Disease modeling and gene correction of LGMDR21 iPSCs elucidates the role of POGLUT1 in skeletal muscle maintenance, regeneration, and the satellite cell niche.

Autor:	Ortiz-Vitali JL; Center for Stem Cell and Regenerative Medicine (CSCRM), University of Texas Health Science Center at Houston, Houston, TX 77030, USA., Wu J; Center for Stem Cell and Regenerative Medicine (CSCRM), University of Texas Health Science Center at Houston, Houston, TX 77030, USA., Xu N; Center for Stem Cell and Regenerative Medicine (CSCRM), University of Texas Health Science Center at Houston, Houston, TX 77030, USA., Shieh AW; Center for Human Genetics, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM), University of Texas Health Science Center at Houston, Houston, TX 77030, USA., Niknejad N; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Takeuchi M; Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA., Paradas C; Neurology Department, Neuromuscular Disorders Unit, Instituto de Biomedicina de Sevilla, Hospital U. Virgen Del Rocío, CSIC, Universidad de Sevilla, Avd. Manuel Siurot s/n, 41013 Sevilla, Spain., Lin C; Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Jafar-Nejad H; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Haltiwanger RS; Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA., Wang SH; Center for Human Genetics, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM), University of Texas Health Science Center at Houston, Houston, TX 77030, USA., Darabi R; Center for Stem Cell and Regenerative Medicine (CSCRM), University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2023 Aug 02; Vol. 33, pp. 683-697. Date of Electronic Publication: 2023 Aug 02 (Print Publication: 2023).
DOI:	10.1016/j.omtn.2023.07.037
Abstrakt:	Autosomal recessive limb-girdle muscular dystrophy 21 (LGMDR21) is caused by pathogenic variants in protein O-glucosyltransferase 1 (POGLUT1), which is responsible for O-glucosylation of specific epidermal growth factor (EGF) repeats found in ∼50 mammalian proteins, including Notch receptors. Previous data from patient biopsies indicated that impaired Notch signaling, reduction of muscle stem cells, and accelerated differentiation are probably involved in disease etiopathology. Using patient induced pluripotent stem cells (iPSCs), their corrected isotypes, and control iPSCs, gene expression profiling indicated dysregulation of POGLUT1, NOTCH, muscle development, extracellular matrix (ECM), cell adhesion, and migration as involved pathways. They also exhibited reduced in vitro POGLUT1 enzymatic activity and NOTCH signaling as well as defective myogenesis, proliferation, migration and differentiation. Furthermore, in vivo studies demonstrated significant reductions in engraftment, muscle stem cell formation, PAX7 expression, and maintenance, along with an increased percentage of mislocalized PAX7 + cells in the interstitial space. Gene correction in patient iPSCs using CRISPR-Cas9 nickase led to the rescue of the main  in vitro and in vivo phenotypes. These results demonstrate the efficacy of iPSCs and gene correction in disease modeling and rescue of the phenotypes and provide evidence of the involvement of muscle stem cell niche localization, PAX7 expression, and cell migration as possible mechanisms in LGMDR21. Competing Interests: The authors declare no competing interests. (© 2023 The Authors.)
Databáze:	MEDLINE
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