Engraftment and proliferation potential of embryonic lung tissue cells in irradiated mice with emphysema

Kazushige Shiraishi,Tatsuya Tsukui,Shigeyuki Shichino,Shinichi Hashimoto,Kouji Matsushima,Satoshi Ueha

doi:10.1038/s41598-019-40237-x

Kazushige Shiraishi, Tatsuya Tsukui + Show 4 more

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https://doi.org/10.1038/s41598-019-40237-x

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Abstract

Recently, there has been increasing interest in stem cell transplantation therapy, to treat chronic respiratory diseases, using lung epithelial cells or alveolospheres derived from endogenous lung progenitor cells. However, optimal transplantation strategy of these cells has not been addressed. To gain insight into the optimization of stem cell transplantation therapy, we investigated whether lung cell engraftment potential differ among different developmental stages. After preconditioning with irradiation and elastase to induce lung damage, we infused embryonic day 15.5 (E15.5) CAG-EGFP whole lung cells, and confirmed the engraftment of epithelial cells, endothelial cells, and mesenchymal cells. The number of EGFP-positive epithelial cells increased from day 7 to 28 after infusion. Among epithelial cells derived from E13.5, E15.5, E18.5, P7, P14, and P56 mice, E15.5 cells demonstrated the most efficient engraftment. In vitro, E15.5 epithelial cells showed high proliferation potential. Transcriptome analyses of sorted epithelial cells from E13.5, E15.5, E18.5, P14, and P56 mice revealed that cell cycle and cell-cell adhesion genes were highly enriched in E15.5 epithelial cells. Our findings suggest that cell therapy for lung diseases might be most effective when epithelial cells with transcriptional traits similar to those of E15.5 epithelial cells are used.

Highlights

Stem cell transplantation therapy for chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD), is attracting widespread interest in the field of respiratory medicine[1]
To determine whether fetal lung progenitors can be engrafted into mouse models of emphysema, and whether these progenitor cells have the potential to reconstruct alveolar walls, we first intratracheally transplanted E15.5 CAG-EGFP total lung cells or sorted Epcam+ cells into elastase-treated mice, it did not yield efficient engraftment (Supplementary Fig. S1A, S1B)
To gain insight into the optimization of stem cell transplantation therapy, we showed that E15.5 epithelial cells have maximal engraftment potential in vivo, and exhibit high proliferation potential in vitro, compared to those of epithelial cells derived from other developmental stages

Summary

Introduction

Stem cell transplantation therapy for chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD), is attracting widespread interest in the field of respiratory medicine[1]. Lung epithelial cells or alveolospheres, derived from induced pluripotent stem (iPS) cells, and endogenous lung progenitor cells are potentially suitable for transplantation therapy to treat chronic respiratory diseases[1]. Difficulties underlying the successful transplantation of progenitor cells have delayed progress in this field This problem was partially solved by Rosen et al, who reported that intravenously administered murine canalicular-stage fetal lung progenitors can be successfully engrafted into irradiated mice with naphthalene-induced damage to the airway[8]. To gain insight into the optimization of stem cell transplantation therapies, we investigated whether cell engraftment or proliferation potential differs among different lung developmental stages using mouse models of elastase-induced emphysema, in which alveoli are expected to be injured. We clarified the in vitro proliferation potential and transcriptional signatures of the potent epithelial cell population

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