HNF4α Acts as Upstream Functional Regulator of Intestinal Wnt3 and Paneth Cell Fate

Area of Science:

• Gastroenterology
• Stem Cell Biology
• Molecular Biology

Background:

• The intestinal epithelium renews via Lgr5+ stem cells, supported by an epithelial stem cell niche.
• Paneth cells supply Wnt3, crucial for stem cell activity, but their maturation regulators are poorly understood.
• HNF4α's role in intestinal differentiation is unclear, especially its intrinsic function without mesenchymal Wnt support.

Purpose of the Study:

• To investigate the intrinsic role of HNF4α in intestinal epithelial cell growth and fate.
• To dissect HNF4α's function in maintaining jejunal epithelial cultures (enteroids) with or without mesenchymal cells.

Main Methods:

• Transcriptomic analyses of jejunal enteroids cultured ex vivo.
• Comparison of enteroids with and without compensatory mesenchymal cells.
• Assessment of HNF4α's role following its deletion in enteroids.

Main Results:

• HNF4α is critical for the growth and survival of jejunal enteroids.
• HNF4α autonomously regulates Wnt3 transcription and Paneth cell differentiation.
• Wnt3a supplementation or mesenchymal co-culture rescued enteroid death upon Hnf4a deletion.

Conclusions:

• HNF4α intrinsically regulates Paneth cell homeostasis.
• HNF4α is vital for intestinal epithelium renewal independently of mesenchymal Wnt signaling.