Functional maturation of preterm intestinal epithelium through CFTR activation

Area of Science:

• Developmental Biology
• Gastroenterology
• Regenerative Medicine

Background:

• Preterm birth impedes intestinal epithelial development, leading to impaired digestive and absorptive functions.
• Understanding the molecular mechanisms of intestinal maturation is crucial for addressing preterm-related complications.

Purpose of the Study:

• To investigate the potential of extracellular vesicles (EVs) from human Wharton's jelly mesenchymal stem cells to promote intestinal maturation in preterm infants.
• To identify the specific pathways and mediators involved in EV-driven intestinal maturation.

Main Methods:

• Integrated analysis of single-cell RNA sequencing datasets from fetal to adult human intestines.
• Utilized human preterm intestinal models derived from ileal tissue.
• Treated models with extracellular vesicles (EVs), focusing on the EV39 line.
• Performed gene set enrichment analysis and proteomic analysis.
• Assessed cell proliferation, epithelial barrier integrity, and fatty acid uptake.

Main Results:

• Identified distinct enterocyte differentiation trajectories during human intestinal development.
• EV39 treatment significantly upregulated maturation-specific genes and enhanced enterocyte function.
• TGFβ1 signaling pathways were enriched, with TGFβ1 and FGF2 identified as key mediators.
• EV treatment improved cell proliferation, epithelial barrier integrity, and fatty acid uptake via CFTR-dependent mechanisms.

Conclusions:

• Extracellular vesicles, particularly the EV39 line, effectively promote functional maturation of the premature human intestine.
• TGFβ1 and FGF2 are key mediators of EV39's therapeutic effects.
• CFTR activation is a critical component of EV-driven maturation in human preterm models, offering translational potential for clinical applications.