Functional replacement of mouse lungs by human-derived lung cells

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K19525
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 53:Organ-based internal medicine and related fields
• Research Institution: Kyoto University
• Principal Investigator: Gotoh Shimpei 京都大学, iPS細胞研究所, 教授 (50747219)
• Co-Investigator(Kenkyū-buntansha): 濱路 政嗣 京都大学, 医学研究科, 講師 (70782142)
• Project Period (FY): 2022-06-30 – 2024-03-31
• Keywords: 肺胞 / iPS細胞 / 多能性幹細胞 / 移植 / 再生

Outline of Final Research Achievements

First, a human iPS cell reporter line was established for visualizing the engrafted cells in the living mice. Next, we stepwise induced lung progenitor cells and transplanted them to the left lung of the host mice after ablating the left lung type II alveolar epithelial cells and intubation using a mouse bronchoscope. However, because of the severe lung injury caused by alveolar type II cell ablation, we decided to avoid cell transplantation into both lungs. Instead, we prioritized improving the replacement of the mouse lung cells by engrafted human cells in the left lung. To evaluate the function of human alveolar epithelium engrafted in the mouse lung, we transplanted the lung progenitor cells derived from the disease-specific iPS cells whose alveolar epithelium were responsible for the disease progression. We successfully engrafted them in the mice lung and were able to recapitulate a part of the disease.

Free Research Field

呼吸器学

Academic Significance and Societal Importance of the Research Achievements

ヒト多能性幹細胞から分化誘導して得られた細胞が移植後に生体内で適切に機能しているかどうかを検証する手段には従来より限界があったが、本研究成果はこの問題の解決に向けたものである。ヒトiPS細胞から分化誘導した肺前駆細胞をマウス肺に移植し、様々な細胞間相互作用や呼吸や循環動態に伴う物理的な力も加わる生体内での機能再構築を試みた研究成果として、ヒトiPS細胞由来の肺胞上皮細胞が肺胞領域に生着して機能まで示せたのは世界初の画期的な知見といえる。呼吸器の再生医療の技術開発の突破口の一つであり、ヒト由来細胞の疾患モデルの今後の新しい展開も期待できる挑戦的萌芽研究に相応しい結果を得ることができた。