Article Impact Level: HIGH Data Quality: STRONG Summary of Cell, S0092867425006282. https://doi.org/10.1016/j.cell.2025.05.041 Dr. Yifei Miao et al.
Points
- Researchers grew vascularized lung and intestinal organoids from stem cells by simultaneously co-differentiating mesodermal and endodermal tissues, which better mimics the natural human organogenesis that occurs during early development.
- The crucial Bone Morphogenetic Protein signaling pathway was identified as precisely controlling the ratio of epithelial to endothelial progenitor cells required to form organ-specific vascular networks.
- These advanced organoids demonstrated significantly enhanced maturation and cellular diversity, and their engineered vasculature successfully integrated with host circulation while retaining organ specificity when transplanted into mice.
- Using patient-derived stem cells, this new method successfully recreated the primary vascular defects and secondary lung abnormalities found in a rare congenital disease caused by FOXF1 mutations.
- This multilineage organoid system offers a powerful new platform for investigating complex cell-to-cell communications, advancing disease modeling, and reducing reliance on traditional animal testing for research.
Summary
A recent study details the successful generation of vascularized lung and intestinal organoids from induced pluripotent stem cells (iPSCs) using a novel co-differentiation method. Researchers have discovered that directing iPSCs to simultaneously differentiate into both mesodermal and endodermal lineages within the same spheroid more accurately recapitulates embryonic development than assembling pre-differentiated components. This approach addresses a critical limitation of conventional organoid models, which typically lack an integrated, organ-specific vascular network essential for physiological function and maturation. This integrated system provides a more accurate in vitro model of human organogenesis.
The investigators identified Bone Morphogenetic Protein (BMP) signaling as the key pathway for modulating the endoderm-to-mesoderm ratio, enabling precise control over the proportions of epithelial and endothelial progenitors. Subsequent single-cell RNA sequencing (scRNA-seq) analysis confirmed the development of distinct, organ-specific gene signatures in the endothelium and mesenchyme. Functionally, the resulting organotypic vasculature significantly enhanced organoid maturation, cellular diversity, and tissue-specific features, including alveolar formation in lung models. When transplanted into mice, the engineered vasculature successfully anastomosed with the host circulation while retaining its organ-specific identity.
The platform’s translational value was demonstrated by modeling alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), a rare congenital disorder caused by mutations in the forkhead box F1 (FOXF1) gene. Using patient-derived iPSCs, the vascularized lung organoids faithfully recapitulated the disease’s primary vascular defects and secondary epithelial abnormalities. This multilineage organoid system establishes a powerful new platform for investigating complex endothelial-epithelial crosstalk in human development and pathology, with significant potential for disease modeling and future therapeutic screening.
Link to the article: https://www.cell.com/cell/abstract/S0092-8674(25)00628-2
References Miao, Y., Pek, N. M., Tan, C., Jiang, C., Yu, Z., Iwasawa, K., Shi, M., Kechele, D. O., Sundaram, N., Pastrana-Gomez, V., Sinner, D. I., Liu, X., Lin, K. C., Na, C.-L., Kishimoto, K., Yang, M.-C., Maharjan, S., Tchieu, J., Whitsett, J. A., … Gu, M. (2025). Co-development of mesoderm and endoderm enables organotypic vascularization in lung and gut organoids. Cell, S0092867425006282. https://doi.org/10.1016/j.cell.2025.05.041
