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

References

[1] Nagasue N, Yukaya H, Ogawa Y, Kohno H, Nakamura T. Human liver regeneration after major hepatic resection. A study of normal liver and livers with chronic hepatitis and cirrhosis. Ann Surg 1987; 206(1): 30–39

[2] McCusker C, Bryant SV, Gardiner DM. The axolotl limb blastema: cellular and molecular mechanisms driving blastema formation and limb regeneration in tetrapods. Regeneration (Oxf) 2015; 2(2): 54–71

[3] Simkin J, Sammarco MC, Dawson LA, Schanes PP, Yu L, Muneoka K. The mammalian blastema: regeneration at our fingertips. Regeneration (Oxf) 2015; 2(3): 93–105

[4] Tatár-Kiss S, Bardócz S, Kertai P. Changes in L-ornithine decarboxylase activity in regenerating lung lobes. FEBS Lett 1984; 175(1): 131–134

[5] Ad hoc Statement Committee, American Thoracic Society. Mechanisms and limits of induced postnatal lung growth. Am J Respir Crit Care Med 2004; 170(3): 319–343

[6] Gibney BC, Park MA, Chamoto K, Ysasi A, Konerding MA, Tsuda A, Mentzer SJ. Detection of murine post-pneumonectomy lung regeneration by 18FDG PET imaging. EJNMMI Res 2012; 2(1): 48

[7] Butler JP, Loring SH, Patz S, Tsuda A, Yablonskiy DA, Mentzer SJ. Evidence for adult lung growth in humans. N Engl J Med 2012; 367(3): 244–247

[8] Guenthart BA, O’Neill JD, Kim J, Queen D, Chicotka S, Fung K, Simpson M, Donocoff R, Salna M, Marboe CC, Cunningham K, Halligan SP, Wobma HM, Hozain AE, Romanov A, Vunjak-Novakovic G, Bacchetta M. Regeneration of severely damaged lungs using an interventional cross-circulation platform. Nat Commun 2019; 10(1): 1985

[9] Meyer KC.Recent advances in lung transplantation. F1000Res 2018; 7. pii: F1000 Faculty Rev–1684

[10] Hardin CC, Hibbert K. ECMO for severe ARDS. N Engl J Med 2018; 378(21): 2032–2034

[11] Kumar PA, Hu Y, Yamamoto Y, Hoe NB, Wei TS, Mu D, Sun Y, Joo LS, Dagher R, Zielonka EM, Wang Y, Lim B, Chow VT, Crum CP, Xian W, McKeon F. Distal airway stem cells yield alveoli in vitro and during lung regeneration following H1N1 influenza infection. Cell 2011; 147(3): 525–538

[12] Perl AK, Wert SE, Loudy DE, Shan Z, Blair PA, Whitsett JA. Conditional recombination reveals distinct subsets of epithelial cells in trachea, bronchi, and alveoli. Am J Respir Cell Mol Biol 2005; 33(5): 455–462

[13] Rawlins EL, Okubo T, Xue Y, Brass DM, Auten RL, Hasegawa H, Wang F, Hogan BL. The role of Scgb1a1+ Clara cells in the long-term maintenance and repair of lung airway, but not alveolar, epithelium. Cell Stem Cell 2009; 4(6): 525–534

[14] Tata PR, Mou H, Pardo-Saganta A, Zhao R, Prabhu M, Law BM, Vinarsky V, Cho JL, Breton S, Sahay A, Medoff BD, Rajagopal J. Dedifferentiation of committed epithelial cells into stem cells in vivo. Nature 2013; 503(7475): 218–223

[15] Guha A, Vasconcelos M, Cai Y, Yoneda M, Hinds A, Qian J, Li G, Dickel L, Johnson JE, Kimura S, Guo J, McMahon J, McMahon AP, Cardoso WV. Neuroepithelial body microenvironment is a niche for a distinct subset of Clara-like precursors in the developing airways. Proc Natl Acad Sci USA 2012; 109(31): 12592–12597

[16] Barkauskas CE, Cronce MJ, Rackley CR, Bowie EJ, Keene DR, Stripp BR, Randell SH, Noble PW, Hogan BL. Type 2 alveolar cells are stem cells in adult lung. J Clin Invest 2013; 123(7): 3025–3036

[17] Desai TJ, Brownfield DG, Krasnow MA. Alveolar progenitor and stem cells in lung development, renewal and cancer. Nature 2014; 507(7491): 190–194

[18] Jain R, Barkauskas CE, Takeda N, Bowie EJ, Aghajanian H, Wang Q, Padmanabhan A, Manderfield LJ, Gupta M, Li D, Li L, Trivedi CM, Hogan BLM, Epstein JA. Plasticity of Hopx⁺ type I alveolar cells to regenerate type II cells in the lung. Nat Commun 2015; 6(1): 6727

[19] Wang Y, Tang Z, Huang H, Li J, Wang Z, Yu Y, Zhang C, Li J, Dai H, Wang F, Cai T, Tang N. Pulmonary alveolar type I cell population consists of two distinct subtypes that differ in cell fate. Proc Natl Acad Sci USA 2018; 115(10): 2407–2412

[20] Liu Q, Liu K, Cui G, Huang X, Yao S, Guo W, Qin Z, Li Y, Yang R, Pu W, Zhang L, He L, Zhao H, Yu W, Tang M, Tian X, Cai D, Nie Y, Hu S, Ren T, Qiao Z, Huang H, Zeng YA, Jing N, Peng G, Ji H, Zhou B. Lung regeneration by multipotent stem cells residing at the bronchioalveolar-duct junction. Nat Genet 2019; 51(4): 728–738

[21] Chapman HA, Li X, Alexander JP, Brumwell A, Lorizio W, Tan K, Sonnenberg A, Wei Y, Vu TH. Integrin α6β4 identifies an adult distal lung epithelial population with regenerative potential in mice. J Clin Invest 2011; 121(7): 2855–2862

[22] Kotton DN, Morrisey EE. Lung regeneration: mechanisms, applications and emerging stem cell populations. Nat Med 2014; 20(8): 822–832

[23] Gkatzis K, Taghizadeh S, Huh D, Stainier DYR, Bellusci S. Use of three-dimensional organoids and lung-on-a-chip methods to study lung development, regeneration and disease. Eur Respir J 2018; 52: 1800876

[24] Ornitz DM, Itoh N. The fibroblast growth factor signaling pathway. Wiley Interdiscip Rev Dev Biol 2015; 4(3): 215–266

[25] Bellusci S, Grindley J, Emoto H, Itoh N, Hogan BL. Fibroblast growth factor 10 (FGF10) and branching morphogenesis in the embryonic mouse lung. Development 1997; 124(23): 4867–4878

[26] Guo L, Degenstein L, Fuchs E. Keratinocyte growth factor is required for hair development but not for wound healing. Genes Dev 1996; 10(2): 165–175

[27] Ohuchi H, Hori Y, Yamasaki M, Harada H, Sekine K, Kato S, Itoh N. FGF10 acts as a major ligand for FGF receptor 2 IIIb in mouse multi-organ development. Biochem Biophys Res Commun 2000; 277(3): 643–649

[28] Jones MR, Dilai S, Lingampally A, Chao CM, Danopoulos S, Carraro G, Mukhametshina R, Wilhelm J, Baumgart-Vogt E, Al Alam D, Chen C, Minoo P, Zhang JS, Bellusci S. A comprehensive analysis of fibroblast growth factor receptor 2b signaling on epithelial tip progenitor cells during early mouse lung branching morphogenesis. Front Genet 2019a; 9: 746

[29] Chao CM, Yahya F, Moiseenko A, Tiozzo C, Shrestha A, Ahmadvand N, El Agha E, Quantius J, Dilai S, Kheirollahi V, Jones M, Wilhem J, Carraro G, Ehrhardt H, Zimmer KP, Barreto G, Ahlbrecht K, Morty RE, Herold S, Abellar RG, Seeger W, Schermuly R, Zhang JS, Minoo P, Bellusci S. Fgf10 deficiency is causative for lethality in a mouse model of bronchopulmonary dysplasia. J Pathol 2017; 241(1): 91–103

[30] Volckaert T, Dill E, Campbell A, Tiozzo C, Majka S, Bellusci S, De Langhe SP. Parabronchial smooth muscle constitutes an airway epithelial stem cell niche in the mouse lung after injury. J Clin Invest 2011; 121(11): 4409–4419

[31] Jones M, Zhang JS, Bellusci S. Bronchioalveolar stem cells vindicated! Biotarget 2019; 3: 4

[32] Volckaert T, Yuan T, Chao CM, Bell H, Sitaula A, Szimmtenings L, El Agha E, Chanda D, Majka S, Bellusci S, Thannickal VJ, Fässler R, De Langhe SP. Fgf10-Hippo epithelial-mesenchymal crosstalk maintains and recruits lung basal stem cells. Dev Cell 2017; 43(1): 48–59.e45

[33] Peng T, Frank DB, Kadzik RS, Morley MP, Rathi KS, Wang T, Zhou S, Cheng L, Lu MM, Morrisey EE. Hedgehog actively maintains adult lung quiescence and regulates repair and regeneration. Nature 2015; 526(7574): 578–582

[34] Al Alam D, El Agha E, Sakurai R, Kheirollahi V, Moiseenko A, Danopoulos S, Shrestha A, Schmoldt C, Quantius J, Herold S, Chao CM, Tiozzo C, De Langhe S, Plikus MV, Thornton M, Grubbs B, Minoo P, Rehan VK, Bellusci S. Evidence for the involvement of fibroblast growth factor 10 in lipofibroblast formation during embryonic lung development. Development 2015; 142(23): 4139–4150

[35] Ntokou A, Klein F, Dontireddy D, Becker S, Bellusci S, Richardson WD, Szibor M, Braun T, Morty RE, Seeger W, Voswinckel R, Ahlbrecht K. Characterization of the platelet-derived growth factor receptor-α-positive cell lineage during murine late lung development. Am J Physiol Lung Cell Mol Physiol 2015; 309(9): L942–L958

[36] Ntokou A, Szibor M, Rodríguez-Castillo JA, Quantius J, Herold S, El Agha E, Bellusci S, Salwig I, Braun T, Voswinckel R, Seeger W, Morty RE, Ahlbrecht K. A novel mouse Cre-driver line targeting Perilipin 2-expressing cells in the neonatal lung. Genesis 2017; 55(12): e23080

[37] Zepp JA, Zacharias WJ, Frank DB, Cavanaugh CA, Zhou S, Morley MP, Morrisey EE. Distinct mesenchymal lineages and niches promote epithelial self-renewal and myofibrogenesis in the lung. Cell 2017; 170: 1134–1148.e1110

[38] El Agha E, Moiseenko A, Kheirollahi V, De Langhe S, Crnkovic S, Kwapiszewska G, Szibor M, Kosanovic D, Schwind F, Schermuly RT, Henneke I, MacKenzie B, Quantius J, Herold S, Ntokou A, Ahlbrecht K, Braun T, Morty RE, Günther A, Seeger W, Bellusci S. Two-way conversion between lipogenic and myogenic fibroblastic phenotypes marks the progression and resolution of lung fibrosis. Cell Stem Cell 2017b; 20: 261–273.e263

[39] El Agha E, Kramann R, Schneider RK, Li X, Seeger W, Humphreys BD, Bellusci S. Mesenchymal stem cells in fibrotic disease. Cell Stem Cell 2017a; 21(2): 166–177

[40] Entesarian M, Matsson H, Klar J, Bergendal B, Olson L, Arakaki R, Hayashi Y, Ohuchi H, Falahat B, Bolstad AI, Jonsson R, Wahren-Herlenius M, Dahl N. Mutations in the gene encoding fibroblast growth factor 10 are associated with aplasia of lacrimal and salivary glands. Nat Genet 2005; 37(2): 125–127

[41] Rohmann E, Brunner HG, Kayserili H, Uyguner O, Nürnberg G, Lew ED, Dobbie A, Eswarakumar VP, Uzumcu A, Ulubil-Emeroglu M, Leroy JG, Li Y, Becker C, Lehnerdt K, Cremers CW, Yüksel-Apak M, Nürnberg P, Kubisch C, Schlessinger J, van Bokhoven H, Wollnik B. Mutations in different components of FGF signaling in LADD syndrome. Nat Genet 2006; 38(4): 414–417

[42] Klar J, Blomstrand P, Brunmark C, Badhai J, Håkansson HF, Brange CS, Bergendal B, Dahl N. Fibroblast growth factor 10 haploinsufficiency causes chronic obstructive pulmonary disease. J Med Genet 2011; 48(10): 705–709

[43] Klinger G, Levy I, Sirota L, Boyko V, Lerner-Geva L, Reichman B; Israel Neonatal Network. Outcome of early-onset sepsis in a national cohort of very low birth weight infants. Pediatrics 2010; 125(4): e736–e740

[44] Carver BJ, Plosa EJ, Stinnett AM, Blackwell TS, Prince LS. Interactions between NF-kB and SP3 connect inflammatory signaling with reduced FGF-10 expression. J Biol Chem 2013; 288(21): 15318–15325

[45] Benjamin JT, Smith RJ, Halloran BA, Day TJ, Kelly DR, Prince LS. FGF-10 is decreased in bronchopulmonary dysplasia and suppressed by Toll-like receptor activation. Am J Physiol Lung Cell Mol Physiol 2007; 292(2): L550–L558

[46] Danopoulos S, Parsa S, Al Alam D, Tabatabai R, Baptista S, Tiozzo C, Carraro G, Wheeler M, Barreto G, Braun T, Li X, Hajihosseini MK, Bellusci S. Transient inhibition of FGFR2b-ligands signaling leads to irreversible loss of cellular β-catenin organization and signaling in AER during mouse limb development. PLoS One 2013; 8(10): e76248

[47] Nelson WJ, Nusse R. Convergence of Wnt, β-catenin, and cadherin pathways. Science 2004; 303(5663): 1483–1487

[48] Tanjore H, Degryse AL, Crossno PF, Xu XC, McConaha ME, Jones BR, Polosukhin VV, Bryant AJ, Cheng DS, Newcomb DC, McMahon FB, Gleaves LA, Blackwell TS, Lawson WE. β-catenin in the alveolar epithelium protects from lung fibrosis after intratracheal bleomycin. Am J Respir Crit Care Med 2013; 187(6): 630–639

[49] Deterding RR, Havill AM, Yano T, Middleton SC, Jacoby CR, Shannon JM, Simonet WS, Mason RJ. Prevention of bleomycin-induced lung injury in rats by keratinocyte growth factor. Proc Assoc Am Physicians 1997; 109(3): 254–268

[50] Sugahara K, Iyama K, Kuroda MJ, Sano K. Double intratracheal instillation of keratinocyte growth factor prevents bleomycin-induced lung fibrosis in rats. J Pathol 1998; 186(1): 90–98

[51] Gupte VV, Ramasamy SK, Reddy R, Lee J, Weinreb PH, Violette SM, Guenther A, Warburton D, Driscoll B, Minoo P, Bellusci S. Overexpression of fibroblast growth factor-10 during both inflammatory and fibrotic phases attenuates bleomycin-induced pulmonary fibrosis in mice. Am J Respir Crit Care Med 2009; 180(5): 424–436

[52] MacKenzie B, Henneke I, Hezel S, Al Alam D, El Agha E, Chao CM, Quantius J, Wilhelm J, Jones M, Goth K, Li X, Seeger W, Königshoff M, Herold S, Rizvanov AA, Günther A, Bellusci S. Attenuating endogenous Fgfr2b ligands during bleomycin-induced lung fibrosis does not compromise murine lung repair. Am J Physiol Lung Cell Mol Physiol 2015; 308(10): L1014–L1024

[53] Quantius J, Schmoldt C, Vazquez-Armendariz AI, Becker C, El Agha E, Wilhelm J, Morty RE, Vadász I, Mayer K, Gattenloehner S, Fink L, Matrosovich M, Li X, Seeger W, Lohmeyer J, Bellusci S, Herold S. Influenza virus infects epithelial stem/progenitor cells of the distal lung: impact on Fgfr2b-driven epithelial repair. PLoS Pathog 2016; 12(6): e1005544

[54] Crosby LM, Waters CM. Epithelial repair mechanisms in the lung. Am J Physiol Lung Cell Mol Physiol 2010; 298(6): L715–L731

[55] Chandel NS, Budinger GR, Mutlu GM, Varga J, Synenki L, Donnelly HK, Zirk A, Eisenbart J, Jovanovic B, Jain M. Keratinocyte growth factor expression is suppressed in early acute lung injury/acute respiratory distress syndrome by smad and c-Abl pathways. Crit Care Med 2009; 37(5): 1678–1684

[56] Matthay MA, Ware LB, Zimmerman GA. The acute respiratory distress syndrome. J Clin Invest 2012; 122(8): 2731–2740

[57] Shyamsundar M, McAuley DF, Ingram RJ, Gibson DS, O’Kane D, McKeown ST, Edwards A, Taggart C, Elborn JS, Calfee CS, Matthay MA, O’Kane CM. Keratinocyte growth factor promotes epithelial survival and resolution in a human model of lung injury. Am J Respir Crit Care Med 2014; 189(12): 1520–1529

[58] Spielberger R, Stiff P, Bensinger W, Gentile T, Weisdorf D, Kewalramani T, Shea T, Yanovich S, Hansen K, Noga S, McCarty J, LeMaistre CF, Sung EC, Blazar BR, Elhardt D, Chen MG, Emmanouilides C. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med 2004; 351(25): 2590–2598

[59] McAuley DF, Cross LM, Hamid U, Gardner E, Elborn JS, Cullen KM, Dushianthan A, Grocott MP, Matthay MA, O’Kane CM. Keratinocyte growth factor for the treatment of the acute respiratory distress syndrome (KARE): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Respir Med 2017; 5(6): 484–491

[60] Herold S, Hoegner K, Vadász I, Gessler T, Wilhelm J, Mayer K, Morty RE, Walmrath HD, Seeger W, Lohmeyer J. Inhaled granulocyte/macrophage colony-stimulating factor as treatment of pneumonia-associated acute respiratory distress syndrome. Am J Respir Crit Care Med 2014; 189(5): 609–611

[61] HongKU, Reynolds SD, Watkins S, Fuchs E, Stripp BR. Basal cells are a multipotent progenitor capable of renewing the bronchial epithelium. Am J Pathol 2004; 164(2): 577–588

[62] Sekine K, Ohuchi H, Fujiwara M, Yamasaki M, Yoshizawa T, Sato T, Yagishita N, Matsui D, Koga Y, Itoh N, Kato S. Fgf10 is essential for limb and lung formation. Nat Genet 1999; 21(1): 138–141

[63] Francavilla C, Rigbolt KT, Emdal KB, Carraro G, Vernet E, Bekker-Jensen DB, Streicher W, Wikström M, Sundström M, Bellusci S, Cavallaro U, Blagoev B, Olsen JV. Functional proteomics defines the molecular switch underlying FGF receptor trafficking and cellular outputs. Mol Cell 2013; 51(6): 707–722

[64] Zhou H, Rigoutsos I. The emerging roles of GPRC5A in diseases. Oncoscience 2014; 1(12): 765–776

[65] Rock JR, Onaitis MW, Rawlins EL, Lu Y, Clark CP, Xue Y, Randell SC, Hogan LM. Basal cells as stem cells of the mouse trachea and human airway epithelium. Proc Natl Acad Sci U S A 2009; 106(31): 12771–12775

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.

RIGHTS & PERMISSIONS

2019 Higher Education Press and Springer-Verlag GmbH Germany, part of Springer Nature