Vessel Organoids Reveal FOXF1 Variant-Specific Regulation of Mesoderm and Capillary Development

Area of Science:

• Developmental Biology
• Genetics
• Stem Cell Biology

Background:

• Understanding how genetic variants in transcription factors affect human development is limited by a lack of suitable models.
• Forkhead Box F1 (FOXF1) is crucial for mesoderm and vascular development, but its variant-specific roles are unclear.

Purpose of the Study:

• To investigate the variant-specific functions of FOXF1 in human mesoderm and vascular development using patient-derived induced pluripotent stem cells (hiPSCs) and organoids.
• To elucidate the molecular mechanisms underlying different FOXF1 variant effects on capillary development.

Main Methods:

• Generation of vessel organoids from hiPSCs harboring unique FOXF1 variants.
• Single-nucleus multiomic analysis to assess variant-specific effects on cell differentiation and states.
• Lipid nanoparticle-mediated mRNA delivery to restore wild-type FOXF1 function.

Main Results:

• Heterozygous FOXF1 variants cause capillary maldevelopment of varying severity.
• A severe variant (p.F85I) impairs mesoderm differentiation and vascular progenitor specification.
• Moderate variants alter vascular progenitor cell states and function.
• FOXF1 mRNA delivery rescued capillary formation in a variant- and stage-dependent manner.

Conclusions:

• Different FOXF1 variants disrupt distinct, stage-specific functions in human mesoderm-to-vascular development.
• Findings highlight the necessity for variant-specific therapeutic approaches for capillary disorders.
• Human vessel organoids are a powerful model for studying developmental gene variant functions.