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  • 1
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    Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease (2011)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2011-11-08
    Description: Human pluripotent stem cells (PSCs) are a promising source of cells for applications in regenerative medicine. Directed differentiation of PSCs into specialized cells such as spinal motoneurons or midbrain dopamine (DA) neurons has been achieved. However, the effective use of PSCs for cell therapy has lagged behind. Whereas mouse PSC-derived DA neurons have shown efficacy in models of Parkinson's disease, DA neurons from human PSCs generally show poor in vivo performance. There are also considerable safety concerns for PSCs related to their potential for teratoma formation or neural overgrowth. Here we present a novel floor-plate-based strategy for the derivation of human DA neurons that efficiently engraft in vivo, suggesting that past failures were due to incomplete specification rather than a specific vulnerability of the cells. Midbrain floor-plate precursors are derived from PSCs 11 days after exposure to small molecule activators of sonic hedgehog (SHH) and canonical WNT signalling. Engraftable midbrain DA neurons are obtained by day 25 and can be maintained in vitro for several months. Extensive molecular profiling, biochemical and electrophysiological data define developmental progression and confirm identity of PSC-derived midbrain DA neurons. In vivo survival and function is demonstrated in Parkinson's disease models using three host species. Long-term engraftment in 6-hydroxy-dopamine-lesioned mice and rats demonstrates robust survival of midbrain DA neurons derived from human embryonic stem (ES) cells, complete restoration of amphetamine-induced rotation behaviour and improvements in tests of forelimb use and akinesia. Finally, scalability is demonstrated by transplantation into parkinsonian monkeys. Excellent DA neuron survival, function and lack of neural overgrowth in the three animal models indicate promise for the development of cell-based therapies in Parkinson's disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3245796/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3245796/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kriks, Sonja -- Shim, Jae-Won -- Piao, Jinghua -- Ganat, Yosif M -- Wakeman, Dustin R -- Xie, Zhong -- Carrillo-Reid, Luis -- Auyeung, Gordon -- Antonacci, Chris -- Buch, Amanda -- Yang, Lichuan -- Beal, M Flint -- Surmeier, D James -- Kordower, Jeffrey H -- Tabar, Viviane -- Studer, Lorenz -- NS052671/NS/NINDS NIH HHS/ -- P50 NS047085/NS/NINDS NIH HHS/ -- P50 NS071669/NS/NINDS NIH HHS/ -- P50 NS071669-03/NS/NINDS NIH HHS/ -- England -- Nature. 2011 Nov 6;480(7378):547-51. doi: 10.1038/nature10648.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Stem Cell Biology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22056989" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Brain Tissue Transplantation ; Cell Differentiation ; Cell Line ; Cell Survival ; Dopaminergic Neurons/*cytology/*transplantation ; Embryonic Stem Cells/*cytology ; Female ; Humans ; Macaca mulatta ; Mesencephalon/cytology ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Parkinson Disease/*therapy ; Rats ; Rats, Sprague-Dawley
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-10-30
    Description: In the course of primary infection with herpes simplex virus 1 (HSV-1), children with inborn errors of toll-like receptor 3 (TLR3) immunity are prone to HSV-1 encephalitis (HSE). We tested the hypothesis that the pathogenesis of HSE involves non-haematopoietic CNS-resident cells. We derived induced pluripotent stem cells (iPSCs) from the dermal fibroblasts of TLR3- and UNC-93B-deficient patients and from controls. These iPSCs were differentiated into highly purified populations of neural stem cells (NSCs), neurons, astrocytes and oligodendrocytes. The induction of interferon-beta (IFN-beta) and/or IFN-lambda1 in response to stimulation by the dsRNA analogue polyinosinic:polycytidylic acid (poly(I:C)) was dependent on TLR3 and UNC-93B in all cells tested. However, the induction of IFN-beta and IFN-lambda1 in response to HSV-1 infection was impaired selectively in UNC-93B-deficient neurons and oligodendrocytes. These cells were also much more susceptible to HSV-1 infection than control cells, whereas UNC-93B-deficient NSCs and astrocytes were not. TLR3-deficient neurons were also found to be susceptible to HSV-1 infection. The rescue of UNC-93B- and TLR3-deficient cells with the corresponding wild-type allele showed that the genetic defect was the cause of the poly(I:C) and HSV-1 phenotypes. The viral infection phenotype was rescued further by treatment with exogenous IFN-alpha or IFN-beta ( IFN-alpha/beta) but not IFN-lambda1. Thus, impaired TLR3- and UNC-93B-dependent IFN-alpha/beta intrinsic immunity to HSV-1 in the CNS, in neurons and oligodendrocytes in particular, may underlie the pathogenesis of HSE in children with TLR3-pathway deficiencies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3527075/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3527075/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lafaille, Fabien G -- Pessach, Itai M -- Zhang, Shen-Ying -- Ciancanelli, Michael J -- Herman, Melina -- Abhyankar, Avinash -- Ying, Shui-Wang -- Keros, Sotirios -- Goldstein, Peter A -- Mostoslavsky, Gustavo -- Ordovas-Montanes, Jose -- Jouanguy, Emmanuelle -- Plancoulaine, Sabine -- Tu, Edmund -- Elkabetz, Yechiel -- Al-Muhsen, Saleh -- Tardieu, Marc -- Schlaeger, Thorsten M -- Daley, George Q -- Abel, Laurent -- Casanova, Jean-Laurent -- Studer, Lorenz -- Notarangelo, Luigi D -- 1R01NS066390/NS/NINDS NIH HHS/ -- 1R03AI0883502-01/AI/NIAID NIH HHS/ -- 5R01NS072381-02/NS/NINDS NIH HHS/ -- 8UL1TR000043/TR/NCATS NIH HHS/ -- K12 NS066274/NS/NINDS NIH HHS/ -- R01 NS066390/NS/NINDS NIH HHS/ -- R01 NS072381/NS/NINDS NIH HHS/ -- R03 AI088352/AI/NIAID NIH HHS/ -- UL1 TR000043/TR/NCATS NIH HHS/ -- England -- Nature. 2012 Nov 29;491(7426):769-73. doi: 10.1038/nature11583. Epub 2012 Oct 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Stem Cell Biology, Sloan-Kettering Institute for Cancer Research, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23103873" target="_blank"〉PubMed〈/a〉
    Keywords: Astrocytes/immunology/virology ; Biomarkers ; Cell Differentiation ; Cell Lineage ; Cell Separation ; Cells, Cultured ; Central Nervous System/cytology/immunology/*pathology/virology ; Child ; Disease Susceptibility ; Encephalitis, Herpes Simplex/immunology/metabolism/pathology/virology ; Herpesvirus 1, Human/*immunology/pathogenicity ; Humans ; Immunity, Innate ; Induced Pluripotent Stem Cells/*cytology/virology ; Interferons/immunology ; Membrane Transport Proteins/deficiency/genetics ; Neural Stem Cells/immunology/virology ; Neurons/immunology/pathology/virology ; Oligodendroglia/immunology/pathology/virology ; Toll-Like Receptor 3/*deficiency/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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