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J Cell Biol. 2016 Oct 24;215(2):187-202. Epub 2016 Oct 17.

The mitochondrial protein CHCHD2 primes the differentiation potential of human induced pluripotent stem cells to neuroectodermal lineages.

Author information

1
Institute of Genetic Medicine, Newcastle University, Newcastle NE1 3BZ, England, UK.
2
Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle NE1 3BZ, England, UK.
3
Institute for Ageing and Health, Newcastle University, Newcastle NE1 3BZ, England, UK.
4
Wellcome Trust-Medical Research Council Stem Cell Institute, Hinxton, Cambridge CB10 1SA, England, UK.
5
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, England, UK.
6
Princess Al Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
7
Institute of Genetic Medicine, Newcastle University, Newcastle NE1 3BZ, England, UK lyle.armstrong@ncl.ac.uk majlinda.lako@ncl.ac.uk.

Abstract

Human induced pluripotent stem cell (hiPSC) utility is limited by variations in the ability of these cells to undergo lineage-specific differentiation. We have undertaken a transcriptional comparison of human embryonic stem cell (hESC) lines and hiPSC lines and have shown that hiPSCs are inferior in their ability to undergo neuroectodermal differentiation. Among the differentially expressed candidates between hESCs and hiPSCs, we identified a mitochondrial protein, CHCHD2, whose expression seems to correlate with neuroectodermal differentiation potential of pluripotent stem cells. We provide evidence that hiPSC variability with respect to CHCHD2 expression and differentiation potential is caused by clonal variation during the reprogramming process and that CHCHD2 primes neuroectodermal differentiation of hESCs and hiPSCs by binding and sequestering SMAD4 to the mitochondria, resulting in suppression of the activity of the TGFβ signaling pathway. Using CHCHD2 as a marker for assessing and comparing the hiPSC clonal and/or line differentiation potential provides a tool for large scale differentiation and hiPSC banking studies.

PMID:
27810911
PMCID:
PMC5084643
DOI:
10.1083/jcb.201601061
[Indexed for MEDLINE]
Free PMC Article

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