Evidence for lung repair and regeneration in humans: key stem cells and therapeutic functions of fibroblast growth factors

Abstract

Regeneration carries the idea of regrowing partially or completely a missing organ. Repair, on the other hand, allows restoring the function of an existing but failing organ. The recognition that human lungs can both repair and regenerate is quite novel, the concept has not been widely used to treat patients. We present evidence that the human adult lung does repair and regenerate and introduce different ways to harness this power. Various types of lung stem cells are capable of proliferating and differentiating upon injury driving the repair/regeneration process. Injury models, primarily in mice, combined with lineage tracing studies, have allowed the identification of these important cells. Some of these cells, such as basal cells, broncho-alveolar stem cells, and alveolar type 2 cells, rely on fibroblast growth factor (FGF) signaling for their survival, proliferation and/or differentiation. While pre-clinical studies have shown the therapeutic benefits of FGFs, a recent clinical trial for acute respiratory distress syndrome (ARDS) using intravenous injection of FGF7 did not report the expected beneficial effects. We discuss the potential reasons for these negative results and propose the rationale for new approaches for future clinical trials, such as delivery of FGFs to the damaged lungs through efficient inhalation systems, which may be more promising than systemic exposure to FGFs. While this change in the administration route presents a challenge, the therapeutic promises displayed by FGFs are worth the effort.

Keywords

FGF / human lung / repair / regeneration / stem cells

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Acknowledgements

We would like to thank Matthew Jones for the critical reading of this manuscript. Saverio Bellusci is supported by the Cardio-Pulmonary Institute and by grants from the Deutsche Forschungsgemeinschaft (DFG; Nos. BE4443/1-1, BE4443/4-1, BE4443/6-1, KFO309 P7, and SFB1213-projects A02 and A04). Jin-San Zhang is partially supported by start-up packages from Whenzhou Medical University and Wenzhou University. Xiaokun Li is partially funded by the National Key R&D Program of China (No. 2017YFA0506000). Chengshui Chen and Chaolei Chen are funded by the National Natural Science Foundation of China (Nos. 81570075, 81770074, 81600062).

Compliance with ethics guidelines

Xuran Chu, Chengshui Chen, Chaolei Chen, Jin-San Zhang, Saverio Bellusci, and Xiaokun Li declare that they have no conflict of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

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