Dystrophin Deficiency Leads to Genomic Instability in Human Pluripotent Stem Cells via NO Synthase-Induced Oxidative Stress
| Autor: | Martin Pešl, Jan Vrbsky, Renata Gaillyová, Lenka Marková, Aleksandra Vilotić, Ivan Frák, Giancarlo Forte, Albano C. Meli, Iveta Valášková, Alain Lacampagne, Aneta Kohutova, Miriama Krutá, Tereza Jurakova, Petr Dvorak, Vladimír Rotrekl, Petr Fojtík, Šárka Jelínková |
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| Přispěvatelé: | St. Anne’s University Hospital [Brno], Masaryk University [Brno] (MUNI), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), MORNET, Dominique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Genome instability
musculoskeletal diseases congenital hereditary and neonatal diseases and abnormalities Nitric Oxide Synthase Type III DNA damage Duchenne muscular dystrophy Induced Pluripotent Stem Cells Nitric Oxide Synthase Type II Nitric Oxide Synthase Type I Genomic Instability Article dystrophin Cell Line 03 medical and health sciences 0302 clinical medicine [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry Molecular Biology/Genomics [q-bio.GN] DMD medicine Humans Induced pluripotent stem cell lcsh:QH301-705.5 030304 developmental biology 0303 health sciences NO synthases biology ROS General Medicine medicine.disease Embryonic stem cell Cell biology Muscular Dystrophy Duchenne Oxidative Stress lcsh:Biology (General) biology.protein [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry Molecular Biology/Genomics [q-bio.GN] Stem cell pluripotent stem cells Dystrophin Reactive Oxygen Species Reprogramming 030217 neurology & neurosurgery genome stability |
| Zdroj: | Cells Cells, MDPI, 2019, 8 (1), pp.53. ⟨10.3390/cells8010053⟩ Volume 8 Issue 1 Cells, Vol 8, Iss 1, p 53 (2019) Cells, 2019, 8 (1), pp.53. ⟨10.3390/cells8010053⟩ |
| ISSN: | 2073-4409 |
| Popis: | International audience; Recent data on Duchenne muscular dystrophy (DMD) show myocyte progenitor’s involvement in the disease pathology often leading to the DMD patient’s death. The molecular mechanism underlying stem cell impairment in DMD has not been described. We created dystrophin-deficient human pluripotent stem cell (hPSC) lines by reprogramming cells from two DMD patients, and also by introducing dystrophin mutation into human embryonic stem cells via CRISPR/Cas9. While dystrophin is expressed in healthy hPSC, its deficiency in DMD hPSC lines induces the release of reactive oxygen species (ROS) through dysregulated activity of all three isoforms of nitric oxide synthase (further abrev. as, NOS). NOS-induced ROS release leads to DNA damage and genomic instability in DMD hPSC. We were able to reduce both the ROS release as well as DNA damage to the level of wild-type hPSC by inhibiting NOS activity |
| Databáze: | OpenAIRE |
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