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

Bipasha Mukherjee-Clavin; Ruifa Mi; Barbara Kern; In Young Choi; Hotae Lim; Yohan Oh; Benjamin Lannon; Kevin J Kim; Shaughn Bell; Junho K Hur; Woochang Hwang; Young Hyun Che; Omer Habib; Robert H Baloh; Kevin Eggan; Gerald Brandacher; Ahmet Hoke; Lorenz Studer; Yong Jun Kim; Gabsang Lee

doi:10.1038/s41551-019-0381-8

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

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

Authors

Bipasha Mukherjee-Clavin^{1

2}, Ruifa Mi^{2

3}, Barbara Kern^{4

5}, In Young Choi¹, Hotae Lim¹, Yohan Oh^{1

6}, Benjamin Lannon^{7

8

9}, Kevin J Kim¹⁰, Shaughn Bell¹⁰, Junho K Hur^{11

12}, Woochang Hwang¹³, Young Hyun Che¹², Omer Habib¹¹, Robert H Baloh^{10

14}, Kevin Eggan⁷, Gerald Brandacher⁴, Ahmet Hoke^{2

3}, Lorenz Studer¹⁵, Yong Jun Kim^{16

17}, Gabsang Lee^{18

19

20}

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Animals
CRISPR-Cas Systems
Cell Differentiation / genetics
Cell Line
Cell Lineage / genetics
Cells, Cultured
Cellular Reprogramming
Chemokine CCL2 / genetics*
Chemokine CCL2 / metabolism
Chemokine CXCL1 / genetics*
Chemokine CXCL1 / metabolism
Chemokines
Embryonic Stem Cells / pathology
Female
Gene Editing
Gene Expression
Gene Expression Profiling
Genetic Diseases, Inborn*
Genetic Predisposition to Disease / genetics
Human Genetics
Humans
Induced Pluripotent Stem Cells / metabolism*
Induced Pluripotent Stem Cells / pathology
Male
Mice
Mice, Inbred NOD
Myelin Proteins / genetics
Myelin Proteins / metabolism
Octamer Transcription Factor-3 / genetics
Octamer Transcription Factor-3 / metabolism
Phenotype
Rats
SOXE Transcription Factors / genetics
SOXE Transcription Factors / metabolism
Schwann Cells / metabolism*
Schwann Cells / pathology
Transplantation

Substances

CCL2 protein, human
CXCL1 protein, human
Chemokine CCL2
Chemokine CXCL1
Chemokines
Myelin Proteins
Octamer Transcription Factor-3
PMP22 protein, human
POU5F1 protein, human
SOX10 protein, human
SOXE Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding