Functional antagonism between ΔNp63α and GCM1 regulates human trophoblast stemness and differentiation

Area of Science:

• Developmental Biology
• Stem Cell Biology
• Reproductive Medicine

Background:

• Chemical induction using EGF/CASVY cocktail efficiently derives trophoblast stem (TS) cells from human blastocysts and early placental cells.
• Deriving TS cells from term cytotrophoblasts remains challenging, with the underlying molecular mechanisms unclear.

Purpose of the Study:

• To elucidate the molecular mechanism of chemical induction of trophoblast stem cells from human term cytotrophoblasts.
• To establish an efficient method for deriving TS cells from term placentas.

Main Methods:

• Investigated the functional antagonism between placental transcription factor GCM1 and stemness regulator ΔNp63α.
• Utilized EGF/CASVY cocktail and hypoxia to modulate GCM1 and ΔNp63α activity.
• Identified GCM1 target genes, including mitochondrial creatine kinase 1 (CKMT1).

Main Results:

• Demonstrated that ΔNp63α antagonizes GCM1 activity, and EGF/CASVY cocktail activates ΔNp63α, facilitating TS cell derivation.
• Showed that hypoxia further reduces GCM1 activity, enabling TS cell induction from term cytotrophoblasts.
• Identified CKMT1 as a key GCM1 target essential for syncytiotrophoblast differentiation and found its expression decreased in preeclampsia.

Conclusions:

• The study reveals the molecular basis of trophoblast stemness and differentiation, centered on GCM1 and ΔNp63α antagonism.
• An efficient method for deriving TS cells from term placentas was established, offering potential for preeclampsia research.
• Decreased CKMT1 expression in preeclampsia highlights its role in placental dysfunction.