Induced pluripotent stem cell models from X-linked adrenoleukodystrophy patients

Authors

  • Jiho Jang PhD,

    1. Department of Physiology, Brain Korea 21 Project for Medical Science and Severance Biomedical Science Institute, Seoul, Korea
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  • Hoon-Chul Kang MD, PhD,

    1. Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea
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  • Han-Soo Kim PhD,

    1. Department of Laboratory Medicine and Cell Therapy Center, Yonsei University College of Medicine, Seoul, Korea
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  • Ji Young Kim MS,

    1. Department of Physiology, Brain Korea 21 Project for Medical Science and Severance Biomedical Science Institute, Seoul, Korea
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  • Yong Jun Huh MS,

    1. Department of Physiology, Brain Korea 21 Project for Medical Science and Severance Biomedical Science Institute, Seoul, Korea
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  • Dae-Sung Kim PhD,

    1. Department of Physiology, Brain Korea 21 Project for Medical Science and Severance Biomedical Science Institute, Seoul, Korea
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  • Jeong-Eun Yoo BS,

    1. Department of Physiology, Brain Korea 21 Project for Medical Science and Severance Biomedical Science Institute, Seoul, Korea
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  • Jeong-Ah Lee BS,

    1. Department of Physiology, Brain Korea 21 Project for Medical Science and Severance Biomedical Science Institute, Seoul, Korea
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  • Boyoung Lim BS,

    1. Department of Physiology, Brain Korea 21 Project for Medical Science and Severance Biomedical Science Institute, Seoul, Korea
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  • Jiwon Lee MS,

    1. Department of Physiology, Brain Korea 21 Project for Medical Science and Severance Biomedical Science Institute, Seoul, Korea
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  • Tae-Min Yoon MS,

    1. CHA Stem Cell Institute, CHA University College of Medicine, Seoul, Korea
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  • In-Hyun Park PhD,

    1. Department of Medicine, Division of Pediatric Hematology and Oncology, Children's Hospital Boston, Boston, MA
    2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA
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  • Dong-Youn Hwang PhD,

    1. CHA Stem Cell Institute, CHA University College of Medicine, Seoul, Korea
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  • George Q. Daley MD, PhD,

    1. Department of Medicine, Division of Pediatric Hematology and Oncology, Children's Hospital Boston, Boston, MA
    2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA
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  • Dong-Wook Kim PhD

    Corresponding author
    1. Department of Physiology, Brain Korea 21 Project for Medical Science and Severance Biomedical Science Institute, Seoul, Korea
    • Department of Physiology, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemoon-gu, Seoul, Korea 120-752
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Abstract

Objective:

Because of a lack of an appropriate animal model system and the inaccessibility of human oligodendrocytes in vivo, X-linked adrenoleukodystrophy (X-ALD)-induced pluripotent stem cells (iPSCs) would provide a unique cellular model for studying etiopathophysiology and development of therapeutics for X-ALD.

Methods:

We generated and characterized iPSCs of the 2 major types of X-ALD, childhood cerebral ALD (CCALD) and adrenomyeloneuropathy (AMN), and differentiated them into oligodendrocytes and neurons. We evaluated disease-relevant phenotypes by pharmacological and genetic approaches.

Results:

We established iPSCs from the patients with CCALD and AMN. Both CCALD and AMN iPSCs normally differentiated into oligodendrocytes, the cell type primarily affected in the X-ALD brain, indicating no developmental defect due to the ABCD1 mutations. Although low in X-ALD iPSCs, very long chain fatty acid (VLCFA) level was significantly increased after oligodendrocyte differentiation. VLCFA accumulation was much higher in CCALD oligodendrocytes than AMN oligodendrocytes but was not significantly different between CCALD and AMN neurons, indicating that the severe clinical manifestations in CCALD might be associated with abnormal VLCFA accumulation in oligodendrocytes. Furthermore, the abnormal accumulation of VLCFA in the X-ALD oligodendrocytes can be reduced by the upregulated ABCD2 gene expression after treatment with lovastatin or 4-phenylbutyrate.

Interpretation:

X-ALD iPSC model recapitulates the key events of disease development (ie, VLCFA accumulation in oligodendrocytes), provides new clues for better understanding of the disease, and allows for early and accurate diagnosis of the disease subtypes. X-ALD oligodendrocytes can be a useful cell model system to develop new therapeutics for treating X-ALD. ANN NEUROL 2011;

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