The mitochondrial protein CHCHD2 primes the differentiation potential of human induced pluripotent stem cells to neuroectodermal lineages.
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.
Institute of Genetic Medicine, Newcastle University, Newcastle NE1 3BZ, England, UK.
Lili
http://orcid.org/0000-0002-1054-1359
L
Zhu
Institute of Genetic Medicine, Newcastle University, Newcastle NE1 3BZ, England, UK.|Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle NE1 3BZ, England, UK.
Aurora
A
Gomez-Duran
Institute for Ageing and Health, Newcastle University, Newcastle NE1 3BZ, England, UK.
Gabriele
http://orcid.org/0000-0003-2100-8223
G
Saretzki
Institute of Genetic Medicine, Newcastle University, Newcastle NE1 3BZ, England, UK.
Shibo
http://orcid.org/0000-0003-3514-4605
S
Jin
Wellcome Trust-Medical Research Council Stem Cell Institute, Hinxton, Cambridge CB10 1SA, England, UK.|Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, England, UK.
Katarzyna
K
Tilgner
Institute of Genetic Medicine, Newcastle University, Newcastle NE1 3BZ, England, UK.
Dario
http://orcid.org/0000-0002-5728-4345
D
Melguizo-Sanchis
Institute of Genetic Medicine, Newcastle University, Newcastle NE1 3BZ, England, UK.
Georgios
http://orcid.org/0000-0001-5647-3841
G
Anyfantis
Princess Al Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
Jumana
J
Al-Aama
Wellcome Trust-Medical Research Council Stem Cell Institute, Hinxton, Cambridge CB10 1SA, England, UK.
Ludovic
L
Vallier
Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle NE1 3BZ, England, UK.
Patrick
P
Chinnery
Institute of Genetic Medicine, Newcastle University, Newcastle NE1 3BZ, England, UK lyle.armstrong@ncl.ac.uk majlinda.lako@ncl.ac.uk.
Majlinda
http://orcid.org/0000-0003-1327-8573
M
Lako
Institute of Genetic Medicine, Newcastle University, Newcastle NE1 3BZ, England, UK lyle.armstrong@ncl.ac.uk majlinda.lako@ncl.ac.uk.
Lyle
http://orcid.org/0000-0002-7234-9362
L
Armstrong
D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D002465:Cell Movement / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D065150:Cellular Reprogramming / Q000235:genetics; D004268:DNA-Binding Proteins; D020869:Gene Expression Profiling; D000066449:Human Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D054258:Neural Plate / Q000166:cytology*; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
C580880:CHCHD2 protein, human; D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D016212:Transforming Growth Factor beta