iPSC-derived mesenchymal cells that support alveolar organoid development

Area of Science:

• Stem cell biology
• Developmental biology
• Respiratory medicine

Background:

• Mesenchymal cells are crucial for organ development, with lung fibroblasts supporting airway and alveolar epithelial cells.
• Generating functional lung organoids is essential for studying lung development and disease.

Purpose of the Study:

• To develop a method for generating human induced pluripotent stem cell-derived mesenchymal cells (iMESs).
• To investigate the potential of iMESs to induce human alveolar and airway epithelial lineages in organoids.
• To assess the utility of iPSC-derived lung organoids for disease modeling.

Main Methods:

• Generation of human induced pluripotent stem cell-derived mesenchymal cells (iMESs).
• Transcriptome comparison of iMESs with dermal and lung fibroblasts.
• Co-culture of iMESs with iPSC-derived epithelial cells to form organoids.
• Infection of organoids with influenza A (H1N1) and SARS-CoV-2 viruses.

Main Results:

• iMESs exhibited lung mesenchyme features and induced alveolar type 2 (AT2) cell differentiation.
• RSPO2 and RSPO3 expression in iMESs was critical for AT2 cell induction.
• iPSC-derived alveolar organoids effectively modeled responses to influenza A and SARS-CoV-2 infections.

Conclusions:

• Human iPSC-derived mesenchymal cells (iMESs) provide a valuable tool for generating lung organoids without fetal fibroblasts.
• iMESs possess the capacity to induce key lung epithelial cell types, facilitating organoid development.
• These iPSC-derived lung organoids serve as a robust platform for studying viral respiratory infections and modeling lung diseases.