Deciphering Endothelial and Mesenchymal Organ Specification in Vascularized Lung and Intestinal Organoids

Area of Science:

• Developmental Biology
• Stem Cell Biology
• Organogenesis

Background:

• Investigating the co-development of vasculature, mesenchyme, and epithelium is crucial for understanding organogenesis.
• Human pluripotent stem cells offer a model for studying early human development and organ formation.

Approach:

• Constructed a human pluripotent stem cell-derived organoid system with lung or intestinal epithelium, mesenchyme, and vasculature.
• Utilized single-cell RNA sequencing to analyze organ specificity and identify key signaling ligands.
• Transplanted organoids into mice to assess maturation and vascularization in vivo.

Key Points:

• BMP signaling regulates mesoderm and endoderm co-differentiation for multilineage organoid generation and gut tube patterning.
• Organoids exhibit organ-specific characteristics in mesenchyme and endothelium, resembling human fetal organs.
• Identified specific ligands (e.g., WNT2B, Semaphorins, GDF15) driving lung or intestinal endothelial specification.
• Organoids recapitulated abnormal endothelial-epithelial crosstalk observed in FOXF1-associated disorders.

Conclusions:

• Multilineage organoids serve as a platform to study developmental cues influencing cell fate determination.
• This model facilitates investigation of cell-cell communications in human organogenesis and disease.
• The system enables research into the mechanisms underlying developmental disorders like FOXF1-associated conditions.