Yifei Miao, Nicole M. Pek, Cheng Tan, Cheng Jiang, Zhiyun Yu, Kentaro Iwasawa, Min Shi, Daniel O. Kechele, Nambirajan Sundaram, Victor Pastrana-Gomez, Debora I. Sinner, Xingchen Liu, Ko Chih Lin, Cheng-Lun Na, Keishi Kishimoto, Min-Chi Yang, Sushila Maharjan, Jason Tchieu, Jeffrey A. Whitsett, Yu Shrike Zhang, Kyle W. McCracken, Robbert J. Rottier, Darrell N. Kotton, Michael A. Helmrath, James M. Wells, Takanori Takebe, Aaron M. Zorn, Ya-Wen Chen, Minzhe Guo, Mingxia Gu
Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine. Brigham and Women’s Hospital and Harvard Medical School. Icahn School of Medicine at Mount Sinai. Erasmus MC and Sophia Children’s Hospital. Boston University and Boston Medical Center. David Geffen School of Medicine of the University of California, Los Angeles.
United States and Netherlands
Cell
Cell 2025;
DOI: 10.1016/j.cell.2025.05.041
Abstract
The vasculature and mesenchyme exhibit distinct organ-specific characteristics adapted to local physiological needs, shaped by microenvironmental and cell-cell interactions from early development. To recapitulate this entire process, we co-differentiated mesoderm and endoderm within the same spheroid to vascularize lung and intestinal organoids from induced pluripotent stem cells (iPSCs). Bone morphogenetic protein (BMP) signaling fine-tuned the endoderm-to-mesoderm ratio, a critical step in generating appropriate proportions of endothelial and epithelial progenitors with tissue specificity. Single-cell RNA sequencing (scRNA-seq) revealed organ-specific gene signatures of endothelium and mesenchyme and identified key ligands driving endothelial specification. The endothelium exhibited tissue-specific barrier function, enhanced organoid maturation, cellular diversity, and alveolar formation on the engineered lung scaffold. Upon transplantation into mice, the organoid vasculature integrated with the host circulation while preserving organ specificity, further promoting organoid maturation. Leveraging these vascularized organoids, we uncovered abnormal endothelial-epithelial crosstalk in patients with forkhead box F1 (FOXF1) mutations. Multilineage organoids provide an advanced platform to study intricate cell-to-cell communications in human organogenesis and disease.
Category
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Mechanical and Computer Models of Pulmonary Vascular Disease and Therapy
Genetic Factors Associated with Pulmonary Vascular Disease
Pulmonary Vascular Pathology
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
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