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Nat Biomed Eng. 2019 Jul;3(7):571-582. doi: 10.1038/s41551-019-0381-8. Epub 2019 Apr 8.

Comparison of three congruent patient-specific cell types for the modelling of a human genetic Schwann-cell disorder.

Mukherjee-Clavin B1,2, Mi R2,3, Kern B4,5, Choi IY1, Lim H1, Oh Y1,6, Lannon B7,8,9, Kim KJ10, Bell S10, Hur JK11,12, Hwang W13, Che YH12, Habib O11, Baloh RH10,14, Eggan K7, Brandacher G4, Hoke A2,3, Studer L15, Kim YJ16,17, Lee G18,19,20.

Author information

1
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
2
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
3
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
4
Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
5
Department of Surgery, Charité-Universitätsmedizin, Berlin, Germany.
6
Department of Medicine, College of Medicine, Hanyang University, Seoul, South Korea.
7
Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.
8
Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
9
Boston IVF, Waltham, MA, USA.
10
Board of Governors Regenerative Medicine Institute, Los Angeles, CA, USA.
11
Department of Pathology, College of Medicine, Kyung Hee University, Seoul, South Korea.
12
Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul, South Korea.
13
Data Science for Knowledge Creation Research Centre, Seoul National University, Seoul, South Korea.
14
Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
15
Developmental Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY, USA.
16
Department of Pathology, College of Medicine, Kyung Hee University, Seoul, South Korea. yjkim1@khu.ac.kr.
17
Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul, South Korea. yjkim1@khu.ac.kr.
18
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA. glee48@jhmi.edu.
19
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. glee48@jhmi.edu.
20
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. glee48@jhmi.edu.

Abstract

Patient-specific human-induced pluripotent stem cells (hiPSCs) hold great promise for the modelling of genetic disorders. However, these cells display wide intra- and interindividual variations in gene expression, which makes distinguishing true-positive and false-positive phenotypes challenging. Data from hiPSC phenotypes and human embryonic stem cells (hESCs) harbouring the same disease mutation are also lacking. Here, we report a comparison of the molecular, cellular and functional characteristics of three congruent patient-specific cell types-hiPSCs, hESCs and direct-lineage-converted cells-derived from currently available differentiation and direct-reprogramming technologies for use in the modelling of Charcot-Marie-Tooth 1A, a human genetic Schwann-cell disorder featuring a 1.4 Mb chromosomal duplication. We find that the chemokines C-X-C motif ligand chemokine-1 (CXCL1) and macrophage chemoattractant protein-1 (MCP1) are commonly upregulated in all three congruent models and in clinical patient samples. The development of congruent models of a single genetic disease using somatic cells from a common patient will facilitate the search for convergent phenotypes.

PMID:
30962586
PMCID:
PMC6612317
[Available on 2019-10-08]
DOI:
10.1038/s41551-019-0381-8

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