한빛사 논문
Abstract
Jiho Jang PhD1, Hoon-Chul Kang MD, PhD2, Han-Soo Kim PhD3, Ji Young Kim MS1, Yong Jun Huh MS1, Dae-Sung Kim PhD1, Jeong-Eun Yoo BS1, Jeong-Ah Lee BS1, Boyoung Lim BS1, Jiwon Lee MS1, Tae-Min Yoon MS4, In-Hyun Park PhD5,6, Dong-Youn Hwang PhD4, George Q. Daley MD, PhD5,6, Dong-Wook Kim PhD1,*
1Department of Physiology, Brain Korea 21 Project for Medical Science and Severance Biomedical Science Institute, Seoul, Korea
2Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea
3Department of Laboratory Medicine and Cell Therapy Center, Yonsei University College of Medicine, Seoul, Korea
4CHA Stem Cell Institute, CHA University College of Medicine, Seoul, Korea
5Department of Medicine, Division of Pediatric Hematology and Oncology, Children's Hospital Boston, Boston, MA
6Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA
Jiho Jang and Hoon-Chul Kang contributed equally to this work.
*Correspondence: Dong-Wook Kim PhD, Department of Physiology, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemoon-gu, Seoul, Korea 120-752
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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