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

J Cell Biol. 2016 Oct 24;215(2):187-202. doi: 10.1083/jcb.201601061. Epub 2016 Oct 17.


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.

MeSH terms

  • Apoptosis / genetics
  • Base Sequence
  • Cell Differentiation*
  • Cell Line
  • Cell Lineage*
  • Cell Movement / genetics
  • Cell Survival / genetics
  • Cellular Reprogramming / genetics
  • DNA-Binding Proteins
  • Gene Expression Profiling
  • Human Embryonic Stem Cells / cytology
  • Human Embryonic Stem Cells / metabolism
  • Humans
  • Induced Pluripotent Stem Cells / cytology*
  • Induced Pluripotent Stem Cells / metabolism
  • Mitochondria / metabolism
  • Mitochondrial Proteins / metabolism*
  • Neural Plate / cytology*
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction / genetics
  • Transcription Factors / metabolism*
  • Transforming Growth Factor beta / metabolism


  • CHCHD2 protein, human
  • DNA-Binding Proteins
  • Mitochondrial Proteins
  • RNA, Messenger
  • Transcription Factors
  • Transforming Growth Factor beta