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

• DOI: 10.1101/2024.02.06.577460
• Publication Date: 2024-02-08T01:20:30Z
• Authors: Yifei Miao; Cheng Tan; Nicole M. Pek; Zhiyun Yu; Kentaro Iwasawa; Daniel O. Kechele; Nambirajan Sundaram; Victor Pastrana-G...; Keishi Kishimoto; Min-Chi Yang; Cheng Jiang; Jason Tchieu; Jeffrey A. Whitsett; 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
• Keywords: Mesenchyme; Organoid; Cell fate determination

Summary To investigate the co-development of vasculature, mesenchyme, and epithelium crucial for organogenesis acquisition organ-specific characteristics, we constructed a human pluripotent stem cell-derived organoid system comprising lung or intestinal surrounded by organotypic mesenchyme vasculature. We demonstrated pivotal role co-differentiating mesoderm endoderm via precise BMP regulation in generating multilineage organoids gut tube patterning. Single-cell RNA-seq analysis revealed organ specificity endothelium uncovered key ligands driving endothelial specification (e.g., WNT2B Semaphorins) intestine GDF15). Upon transplantation under kidney capsule mice, these further matured developed perfusable human-specific sub-epithelial capillaries. Additionally, our model recapitulated abnormal endothelial-epithelial crosstalk patients with FOXF1 deletion mutations. Multilineage provide unique platform to study developmental cues guiding mesenchymal cell fate determination, intricate cell-cell communications disease. Highlights signaling fine-tunes co-differentiation endoderm. The cellular composition resembles that fetal organs. Mesenchyme co-developed within adopt characteristics. recapitulate FOXF1-associated disorders.