iPSC-derived mesenchymal cells that support alveolar organoid development

Koji Tamai; Kouji Sakai; Haruka Yamaki; Keita Moriguchi; Koichi Igura; Shotaro Maehana; Takahiro Suezawa; Kazuaki Takehara; Masatoshi Hagiwara; Toyohiro Hirai; Shimpei Gotoh

doi:10.1016/j.crmeth.2022.100314

iPSC-derived mesenchymal cells that support alveolar organoid development

Cell Rep Methods. 2022 Sep 19;2(10):100314. doi: 10.1016/j.crmeth.2022.100314. eCollection 2022 Oct 24.

Authors

Koji Tamai¹, Kouji Sakai^{2

3}, Haruka Yamaki¹, Keita Moriguchi⁴, Koichi Igura¹, Shotaro Maehana^{5

6

7}, Takahiro Suezawa⁴, Kazuaki Takehara^{8

9}, Masatoshi Hagiwara¹⁰, Toyohiro Hirai¹, Shimpei Gotoh^{1

4

11}

Affiliations

¹ Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
² Department of Veterinary Science, National Institute of Infectious Diseases, Tokyo, Japan.
³ Department of Virology 3, National Institute of Infectious Diseases, Tokyo, Japan.
⁴ Department of Drug Discovery for Lung Diseases, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
⁵ Department of Environmental Microbiology, Graduate School of Medical Sciences, Kitasato University, Kanagawa, Japan.
⁶ Department of Microbiology, School of Allied Health Sciences, Kitasato University, Kanagawa, Japan.
⁷ Regenerative Medicine and Cell Design Research Facility, Kanagawa, Japan.
⁸ Laboratory of Animal Health, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan.
⁹ Laboratory of Animal Health, Cooperative Division of Veterinary Science, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan.
¹⁰ Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
¹¹ Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.

Abstract

Mesenchymal cells are necessary for organ development. In the lung, distal tip fibroblasts contribute to alveolar and airway epithelial cell differentiation and homeostasis. Here, we report a method for generating human induced pluripotent stem cell (iPSC)-derived mesenchymal cells (iMESs) that can induce human iPSC-derived alveolar and airway epithelial lineages in organoids via epithelial-mesenchymal interaction, without the use of allogenic fetal lung fibroblasts. Through a transcriptome comparison of dermal and lung fibroblasts with their corresponding reprogrammed iPSC-derived iMESs, we found that iMESs had features of lung mesenchyme with the potential to induce alveolar type 2 (AT2) cells. Particularly, RSPO2 and RSPO3 expressed in iMESs directly contributed to AT2 cell induction during organoid formation. We demonstrated that the total iPSC-derived alveolar organoids were useful for characterizing responses to the influenza A (H1N1) virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, demonstrating their utility for disease modeling.

Keywords: SARS-CoV-2; influenza virus; lung; mesenchymal cell; organoid; pluripotent stem cell.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

COVID-19* / metabolism
Humans
Induced Pluripotent Stem Cells*
Influenza A Virus, H1N1 Subtype*
Organoids
SARS-CoV-2