Transplantation of Gene-Edited Hepatocyte-like Cells Modestly Improves Survival of Arginase-1-Deficient Mice.
| Autor: | Sin YY; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada., Ballantyne LL; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada., Richmond CR; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada., Funk CD; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada. Electronic address: funkc@queensu.ca. |
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| Jazyk: | angličtina |
| Zdroj: | Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2018 Mar 02; Vol. 10, pp. 122-130. Date of Electronic Publication: 2017 Dec 01. |
| DOI: | 10.1016/j.omtn.2017.11.012 |
| Abstrakt: | Progress in gene editing research has been accelerated by utilizing engineered nucleases in combination with induced pluripotent stem cell (iPSC) technology. Here, we report transcription activator-like effector nuclease (TALEN)-mediated reincorporation of Arg1 exons 7 and 8 in iPSCs derived from arginase-1-deficient mice possessing Arg1 Δ alleles lacking these terminal exons. The edited cells could be induced to differentiate into hepatocyte-like cells (iHLCs) in vitro and were subsequently used for transplantation into our previously described (Sin et al., PLoS ONE 2013) tamoxifen-inducible Arg1-Cre arginase-1-deficient mouse model. While successful gene-targeted repair was achieved in iPSCs containing Arg1 Δ alleles, only minimal restoration of urea cycle function could be observed in the iHLC-transplanted mice compared to control mice, and survival in this lethal model was extended by up to a week in some mice. The partially rescued phenotype may be due to inadequate regenerative capacity of arginase-1-expressing cells in the correct metabolic zones. Technical hurdles exist and will need to be overcome for gene-edited iPSC to iHLC rescue of arginase-1 deficiency, a rare urea cycle disorder. (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.) |
| Databáze: | MEDLINE |
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