Trisomy 12 compromises the mesendodermal differentiation propensity of human pluripotent stem cells

Area of Science:

• Stem cell biology
• Genetics
• Developmental biology

Background:

• Trisomy 12 is a common chromosomal abnormality in cultured human pluripotent stem cells (hPSCs).
• Previous studies noted potential oncogenic properties and altered cell cycle in trisomy 12 hPSCs.
• The impact of trisomy 12 on hPSC differentiation remained largely unexplored.

Purpose of the Study:

• To investigate the consequences of trisomy 12 on the differentiation potential of hPSCs.
• To determine if trisomy 12 affects mesendodermal differentiation, a critical process for regenerative medicine.

Main Methods:

• Identification of hPSC sublines with trisomy 12 after prolonged culture.
• Transcriptome analysis to identify gene expression abnormalities.
• Assessment of mesendodermal differentiation using embryoid bodies in serum-free conditions.
• Evaluation of BMP4-induced exit from self-renewal and lineage-specific differentiation.

Main Results:

• hPSC sublines with trisomy 12 exhibited abnormal gene expression patterns, including in cancer-related cell cycle and other signaling pathways.
• These trisomy 12 hPSCs showed reduced mesendodermal differentiation capacity.
• BMP4-induced exit from self-renewal and upregulation of key transcription factors were impaired.
• Differentiation efficiency into hematopoietic and hepatic lineages was compromised.

Conclusions:

• Trisomy 12 significantly compromises mesendodermal differentiation in hPSCs.
• This chromosomal abnormality disrupts genome-wide expression patterns essential for proper differentiation.
• The findings have implications for regenerative medicine, drug development, and developmental biology studies utilizing hPSCs.