title: Human Pompe disease-induced pluripotent stem cells for pathogenesis modeling, drug testing and disease marker identification.
abstract: Pompe disease is caused by autosomal recessive mutations in the acid alpha-glucosidase (GAA) gene, which encodes GAA. Although enzyme replacement therapy has recently improved patient survival greatly, the results in skeletal muscles and for advanced disease are still not satisfactory. Here, we report the derivation of Pompe disease-induced pluripotent stem cells (PomD-iPSCs) from two patients with different GAA mutations and their potential for pathogenesis modeling, drug testing and disease marker identification. PomD-iPSCs maintained pluripotent features and had low GAA activity and high glycogen content. Cardiomyocyte-like cells (CMLCs) differentiated from PomD-iPSCs recapitulated the hallmark Pompe disease pathophysiological phenotypes, including high levels of glycogen and multiple ultrastructural aberrances. Drug rescue assessment showed that exposure of PomD-iPSC-derived CMLCs to recombinant human GAA reversed the major pathologic phenotypes. Furthermore, l-carnitine treatment reduced defective cellular respiration in the diseased cells. By comparative transcriptome analysis, we identified glycogen metabolism, lysosome and mitochondria-related marker genes whose expression robustly correlated with the therapeutic effect of drug treatment in PomD-iPSC-derived CMLCs. Collectively, these results demonstrate that PomD-iPSCs are a promising in vitro disease model for the development of novel therapeutic strategies for Pompe disease.
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Hsiang-Po
authors.initials: HP
authors.lastname: Huang
authors.forename: Pin-Hsun
authors.initials: PH
authors.lastname: Chen
authors.forename: Wuh-Liang
authors.initials: WL
authors.lastname: Hwu
authors.forename: Ching-Yu
authors.initials: CY
authors.lastname: Chuang
authors.forename: Yin-Hsiu
authors.initials: YH
authors.lastname: Chien
authors.forename: Lee
authors.initials: L
authors.lastname: Stone
authors.forename: Chung-Liang
authors.initials: CL
authors.lastname: Chien
authors.forename: Li-Tzu
authors.initials: LT
authors.lastname: Li
authors.forename: Shu-Chuan
authors.initials: SC
authors.lastname: Chiang
authors.forename: Hsin-Fu
authors.initials: HF
authors.lastname: Chen
authors.forename: Hong-Nerng
authors.initials: HN
authors.lastname: Ho
authors.forename: Chung-Hsuan
authors.initials: CH
authors.lastname: Chen
authors.forename: Hung-Chih
authors.initials: HC
authors.lastname: Kuo
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001483:Base Sequence; D015415:Biomarkers / Q000378:metabolism; D002331:Carnitine / Q000494:pharmacology / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects; D016903:Drug Monitoring; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D006009:Glycogen Storage Disease Type II / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000473:pathology*; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D000520:alpha-Glucosidases / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D015415:Biomarkers; C025946:3-methyladenine; D000520:alpha-Glucosidases; D000225:Adenine; D002331:Carnitine