants promote recovery of sensorimotor functions after dorsal root avulsion, and that these effects are mediated by spinal ingrowth of host sensory axons. These results provide a rationale for the development of novel stem cell-based strategies for functionally useful bridging of the peripheral and central nervous system.
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  • Phosphorylation of the par polarity complex protein Par3 at serine 962 is mediated by aurora a and regulates its function in neuronal polarity. 19812038

    The Aurora kinases are a family of serine/threonine protein kinases that perform important functions during the cell cycle. Recently, it was shown that Drosophila Aurora A also regulates the asymmetric localization of Numb to the basal and the partitioning-defective (Par) complex to the apical cortex of neuroblasts by phosphorylating Par6. Here, we show that Aurora A is required for neuronal polarity. Suppression of Aurora A by RNA interference results in the loss of neuronal polarity. Aurora A interacts directly with the atypical protein kinase C binding domain of Par3 and phosphorylates it at serine 962. The phosphorylation of Par3 at serine 962 contributes to its function in the establishment of neuronal polarity.
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  • Transient but not permanent benefit of neuronal progenitor cell therapy after traumatic brain injury: potential causes and translational consequences. 25352780

    Numerous studies have reported a beneficial impact of neural progenitor cell transplantation on functional outcome after traumatic brain injury (TBI) during short and medium follow-up periods. However, our knowledge regarding long-term functional effects is fragmentary while a direct comparison between local and systemic transplantation is missing so far.This study investigated the long-term (12 week) impact of human fetal neuronal progenitor cell (hNPC) transplantation 24 h after severe TBI in rats.Cells were either transplanted stereotactically (1 × 10(5)) into the putamen or systemically (5 × 10(5)) via the tail vein. Control animals received intravenous transplantation of vehicle solution.An overall functional benefit was observed after systemic, but not local hNPC transplantation by area under the curve analysis (p less than 0.01). Surprisingly, this effect vanished during later stages after TBI with all groups exhibiting comparable functional outcomes 84 days after TBI. Investigation of cell-mediated inflammatory processes revealed increasing microglial activation and macrophage presence during these stages, which was statistically significant after systemic cell administration (p less than 0.05). Intracerebral hNPC transplantation slightly diminished astrogliosis in perilesional areas (p less than 0.01), but did not translate into a permanent functional benefit. No significant effects on angiogenesis were observed among the groups.Our results suggest the careful long-term assessment of cell therapies for TBI, as well as to identify potential long-term detrimental effects of such therapies before moving on to clinical trials. Moreover, immunosuppressive protocols, though widely used, should be rigorously assessed for their applicability in the respective setup.
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  • Disruption of astrocyte-vascular coupling and the blood-brain barrier by invading glioma cells. 24943270

    Astrocytic endfeet cover the entire cerebral vasculature and serve as exchange sites for ions, metabolites and energy substrates from the blood to the brain. They maintain endothelial tight junctions that form the blood-brain barrier (BBB) and release vasoactive molecules that regulate vascular tone. Malignant gliomas are highly invasive tumours that use the perivascular space for invasion and co-opt existing vessels as satellite tumour form. Here we use a clinically relevant mouse model of glioma and find that glioma cells, as they populate the perivascular space of preexisting vessels, displace astrocytic endfeet from endothelial or vascular smooth muscle cells. This causes a focal breach in the BBB. Furthermore, astrocyte-mediated gliovascular coupling is lost, and glioma cells seize control over the regulation of vascular tone through Ca(2+)-dependent release of K(+). These findings have important clinical implications regarding blood flow in the tumour-associated brain and the ability to locally deliver chemotherapeutic drugs in disease.
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  • Endogenous cerebellar neurogenesis in adult mice with progressive ataxia. 25574472

    Transplanting exogenous neuronal progenitors to replace damaged neurons in the adult brain following injury or neurodegenerative disorders and achieve functional amelioration is a realistic goal. However, studies so far have rarely taken into consideration the preexisting inflammation triggered by the disease process that could hamper the effectiveness of transplanted cells. Here, we examined the fate and long-term consequences of human cerebellar granule neuron precursors (GNP) transplanted into the cerebellum of Harlequin mice, an adult model of progressive cerebellar degeneration with early-onset microgliosis.Human embryonic stem cell-derived progenitors expressing Atoh1, a transcription factor key to GNP specification, were generated in vitro and stereotaxically transplanted into the cerebellum of preataxic Harlequin mice. The histological and functional impact of these transplants was followed using immunolabeling and Rotarod analysis.Although transplanted GNPs did not survive beyond a few weeks, they triggered the proliferation of endogenous nestin-positive precursors in the leptomeninges that crossed the molecular layer and differentiated into mature neurons. These phenomena were accompanied by the preservation of the granule and Purkinje cell layers and delayed ataxic changes. In vitro neurosphere generation confirmed the enhanced neurogenic potential of the cerebellar leptomeninges of Harlequin mice transplanted with exogenous GNPs.The cerebellar leptomeninges of adult mice contain an endogenous neurogenic niche that can be stimulated to yield mature neurons from an as-yet unidentified population of progenitors. The transplantation of human GNPs not only stimulates this neurogenesis, but, despite the potentially hostile environment, leads to neuroprotection and functional amelioration.
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  • Role of human smooth muscle cell progenitors in atherosclerotic plaque development and composition. 18006460

    We analysed the possible protective role of human endothelial (EPCs) and smooth muscle (SPCs) progenitor cells on atherosclerosis development in apoE(-/-)RAG2(-/-) mice. We determined plasma levels of SPCs in coronary patients.ApoE(-/-)RAG2(-/-) mice received four intravenous injections of saline, 5 x 10(5) SPCs, or 5 x 10(5) EPCs every other week, one (preventive approach) or 12(curative approach) weeks after starting a high fat diet. Derived-SPC levels were quantified from blood mononuclear cells of patients with stable angina (n = 10) and acute coronary syndromes (ACS, n = 9). SPCs reduced atherosclerosis development by 42% (P less than 0.001), but had no effect on lesion progression. In the SPC group, collagen and smooth muscle cell content were increased (+80%, P less than 0.001, +46%, P less than 0.05, respectively), and macrophage content was decreased (-41%, P less than 0.05). In the curative approach, macrophage content decreased by 40.5% (P less than 0.05) after SPC injection. EPC injection had no effect on atherosclerosis development or progression. Peripheral blood-derived SPC levels were reduced in patients with ACS compared with stable angina patients (P less than 0.05).We demonstrate that SPCs limit plaque development and promote changes in plaque composition towards a stable phenotype in mice. Our finding in patients suggests that reduced peripheral blood-derived SPC levels might represent a mechanism contributing to plaque destabilization.
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  • Efficient generation of lung and airway epithelial cells from human pluripotent stem cells. 24291815

    The ability to generate lung and airway epithelial cells from human pluripotent stem cells (hPSCs) would have applications in regenerative medicine, modeling of lung disease, drug screening and studies of human lung development. We have established, based on developmental paradigms, a highly efficient method for directed differentiation of hPSCs into lung and airway epithelial cells. Long-term differentiation of hPSCs in vivo and in vitro yielded basal, goblet, Clara, ciliated, type I and type II alveolar epithelial cells. The type II alveolar epithelial cells were capable of surfactant protein-B uptake and stimulated surfactant release, providing evidence of specific function. Inhibiting or removing retinoic acid, Wnt and BMP-agonists to signaling pathways critical for early lung development in the mouse-recapitulated defects in corresponding genetic mouse knockouts. As this protocol generates most cell types of the respiratory system, it may be useful for deriving patient-specific therapeutic cells.
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  • Human glial chimeric mice reveal astrocytic dependence of JC virus infection. 25401469

    Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease triggered by infection with the human gliotropic JC virus (JCV). Due to the human-selective nature of the virus, there are no animal models available to investigate JCV pathogenesis. To address this issue, we developed mice with humanized white matter by engrafting human glial progenitor cells (GPCs) into neonatal immunodeficient and myelin-deficient mice. Intracerebral delivery of JCV resulted in infection and subsequent demyelination of these chimeric mice. Human GPCs and astrocytes were infected more readily than oligodendrocytes, and viral replication was noted primarily in human astrocytes and GPCs rather than oligodendrocytes, which instead expressed early viral T antigens and exhibited apoptotic death. Engraftment of human GPCs in normally myelinated and immunodeficient mice resulted in humanized white matter that was chimeric for human astrocytes and GPCs. JCV effectively propagated in these mice, which indicates that astroglial infection is sufficient for JCV spread. Sequencing revealed progressive mutation of the JCV capsid protein VP1 after infection, suggesting that PML may evolve with active infection. These results indicate that the principal CNS targets for JCV infection are astrocytes and GPCs and that infection is associated with progressive mutation, while demyelination is a secondary occurrence, following T antigen-triggered oligodendroglial apoptosis. More broadly, this study provides a model by which to further assess the biology and treatment of human-specific gliotropic viruses.
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