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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2020, Vol. 14 Issue (3) : 262-272    https://doi.org/10.1007/s11684-019-0717-5
REVIEW
Evidence for lung repair and regeneration in humans: key stem cells and therapeutic functions of fibroblast growth factors
Xuran Chu1,4, Chengshui Chen2, Chaolei Chen2, Jin-San Zhang1,2,3, Saverio Bellusci2,3,4(), Xiaokun Li1()
1. School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
2. Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
3. Institute of Life Sciences, Wenzhou University, Wenzhou 325035, China
4. Cardio-Pulmonary Institute, Universities of Giessen and Marburg Lung Center, member of the German Center for Lung Research, Justus-Liebig-University Giessen, 35392 Giessen, Germany
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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     
Corresponding Authors: Saverio Bellusci,Xiaokun Li   
Just Accepted Date: 18 September 2019   Online First Date: 19 November 2019    Issue Date: 08 June 2020
 Cite this article:   
Xuran Chu,Chengshui Chen,Chaolei Chen, et al. Evidence for lung repair and regeneration in humans: key stem cells and therapeutic functions of fibroblast growth factors[J]. Front. Med., 2020, 14(3): 262-272.
 URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-019-0717-5
http://academic.hep.com.cn/fmd/EN/Y2020/V14/I3/262
Fig.1  Different populations of cells are located along the proximal-distal axis on the human lung (adapted from [23]).
Stem cells Markers Differentiation capabilities Lineage-tracing Reference
Bronchial and alveolar lineages
Broncho-alveolar stem cells (BASCs) Sftoc, Scgb1a1 BASCs, club, AT2 Sftpc-Dre-ERT2 and Scgb1a1-CreERT2 with a new reporter cassette [20]
Basal cells Trp63, Krt5, Krt14, Ngfr, Pdn Basal, club, ciliated, AT1, AT2 Krt14-CreERT2 [11]
Lineage negative epithelial progenitor cells (LNEPs) Integrin α6, integrin β4 LNEP, club, ciliated, AT1, AT2 Sftpc-CreERT2 [21]
Bronchial lineages
Club cells Scgb1a1, Cyp2f2 high Club, ciliated, basal Scgb1a1-CreERT2 [12-14]
Variant of club cells Scgb1a1, Cyp2f2 low Club, ciliated, basal Scgb1a1-CreERT2, Upk3a-CreERT2 [13,15]
Basal cells Trp63, Krt5, Krt14, Ngfr, Pdn Basal, club, ciliated Krt5-CreERT2, Krt14-CreERT2 [61,65]
Alveolar lineages
AT2 Sftpc AT2, AT1 Sftpc-CreERT2 [16,17]
AT1 Hopx, Aqp5, Pdpn AT1, AT2 Hopx-CreERT2 [18,19]
Tab.1  Key stem cells for regeneration in lung
Fig.2  Key epithelial stem cells and their associated stromal niches involved in repair/regeneration in the distal part of the human lung.
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