辛辛那提大学研究小组在研究中取得进展。他们报道了中胚层和内胚层的共同发育使肺和肠道类器官的器官型血管化成为可能。这一研究成果于2025年6月30日发表在国际顶尖学术期刊《细胞》上。
为了概括整个过程，该团队在同一个球体内共分化中胚层和内胚层，从诱导多能干细胞（iPSCs）中分化成血管化的肺和肠类器官。骨形态发生蛋白（BMP）信号调节内胚层与中胚层的比例，这是产生适当比例的内皮细胞和上皮细胞祖细胞具有组织特异性的关键步骤。单细胞RNA测序（scRNA-seq）揭示了内皮和间质的器官特异性基因特征，并确定了驱动内皮规范的关键配体。内皮细胞表现出组织特异性屏障功能，增强了类器官成熟、细胞多样性和肺泡形成。移植到小鼠体内后，类器官血管与宿主循环结合，同时保持器官特异性，进一步促进类器官成熟。利用这些血管化的类器官，该课题组在叉头盒F1 （FOXF1）突变患者中发现了异常的内皮-上皮串扰。多谱系类器官为研究人类器官发生和疾病中复杂的细胞间通讯提供了一个先进的平台。
据悉，脉管系统和间质表现出不同的器官特异性特征，适应于局部生理需求，由微环境和细胞间相互作用形成。
附：英文原文
Title: Co-development of mesoderm and endoderm enables organotypic vascularization in lung and gut organoids
Author: 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
Issue&Volume: 2025-06-30
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.
DOI: 10.1016/j.cell.2025.05.041
Source: https://www.cell.com/cell/abstract/S0092-8674(25)00628-2