Epithelial-Mesenchymal Niche Dysfunction in COPD: Emerging Opportunities for Targeting Cellular Plasticity and Crosstalk

Abstract

Chronic obstructive pulmonary disease (COPD) is a leading cause of global morbidity and mortality, characterized by progressive airway and alveolar remodeling. The disease pathogenesis is commonly driven by chronic environmental insults, leading to airway obstruction, emphysema, and chronic bronchitis. This review synthesizes emerging evidence that altered epithelial cell behavior and dysfunctional epithelial-mesenchymal interactions serve as pivotal drivers of COPD pathogenesis, orchestrating failed repair and structural degeneration. We detail how altered responses of airway (ciliated, club, basal, goblet) and alveolar (AT1 and AT2) epithelial cells lead to cellular senescence, metaplasia, defective regeneration, and barrier disruption, acting as primary instigators of pathogenesis. We also summarize current knowledge on the mechanisms of activation and pathogenic role of mesenchymal cells, which drive peribronchiolar fibrosis, alveolar destruction, and metabolic reprogramming, alongside the compromised reparative function of mesenchymal stem cells (MSCs). We emphasize how distinct mesenchymal niches (e.g., PDGFRα^Pos MANCs, FGF10^Pos lipofibroblasts, SFRP1^Pos fibroblasts) and distinct epithelial stem/progenitor subpopulations critically contribute to pathogenesis. Key signaling pathways—including FGF10/FGFR2b, WNT, Hippo, NOTCH, and TGF-β—mediate epithelial-mesenchymal transition (EMT), stem cell niche function, and structural remodeling. By dissecting how epithelial injury responses and mesenchymal niche failure collaboratively drive COPD progression, we identify actionable targets to disrupt pathogenesis and restore endogenous repair. We propose targeting EMT, including inhibiting EMT/fibrosis, promoting alveolar regeneration, MSC-based therapies, exosome-delivered biomolecules, and precision cell transplantation strategies, as promising future therapeutic strategies.

Keywords

COPD / Stem cell / Epithelial-mesenchymal interaction / Signaling pathway / Structure remodeling / Therapy

Author Contributions

Conceptualization: J.-S.Z., J.W., C.C.; Writing—original draft: J.W.; Writing—review and editing: J.-S.Z., W.L., S.B.; Figures and Table creation: J.W., J.-S.Z.; Resource and Funding acquisition: J.-S.Z., W.L., C.C.

Ethics Statement

No ethical statement to declare.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Funding

J.-S.Z. is partially supported by research funds from both the Quzhou Affiliated Hospital and the First Affiliated Hospital of Wenzhou Medical University, the Zhejiang Province Public Welfare Fund Project (LY24H050003). C.C. and W.L. were supported in part by the National Natural Science Foundation of China grants No. 82170017 and No. 82330002, respectively.

Declaration of Competing Interest

The authors declared there is no conflict of interest.

References

[1] Dong F, Su R, Ren Y, Yang T. Burden of chronic obstructive pulmonary disease and risk factors in China from 1990 to 2021: Analysis of global burden of disease 2021. Chin. Med. J. Pulm. Crit. Care Med. 2025, 3, 132-140.

[2] Barnes PJ.Chronic obstructive pulmonary disease. N. Engl. J. Med. 2000, 343, 269-280.

[3] Christenson SA, Smith BM, Bafadhel M, Putcha N.Chronic obstructive pulmonary disease. Lancet 2022, 399, 2227-2242.

[4] Stolz D, Mkorombindo T, Schumann DM, Agusti A, Ash SY, Bafadhel M, et al. Towards the elimination of chronic obstructive pulmonary disease: a Lancet Commission. Lancet 2022, 400, 921-972.

[5] Abohalaka R. Bronchial epithelial and airway smooth muscle cell interactions in health and disease. Heliyon 2023, 9, e19976.

[6] Zepp JA, Morrisey EE. Cellular crosstalk in the development and regeneration of the respiratory system. Nat. Rev. Mol. Cell. Biol. 2019, 20, 551-566.

[7] Hogan B, Tata PR. Cellular organization and biology of the respiratory system. Nat. Cell Biol. 2019, doi:10.1038/s41556-019-0357-7.

[8] Pardo-Saganta A, Law BM, Gonzalez-Celeiro M, Vinarsky V, Rajagopal J. Ciliated cells of pseudostratified airway epithelium do not become mucous cells after ovalbumin challenge. Am. J. Respir. Cell. Mol. Biol. 2013, 48, 364-373.

[9] Kotton DN, Morrisey EE. Lung regeneration: mechanisms, applications and emerging stem cell populations. Nat. Med. 2014, 20, 822-832.

[10] Reynolds SD, Reynolds PR, Pryhuber GS, Finder JD, Stripp BR. Secretoglobins SCGB3A1 and SCGB3A2 define secretory cell subsets in mouse and human airways. Am. J. Respir. Crit. Care Med. 2002, 166, 1498-509.

[11] Zhang JS, Dhlamini Q, Guo Q, Quan M, Wu J, Lyu H, et al. Progress and Gaps in Respiratory Disease Research and Treatment: Highlights of the IRM 2024 in Shanghai. J. Respir. Biol. Transl. Med. 2024, 1, 10021.

[12] Giangreco A, Reynolds SD, Stripp BR. Terminal bronchioles harbor a unique airway stem cell population that localizes to the bronchoalveolar duct junction. Am. J. Pathol. 2002, 161, 173-182.

[13] Reynolds SD, Hong KU, Giangreco A, Mango GW, Guron C, Morimoto Y, et al. Conditional clara cell ablation reveals a self-renewing progenitor function of pulmonary neuroendocrine cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 2000, 278, L1256-1263.

[14] Jones-Freeman B, Starkey MR. Bronchioalveolar stem cells in lung repair, regeneration and disease. J. Pathol. 2020, 252, 219-226.

[15] Hong KU, Reynolds SD, Giangreco A, Hurley CM, Stripp BR. Clara cell secretory protein-expressing cells of the airway neuroepithelial body microenvironment include a label-retaining subset and are critical for epithelial renewal after progenitor cell depletion. Am. J. Respir. Cell. Mol. Biol. 2001, 24, 671-681.

[16] Peake JL, Reynolds SD, Stripp BR, Stephens KE, Pinkerton KE. Alteration of pulmonary neuroendocrine cells during epithelial repair of naphthalene-induced airway injury. Am. J. Pathol. 2000, 156, 279-286.

[17] Reynolds SD, Giangreco A, Power JH, Stripp BR. Neuroepithelial bodies of pulmonary airways serve as a reservoir of progenitor cells capable of epithelial regeneration. Am. J. Pathol. 2000, 156, 269-278.

[18] Chen Q, Suresh Kumar V, Finn J, Jiang D, Liang J, Zhao YY, et al. CD44(high) alveolar type II cells show stem cell properties during steady-state alveolar homeostasis. Am. J. Physiol. Lung Cell. Mol. Physiol. 2017, 313, L41-L51.

[19] Zacharias WJ, Frank DB, Zepp JA, Morley MP, Alkhaleel FA, Kong J, et al. Regeneration of the lung alveolus by an evolutionarily conserved epithelial progenitor. Nature 2018, 555, 251-255.

[20] Nabhan AN, Brownfield DG, Harbury PB, Krasnow MA, Desai TJ. Single-cell Wnt signaling niches maintain stemness of alveolar type 2 cells. Science 2018, 359, 1118-1123.

[21] Travaglini KJ, Nabhan AN, Penland L, Sinha R, Gillich A, Sit RV, et al. A molecular cell atlas of the human lung from single-cell RNA sequencing. Nature 2020, 587, 619-625.

[22] Liu Y, Kumar VS, Zhang W, Rehman J, Malik AB. Activation of type II cells into regenerative stem cell antigen-1(+) cells during alveolar repair. Am. J. Respir. Cell. Mol. Biol. 2015, 53, 113-124.

[23] Choi J, Park JE, Tsagkogeorga G, Yanagita M, Koo BK, Han N, et al. Inflammatory Signals Induce AT2 Cell-Derived Damage-Associated Transient Progenitors that Mediate Alveolar Regeneration. Cell Stem Cell 2020, 27, 366-382.e7.

[24] Kobayashi Y, Tata A, Konkimalla A, Katsura H, Lee RF, Ou J, et al. Persistence of a regeneration-associated, transitional alveolar epithelial cell state in pulmonary fibrosis. Nat. Cell Biol. 2020, 22, 934-946.

[25] Riemondy KA, Jansing NL, Jiang P, Redente EF, Gillen AE, Fu R, et al. Single cell RNA sequencing identifies TGFβ as a key regenerative cue following LPS-induced lung injury. JCI Insight 2019, 5, e123637.

[26] Strunz M, Simon LM, Ansari M, Kathiriya JJ, Angelidis I, Mayr CH, et al. Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis. Nat. Commun. 2020, 11, 3559.

[27] Verheyden JM, Sun X. A transitional stem cell state in the lung. Nat. Cell Biol. 2020, 22, 1025-1026.

[28] Wu H, Yu Y, Huang H, Hu Y, Fu S, Wang Z, et al. Progressive pulmonary fibrosis is caused by elevated mechanical tension on alveolar stem cells. Cell 2021, 184, 845-846.

[29] Ahmadvand N, Khosravi F, Lingampally A, Wasnick R, Vazquez-Armendariz AI, Carraro G, et al. Identification of a novel subset of alveolar type 2 cells enriched in PD-L1 and expanded following pneumonectomy. Eur. Respir. J. 2021, 58, 2004168.

[30] Kathiriya JJ, Wang C, Zhou M, Brumwell A, Cassandras M, Le Saux CJ, et al. Human alveolar type 2 epithelium transdifferentiates into metaplastic KRT5(+) basal cells. Nat. Cell Biol. 2022, 24, 10-23.

[31] Quan M, Guo Q, Yan X, Yu C, Yang L, Zhang Y, et al. Parkin deficiency aggravates inflammation-induced acute lung injury by promoting necroptosis in alveolar type II cells. Chin. Med. J. Pulm. Crit. Care Med. 2024, 2, 265-278.

[32] Zepp JA, Zacharias WJ, Frank DB, Cavanaugh CA, Zhou S, Morley MP, et al. Distinct Mesenchymal Lineages and Niches Promote Epithelial Self-Renewal and Myofibrogenesis in the Lung. Cell 2017, 170, 1134-1148.e10.

[33] Barkauskas CE, Cronce MJ, Rackley CR, Bowie EJ, Keene DR, Stripp BR, et al. Type 2 alveolar cells are stem cells in adult lung. J. Clin. Invest. 2013, 123, 3025-3036.

[34] Morrisey EE, Hogan BL. Preparing for the first breath: genetic and cellular mechanisms in lung development. Dev. Cell 2010, 18, 8-23.

[35] 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, 4867-4878.

[36] Hadzic S, Wu CY, Gredic M, Pak O, Loku E, Kraut S, et al. Fibroblast growth factor 10 reverses cigarette smoke- and elastase-induced emphysema and pulmonary hypertension in mice. Eur. Respir. J. 2023, 62, 2201606.

[37] El Agha E, Kramann R, Schneider RK, Li X, Seeger W, Humphreys BD, et al. Mesenchymal Stem Cells in Fibrotic Disease. Cell Stem Cell 2017, 21, 166-177.

[38] El Agha E, Moiseenko A, Kheirollahi V, De Langhe S, Crnkovic S, Kwapiszewska G, et al. Two-Way Conversion between Lipogenic and Myogenic Fibroblastic Phenotypes Marks the Progression and Resolution of Lung Fibrosis. Cell Stem Cell 2017, 20, 261-273.e3.

[39] Lee JH, Tammela T, Hofree M, Choi J, Marjanovic ND, Han S, et al. Anatomically and Functionally Distinct Lung Mesenchymal Populations Marked by Lgr5 and Lgr6. Cell 2017, 170, 1149-1163.e12.

[40] Liu X, Zhang X, Liang J, Noble PW, Jiang D. The concept of Sfrp1(+) transitional fibroblasts: the key to dissociating lineage heterogeneity and fate of invasive fibroblasts in pulmonary fibrosis? Eur. Respir. J. 2024, 63, 2400498.

[41] Mukhatayev Z, Adilbayeva A, Kunz J. CTHRC1: An Emerging Hallmark of Pathogenic Fibroblasts in Lung Fibrosis. Cells 2024, 13, 946.

[42] Feng Y, Hu J, Liu F, Shang Y. Collagen Triple Helix Repeat Containing 1 Deficiency Protects Against Airway Remodeling and Inflammation in Asthma Models In Vivo and In Vitro. Inflammation 2023, 46, 925-940.

[43] Tsukui T, Sun KH, Wetter JB, Wilson-Kanamori JR, Hazelwood LA, Henderson NC, et al. Collagen-producing lung cell atlas identifies multiple subsets with distinct localization and relevance to fibrosis. Nat. Commun. 2020, 11, 1920.

[44] Liu G, Philp AM, Corte T, Travis MA, Schilter H, Hansbro NG, et al. Therapeutic targets in lung tissue remodelling and fibrosis. Pharmacol. Ther. 2021, 225, 107839.

[45] Tang X, Li Z, Yu Z, Li J, Zhang J, Wan N, et al. Effect of curcumin on lung epithelial injury and ferroptosis induced by cigarette smoke. Hum. Exp. Toxicol. 2021, 40, S753-S762.

[46] Wei T, Wang X, Lang K, Song Y, Luo J, Gu Z, et al. Peroxiredoxin 6 Protects Pulmonary Epithelial Cells From Cigarette-related Ferroptosis in Chronic Obstructive Pulmonary Disease. Inflammation 2024, 48, 662-675.

[47] Peng K, Yao YX, Lu X, Wang WJ, Zhang YH, Zhao H, et al. Mitochondrial dysfunction-associated alveolar epithelial senescence is involved in CdCl(2)-induced COPD-like lung injury. J. Hazard. Mater. 2024, 476, 135103.

[48] Liu W, Liang W, Zhang C, Liu H, Li H, Zhou L, et al. LncR-GAS5 decrease in adenine phosphoribosyltransferase expresssion via binding TAF1 to increase kidney damage created by CIH. Heliyon 2024, 10, e33084.

[49] Kurie JM, Shin HJ, Lee JS, Morice RC, Ro JY, Lippman SM, et al. Increased epidermal growth factor receptor expression in metaplastic bronchial epithelium. Clin. Cancer Res. 1996, 2, 1787-1793.

[50] Shaykhiev R, Zuo WL, Chao I, Fukui T, Witover B, Brekman A, et al. EGF shifts human airway basal cell fate toward a smoking-associated airway epithelial phenotype. Proc. Natl. Acad. Sci. USA 2013, 110, 12102-12107.

[51] Bals R, Hiemstra PS. Innate immunity in the lung: how epithelial cells fight against respiratory pathogens. Eur. Respir. J. 2004, 23, 327-333.

[52] Rogers DF.The airway goblet cell. Int. J. Biochem. Cell Biol. 2003, 35, 1-6.

[53] Leopold PL, O'Mahony MJ, Lian XJ, Tilley AE, Harvey BG, Crystal RG. Smoking is associated with shortened airway cilia. PLoS ONE 2009, 4, e8157.

[54] Ramos EM, De Toledo AC, Xavier RF, Fosco LC, Vieira RP, Ramos D, et al. Reversibility of impaired nasal mucociliary clearance in smokers following a smoking cessation programme. Respirology 2011, 16, 849-855.

[55] Carlier FM, de Fays C, Pilette C. Epithelial Barrier Dysfunction in Chronic Respiratory Diseases. Front. Physiol. 2021, 12, 691227.

[56] Coyne CB, Vanhook MK, Gambling TM, Carson JL, Boucher RC, Johnson LG. Regulation of airway tight junctions by proinflammatory cytokines. Mol. Biol. Cell 2002, 13, 3218-334.

[57] Chen R, Cui Y, Ip MS, Mak JC. Cigarette smoke induces endoplasmic reticulum stress-associated mucus hypersecretion via orosomucoid 1-like protein 3 in airway epithelia. Free Radic. Res. 2025, 59, 342-355.

[58] Dong X, Ding M, Zhang J, Ogülür I, Pat Y, Akdis M, et al. Involvement and therapeutic implications of airway epithelial barrier dysfunction in type 2 inflammation of asthma. Chin. Med. J. 2022, 135, 519-531.

[59] Bailey KL. Aging Diminishes Mucociliary Clearance of the Lung. Adv. Geriatr. Med. Res. 2022, 4, e220005.

[60] Alter P, Baker JR, Dauletbaev N, Donnelly LE, Pistenmaa C, Schmeck B, et al. Update in Chronic Obstructive Pulmonary Disease 2019. Am. J. Respir. Crit. Care Med. 2020, 202, 348-355.

[61] Tran HB, Jersmann H, Truong TT, Hamon R, Roscioli E, Ween M, et al. Disrupted epithelial/macrophage crosstalk via Spinster homologue 2-mediated S1P signaling may drive defective macrophage phagocytic function in COPD. PLoS ONE 2017, 12, e0179577.

[62] Van Eeckhoutte HP, Donovan C, Kim RY, Conlon TM, Ansari M, Khan H, et al. RIPK1 kinase-dependent inflammation and cell death contribute to the pathogenesis of COPD. Eur. Respir. J. 2023, 61, 2201506.

[63] Hiemstra PS, Bourdin A. Club cells, CC10 and self-control at the epithelial surface. Eur. Respir. J. 2014, 44, 831-832.

[64] Gamez AS, Gras D, Petit A, Knabe L, Molinari N, Vachier I, et al. Supplementing defect in club cell secretory protein attenuates airway inflammation in COPD. Chest 2015, 147, 1467-1476.

[65] Snyder JC, Reynolds SD, Hollingsworth JW, Li Z, Kaminski N, Stripp BR. Clara cells attenuate the inflammatory response through regulation of macrophage behavior. Am. J. Respir. Cell. Mol. Biol. 2010, 42, 161-171.

[66] Katavolos P, Ackerley CA, Clark ME, Bienzle D. Clara cell secretory protein increases phagocytic and decreases oxidative activity of neutrophils. Vet. Immunol. Immunopathol. 2011, 139, 1-9.

[67] Tokita E, Tanabe T, Asano K, Suzaki H, Rubin BK. Club cell 10-kDa protein attenuates airway mucus hypersecretion and inflammation. Eur. Respir. J. 2014, 44, 1002-1010.

[68] Pilette C, Godding V, Kiss R, Delos M, Verbeken E, Decaestecker C, et al. Club cell protein 16 and disease progression in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2013, 188, 1413-1419.

[69] Perl AK, Riethmacher D, Whitsett JA. Conditional depletion of airway progenitor cells induces peribronchiolar fibrosis. Am. J. Respir. Crit. Care Med. 2011, 183, 511-521.

[70] Pilette C, Godding V, Kiss R, Delos M, Verbeken E, Decaestecker C, et al. Reduced epithelial expression of secretory component in small airways correlates with airflow obstruction in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2001, 163, 185-194.

[71] Shijubo N, Itoh Y, Yamaguchi T, Imada A, Hirasawa M, Yamada T, et al. Clara cell protein-positive epithelial cells are reduced in small airways of asthmatics. Am. J. Respir. Crit. Care Med. 1999, 160, 930-933.

[72] Kelly FL, Kennedy VE, Jain R, Sindhwani NS, Copeland CF, Snyder LD, et al. Epithelial clara cell injury occurs in bronchiolitis obliterans syndrome after human lung transplantation. Am. J. Transplant. 2012, 12, 3076-3084.

[73] Liu K, Meng X, Liu Z, Tang M, Lv Z, Huang X, et al. Tracing the origin of alveolar stem cells in lung repair and regeneration. Cell 2024, 187, 2428-2445.e20.

[74] Hu Y, Hu Q, Ansari M, Riemondy K, Pineda R, Sembrat J, et al. Airway derived emphysema-specific alveolar type II cells exhibit impaired regenerative potential in COPD. Eur. Respir. J. 2024, 64, 2302071.

[75] Rock JR, Onaitis MW, Rawlins EL, Lu Y, Clark CP, Xue Y, et al. Basal cells as stem cells of the mouse trachea and human airway epithelium. Proc. Natl. Acad. Sci. USA 2009, 106, 12771-12775.

[76] Shaykhiev R. Airway Epithelial Progenitors and the Natural History of Chronic Obstructive Pulmonary Disease. Am. J. Respir. Crit. Care Med. 2018, 197, 847-849.

[77] Araya J, Cambier S, Markovics JA, Wolters P, Jablons D, Hill A, et al. Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients. J. Clin. Invest. 2007, 117, 3551-3562.

[78] Rao W, Wang S, Duleba M, Niroula S, Goller K, Xie J, et al. Regenerative Metaplastic Clones in COPD Lung Drive Inflammation and Fibrosis. Cell 2020, 181, 848-864.e18.

[79] Whetstone CE, Ranjbar M, Omer H, Cusack RP, Gauvreau GM. The Role of Airway Epithelial Cell Alarmins in Asthma. Cells 2022, 11, 1105.

[80] Préfontaine D, Hamid Q.Airway epithelial cells in asthma. J. Allergy Clin. Immunol. 2007, 120, 1475-1478.

[81] Jones DL, Morley MP, Li X, Ying Y, Zhao G, Schaefer SE, et al. An injury-induced mesenchymal-epithelial cell niche coordinates regenerative responses in the lung. Science 2024, 386, eado5561.

[82] Warner SM, Hackett TL, Shaheen F, Hallstrand TS, Kicic A, Stick SM, et al. Transcription factor p63 regulates key genes and wound repair in human airway epithelial basal cells. Am. J. Respir. Cell. Mol. Biol. 2013, 49, 978-988.

[83] Stevens PT, Kicic A, Sutanto EN, Knight DA, Stick SM. Dysregulated repair in asthmatic paediatric airway epithelial cells: the role of plasminogen activator inhibitor-1. Clin. Exp. Allergy 2008, 38, 1901-1910.

[84] Nadel JA, Burgel PR. The role of epidermal growth factor in mucus production. Curr. Opin. Pharmacol. 2001, 1, 254-258.

[85] Jing Y, Gimenes JA, Mishra R, Pham D, Comstock AT, Yu D, et al. NOTCH3 contributes to rhinovirus-induced goblet cell hyperplasia in COPD airway epithelial cells. Thorax 2019, 74, 18-32.

[86] Rogers DF. Airway goblet cells: responsive and adaptable front-line defenders. Eur. Respir. J. 1994, 7, 1690-1706.

[87] Kim V, Criner GJ. Chronic bronchitis and chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2013, 187, 228-237.

[88] Zhu H, Leng J, Ju R, Qu S, Tian J, Leng H, et al. Advantages of pulsed electric field ablation for COPD: Excellent killing effect on goblet cells. Bioelectrochemistry 2024, 158, 108726.

[89] Montoro DT, Haber AL, Biton M, Vinarsky V, Lin B, Birket SE, et al. A revised airway epithelial hierarchy includes CFTR-expressing ionocytes. Nature 2018, 560, 319-324.

[90] Noguchi M, Furukawa KT, Morimoto M. Pulmonary neuroendocrine cells: physiology, tissue homeostasis and disease. Dis. Model Mech. 2020, 13, dmm046920.

[91] Strine MS, Wilen CB. Tuft cells are key mediators of interkingdom interactions at mucosal barrier surfaces. PLoS Pathog. 2022, 18, e1010318.

[92] Desai TJ, Brownfield DG, Krasnow MA. Alveolar progenitor and stem cells in lung development, renewal and cancer. Nature 2014, 507, 190-194.

[93] Okutomo K, Fujino N, Yamada M, Saito T, Ono Y, Okada Y, et al. Increased LHX9 expression in alveolar epithelial type 2 cells of patients with chronic obstructive pulmonary disease. Respir. Investig. 2022, 60, 119-128.

[94] Tsutsumi A, Ozaki M, Chubachi S, Irie H, Sato M, Kameyama N, et al.Exposure to Cigarette Smoke Enhances the Stemness of Alveolar Type 2 Cells. Am. J. Respir. Cell. Mol. Biol. 2020, 63, 293-305.

[95] Irie H, Ozaki M, Chubachi S, Hegab AE, Tsutsumi A, Kameyama N, et al. Short-term intermittent cigarette smoke exposure enhances alveolar type 2 cell stemness via fatty acid oxidation. Respir. Res. 2022, 23, 41.

[96] Yu H, Lin Y, Zhong Y, Guo X, Lin Y, Yang S, et al. Impaired AT 2 to AT1 cell transition in PM2.5-induced mouse model of chronic obstructive pulmonary disease. Respir. Res. 2022, 23, 70.

[97] Sauler M, McDonough JE, Adams TS, Kothapalli N, Barnthaler T, Werder RB, et al. Characterization of the COPD alveolar niche using single-cell RNA sequencing. Nat. Commun. 2022, 13, 494.

[98] Wang C, Hyams B, Allen NC, Cautivo K, Monahan K, Zhou M, et al. Dysregulated lung stroma drives emphysema exacerbation by potentiating resident lymphocytes to suppress an epithelial stem cell reservoir. Immunity 2023, 56, 576-591.e10.

[99] Basil MC, Cardenas-Diaz FL, Kathiriya JJ, Morley MP, Carl J, Brumwell AN, et al. Human distal airways contain a multipotent secretory cell that can regenerate alveoli. Nature 2022, 604, 120-126.

[100] Thompson BT, Chambers RC, Liu KD.Acute Respiratory Distress Syndrome. N. Engl. J. Med. 2017, 377, 562-572.

[101] Wang Y, Tang Z, Huang H, Li J, Wang Z, Yu Y, et al. Pulmonary alveolar type I cell population consists of two distinct subtypes that differ in cell fate. Proc. Natl. Acad. Sci. USA 2018, 115, 2407-2412.

[102] Bhattarai P, Lu W, Hardikar A, Dey S, Gaikwad AV, Shahzad AM, et al. Endothelial to mesenchymal transition is an active process in smokers and patients with early COPD contributing to pulmonary arterial pathology. ERJ Open Res. 2024, 10, 00767-2023.

[103] Hogg JC. Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet 2004, 364, 709-721.

[104] McDonough JE, Yuan R, Suzuki M, Seyednejad N, Elliott WM, Sanchez PG, et al. Small-airway obstruction and emphysema in chronic obstructive pulmonary disease. N. Engl. J. Med. 2011, 365, 1567-1575.

[105] Barnes PJ.Small airway fibrosis in COPD. Int. J. Biochem. Cell Biol. 2019, 116, 105598.

[106] Eapen MS, Lu W, Hackett TL, Singhera GK, Mahmood MQ, Hardikar A, et al. Increased myofibroblasts in the small airways, and relationship to remodelling and functional changes in smokers and COPD patients: potential role of epithelial-mesenchymal transition. ERJ Open Res. 2021, 7, 00876-2020.

[107] Michaeloudes C, Kuo CH, Haji G, Finch DK, Halayko AJ, Kirkham P, et al. Metabolic re-patterning in COPD airway smooth muscle cells. Eur. Respir. J. 2017, 50, 1700202.

[108] Araya J, Tsubouchi K, Sato N, Ito S, Minagawa S, Hara H, et al. PRKN-regulated mitophagy and cellular senescence during COPD pathogenesis. Autophagy 2019, 15, 510-526.

[109] Fang L, Zhang M, Li J, Zhou L, Tamm M, Roth M. Airway Smooth Muscle Cell Mitochondria Damage and Mitophagy in COPD via ERK1/2 MAPK. Int. J. Mol. Sci. 2022, 23, 13987.

[110] Krimmer DI, Burgess JK, Wooi TK, Black JL, Oliver BG. Matrix proteins from smoke-exposed fibroblasts are pro-proliferative. Am. J. Respir. Cell. Mol. Biol. 2012, 46, 34-39.

[111] Khedoe PP, van Schadewijk WA, Schwiening M, Ng-Blichfeldt JP, Marciniak SJ, Stolk J, et al. Cigarette smoke restricts the ability of mesenchymal cells to support lung epithelial organoid formation. Front. Cell Dev. Biol. 2023, 11, 1165581.

[112] Cheng PP, Yu F, Chen SJ, Feng X, Jia ZH, Hu SH, et al. PM2.5 exposure-induced senescence-associated secretory phenotype in airway smooth muscle cells contributes to airway remodeling. Environ. Pollut. 2024, 347, 123674.

[113] El Omar R, Beroud J, Stoltz JF, Menu P, Velot E, Decot V. Umbilical cord mesenchymal stem cells: the new gold standard for mesenchymal stem cell-based therapies? Tissue Eng. Part B Rev. 2014, 20, 523-544.

[114] Abbaszadeh H, Ghorbani F, Derakhshani M, Movassaghpour AA, Yousefi M, Talebi M, et al. Regenerative potential of Wharton's jelly-derived mesenchymal stem cells: A new horizon of stem cell therapy. J. Cell Physiol. 2020, 235, 9230-9240.

[115] Wang P, Cui Y, Wang J, Liu D, Tian Y, Liu K, et al. Mesenchymal stem cells protect against acetaminophen hepatotoxicity by secreting regenerative cytokine hepatocyte growth factor. Stem Cell Res. Ther. 2022, 13, 94.

[116] Chen Y, Huang H, Li G, Yu J, Fang F, Qiu W. Dental-derived mesenchymal stem cell sheets: a prospective tissue engineering for regenerative medicine. Stem Cell Res. Ther. 2022, 13, 38.

[117] Ridzuan N, Zakaria N, Widera D, Sheard J, Morimoto M, Kiyokawa H, et al. Human umbilical cord mesenchymal stem cell-derived extracellular vesicles ameliorate airway inflammation in a rat model of chronic obstructive pulmonary disease (COPD). Stem Cell Res. Ther. 2021, 12, 54.

[118] Antunes MA, Lapa e Silva JR, Rocco PR. Mesenchymal stromal cell therapy in COPD: from bench to bedside. Int. J. Chron. Obstruct. Pulmon. Dis. 2017, 12, 3017-3027.

[119] Yen BL, Yen ML, Wang LT, Liu KJ, Sytwu HK. Current status of mesenchymal stem cell therapy for immune/inflammatory lung disorders: Gleaning insights for possible use in COVID-19. Stem Cells Transl. Med. 2020, 9, 1163-1173.

[120] Feng B, Zhu J, Xu Y, Chen W, Sheng X, Feng X, et al. Immunosuppressive effects of mesenchymal stem cells on lung B cell gene expression in LPS-induced acute lung injury. Stem Cell Res. Ther. 2020, 11, 418.

[121] Wang YY, Li XZ, Wang LB. Therapeutic implications of mesenchymal stem cells in acute lung injury/acute respiratory distress syndrome. Stem Cell Res. Ther. 2013, 4, 45.

[122] Zhou Y, Zhou W, Li Y, Zhang J. MSCs regulate oxidative stress through the Nrf2 pathway to treat chronic obstructive pulmonary disease. BMC Pulm. Med. 2025, 25, 304.

[123] Cruz T, Lopez-Giraldo A, Noell G, Guirao A, Casas-Recasens S, Garcia T, et al. Smoking Impairs the Immunomodulatory Capacity of Lung-Resident Mesenchymal Stem Cells in Chronic Obstructive Pulmonary Disease. Am. J. Respir. Cell. Mol. Biol. 2019, 61, 575-583.

[124] Kruk DM, Wisman M, Noordhoek JA, Nizamoglu M, Jonker MR, de Bruin HG, et al. Paracrine Regulation of Alveolar Epithelial Damage and Repair Responses by Human Lung-Resident Mesenchymal Stromal Cells. Cells 2021, 10, 2860.

[125] Najar M, Martel-Pelletier J, Pelletier JP, Fahmi H. Novel insights for improving the therapeutic safety and efficiency of mesenchymal stromal cells. World J. Stem Cells 2020, 12, 1474-1491.

[126] Paris GC, Azevedo AA, Ferreira AL, Azevedo YM, Rainho MA, Oliveira GP, et al. Therapeutic potential of mesenchymal stem cells in multiple organs affected by COVID-19. Life Sci. 2021, 278, 119510.

[127] Jolly MK, Ward C, Eapen MS, Myers S, Hallgren O, Levine H, et al. Epithelial-mesenchymal transition, a spectrum of states: Role in lung development, homeostasis, and disease. Dev. Dyn. 2018, 247, 346-358.

[128] Dongre A, Weinberg RA. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat. Rev. Mol. Cell Biol. 2019, 20, 69-84.

[129] Kim DH, Xing T, Yang Z, Dudek R, Lu Q, Chen YH. Epithelial Mesenchymal Transition in Embryonic Development, Tissue Repair and Cancer: A Comprehensive Overview. J. Clin. Med. 2017, 7, doi:10.3390/jcm7010001..

[130] Knight DA, Grainge CL, Stick SM, Kicic A, Schuliga M. Epithelial Mesenchymal Transition in Respiratory Disease: Fact or Fiction. Chest 2020, 157, 1591-1596.

[131] Koczulla AR, Jonigk D, Wolf T, Herr C, Noeske S, Klepetko W, et al. Krüppel-like zinc finger proteins in end-stage COPD lungs with and without severe alpha1-antitrypsin deficiency. Orphanet. J. Rare Dis. 2012, 7, 29.

[132] Mahmood MQ, Walters EH, Shukla SD, Weston S, Muller HK, Ward C, et al. β-catenin, Twist and Snail: Transcriptional regulation of EMT in smokers and COPD, and relation to airflow obstruction. Sci. Rep. 2017, 7, 10832.

[133] Zheng L, Jiang YL, Fei J, Cao P, Zhang C, Xie GF, et al. Circulatory cadmium positively correlates with epithelial-mesenchymal transition in patients with chronic obstructive pulmonary disease. Ecotoxicol. Environ. Saf. 2021, 215, 112164.

[134] Shirahata T, Nakamura H, Nakajima T, Nakamura M, Chubachi S, Yoshida S, et al. Plasma sE-cadherin and the plasma sE-cadherin/sVE-cadherin ratio are potential biomarkers for chronic obstructive pulmonary disease. Biomarkers 2018, 23, 414-421.

[135] Mahmood MQ, Sohal SS, Shukla SD, Ward C, Hardikar A, Noor WD, et al. Epithelial mesenchymal transition in smokers: large versus small airways and relation to airflow obstruction. Int. J. Chron. Obstruct. Pulmon. Dis. 2015, 10, 1515-1524.

[136] Milara J, Peiró T, Serrano A, Cortijo J. Epithelial to mesenchymal transition is increased in patients with COPD and induced by cigarette smoke. Thorax 2013, 68, 410-420.

[137] Nomura T, Huang WC, Zhau HE, Josson S, Mimata H, Chung LW. β2-Microglobulin-mediated signaling as a target for cancer therapy. Anticancer Agents Med. Chem. 2014, 14, 343-352.

[138] De Cunto G, Brancaleone V, Riemma MA, Cerqua I, Vellecco V, Spaziano G, et al. Functional contribution of sphingosine-1-phosphate to airway pathology in cigarette smoke-exposed mice. Br. J. Pharmacol. 2020, 177, 267-281.

[139] Sharma P, Nag A. CUL4A ubiquitin ligase: a promising drug target for cancer and other human diseases. Open Biol. 2014, 4, 130217.

[140] Ren Y, Zhang Y, Fan L, Jiao Q, Wang Y, Wang Q. The cullin4A is up-regulated in chronic obstructive pulmonary disease patient and contributes to epithelial-mesenchymal transition in small airway epithelium. Respir. Res. 2019, 20, 84.

[141] Ornitz DM, Itoh N. The Fibroblast Growth Factor signaling pathway. Wiley Interdiscip. Rev. Dev. Biol. 2015, 4, 215-266.

[142] Yuan T, Volckaert T, Redente EF, Hopkins S, Klinkhammer K, Wasnick R, et al. FGF10-FGFR2B Signaling Generates Basal Cells and Drives Alveolar Epithelial Regeneration by Bronchial Epithelial Stem Cells after Lung Injury. Stem Cell Rep. 2019, 12, 1041-1055.

[143] Gupte VV, Ramasamy SK, Reddy R, Lee J, Weinreb PH, Violette SM, et al. 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, 424-436.

[144] Volckaert T, Yuan T, Chao CM, Bell H, Sitaula A, Szimmtenings L, et al. Fgf10-Hippo Epithelial-Mesenchymal Crosstalk Maintains and Recruits Lung Basal Stem Cells. Dev. Cell 2017, 43, 48-59.e5.

[145] Moiseenko A, Vazquez-Armendariz AI, Kheirollahi V, Chu X, Tata A, Rivetti S, et al. Identification of a Repair-Supportive Mesenchymal Cell Population during Airway Epithelial Regeneration. Cell Rep. 2020, 33, 108549.

[146] Hadzic S, Wu CY, Avdeev S, Weissmann N, Schermuly RT, Kosanovic D. Lung epithelium damage in COPD - An unstoppable pathological event? Cell Signal 2020, 68, 109540.

[147] Kruk DM, Wisman M, Bruin HG, Lodewijk ME, Hof DJ, Borghuis T, et al. Abnormalities in reparative function of lung-derived mesenchymal stromal cells in emphysema. Am. J. Physiol. Lung Cell. Mol. Physiol. 2021, 320, L832-L844.

[148] Klar J, Blomstrand P, Brunmark C, Badhai J, Håkansson HF, Brange CS, et al. Fibroblast growth factor 10 haploinsufficiency causes chronic obstructive pulmonary disease. J. Med. Genet. 2011, 48, 705-709.

[149] Wu X, van Dijk EM, Ng-Blichfeldt JP, Bos IS, Ciminieri C, Königshoff M, et al. Mesenchymal WNT-5A/5B Signaling Represses Lung Alveolar Epithelial Progenitors. Cells 2019, 8, 1147.

[150] Su Y, Han W, Kovacs-Kasa A, Verin AD, Kovacs L. HDAC6 Activates ERK in Airway and Pulmonary Vascular Remodeling of Chronic Obstructive Pulmonary Disease. Am. J. Respir. Cell. Mol. Biol. 2021, 65, 603-614.

[151] Aravamudan B, Thompson M, Sieck GC, Vassallo R, Pabelick CM, Prakash YS. Functional Effects of Cigarette Smoke-Induced Changes in Airway Smooth Muscle Mitochondrial Morphology. J. Cell Physiol. 2017, 232, 1053-1068.

[152] Boucherat O, Chakir J, Jeannotte L. The loss of Hoxa5 function promotes Notch-dependent goblet cell metaplasia in lung airways. Biol. Open 2012, 1, 677-691.

[153] Danahay H, Pessotti AD, Coote J, Montgomery BE, Xia D, Wilson A, et al. Notch2 is required for inflammatory cytokine-driven goblet cell metaplasia in the lung. Cell Rep. 2015, 10, 239-252.

[154] Elias JA, Lee CG, Zheng T, Ma B, Homer RJ, Zhu Z. New insights into the pathogenesis of asthma. J. Clin. Invest. 2003, 111, 291-297.

[155] Hogg JC, Timens W. The pathology of chronic obstructive pulmonary disease. Annu. Rev. Pathol. 2009, 4, 435-459.

[156] Wilk JB, Chen TH, Gottlieb DJ, Walter RE, Nagle MW, Brandler BJ, et al. A genome-wide association study of pulmonary function measures in the Framingham Heart Study. PLoS Genet. 2009, 5, e1000429.

[157] Zhou X, Baron RM, Hardin M, Cho MH, Zielinski J, Hawrylkiewicz I, et al. Identification of a chronic obstructive pulmonary disease genetic determinant that regulates HHIP. Hum. Mol. Genet. 2012, 21, 1325-1335.

[158] Volckaert T, Campbell A, Dill E, Li C, Minoo P, De Langhe S. Localized Fgf 10 expression is not required for lung branching morphogenesis but prevents differentiation of epithelial progenitors. Development 2013, 140, 3731-3742.

[159] Volckaert T, Dill E, Campbell A, Tiozzo C, Majka S, Bellusci S, et al. Parabronchial smooth muscle constitutes an airway epithelial stem cell niche in the mouse lung after injury. J. Clin. Invest. 2011, 121, 4409-4419.

[160] Tata PR, Mou H, Pardo-Saganta A, Zhao R, Prabhu M, Law BM, et al. Dedifferentiation of committed epithelial cells into stem cells in vivo. Nature 2013, 503, 218-223.

[161] Zhao R, Fallon TR, Saladi SV, Pardo-Saganta A, Villoria J, Mou H, et al. Yap tunes airway epithelial size and architecture by regulating the identity, maintenance, and self-renewal of stem cells. Dev. Cell 2014, 30, 151-165.

[162] Kooistra T, Saez B, Roche M, Egea-Zorrilla A, Li D, Anketell D, et al. Airway basal stem cells are necessary for the maintenance of functional intraepithelial airway macrophages. Cell Rep. 2025, 44, 115860.

[163] Wang Y, Meng Z, Liu M, Zhou Y, Chen D, Zhao Y, et al. Autologous transplantation of P63(+) lung progenitor cells for chronic obstructive pulmonary disease therapy. Sci. Transl. Med. 2024, 16, eadi3360.

[164] Chen Q, Hirai H, Chan M, Zhang J, Cho M, Randell SH, et al. Characterization of perivascular alveolar epithelial stem cells and their niche in lung homeostasis and cancer. Stem Cell Rep. 2024, 19, 890-905.

[165] Zhang J, Liu Y. Epithelial stem cells and niches in lung alveolar regeneration and diseases. Chin. Med. J. Pulm. Crit. Care Med. 2024, 2, 17-26.

[166] Hogan BL, Barkauskas CE, Chapman HA, Epstein JA, Jain R, Hsia CC, et al. Repair and regeneration of the respiratory system: complexity, plasticity, and mechanisms of lung stem cell function. Cell Stem Cell 2014, 15, 123-138.

[167] Adams TS, Schupp JC, Poli S, Ayaub EA, Neumark N, Ahangari F, et al. Single-cell RNA-seq reveals ectopic and aberrant lung-resident cell populations in idiopathic pulmonary fibrosis. Sci. Adv. 2020, 6, eaba1983.

[168] Habermann AC, Gutierrez AJ, Bui LT, Yahn SL, Winters NI, Calvi CL, et al. Single-cell RNA sequencing reveals profibrotic roles of distinct epithelial and mesenchymal lineages in pulmonary fibrosis. Sci. Adv. 2020, 6, eaba1972.

[169] Kadur Lakshminarasimha Murthy P, Sontake V, Tata A, Kobayashi Y, Macadlo L, Okuda K, et al. Human distal lung maps and lineage hierarchies reveal a bipotent progenitor. Nature 2022, 604, 111-119.

[170] Ahmadvand N, Carraro G, Jones MR, Shalashova I, Noori A, Wilhelm J, et al. Cell-Surface Programmed Death Ligand-1 Expression Identifies a Sub-Population of Distal Epithelial Cells Enriched in Idiopathic Pulmonary Fibrosis. Cells 2022, 11, 1593.

[171] Lv YQ, Cai GF, Zeng PP, Dhlamini Q, Chen LF, Chen JJ, et al. FGF10 Therapeutic Administration Promotes Mobilization of Injury-Activated Alveolar Progenitors in a Mouse Fibrosis Model. Cells 2022, 11, 2396.

[172] Chioccioli M, Liu S, Magruder S, Tata A, Borriello L, McDonough JE, et al. Stem cell migration drives lung repair in living mice. Dev. Cell 2024, 59, 830-840.e4.

[173] El Agha E, Thannickal VJ. The lung mesenchyme in development, regeneration, and fibrosis. J. Clin. Invest. 2023, 133, e170498.

[174] Wu J, Chu X, Chen C, Bellusci S. Role of Fibroblast Growth Factor 10 in Mesenchymal Cell Differentiation During Lung Development and Disease. Front. Genet. 2018, 9, 545.

[175] Konkimalla A, Konishi S, Macadlo L, Kobayashi Y, Farino ZJ, Miyashita N, et al. Transitional cell states sculpt tissue topology during lung regeneration. Cell Stem Cell 2023, 30, 1486-1502.e9.

[176] Higham A, Quinn AM, Cançado JE, Singh D. The pathology of small airways disease in COPD: historical aspects and future directions. Respir. Res. 2019, 20, 49.

[177] Yang J, Antin P, Berx G, Blanpain C, Brabletz T, Bronner M, et al. Guidelines and definitions for research on epithelial-mesenchymal transition. Nat. Rev. Mol. Cell. Biol. 2020, 21, 341-352.

[178] Kheirollahi V, Wasnick RM, Biasin V, Vazquez-Armendariz AI, Chu X, Moiseenko A, et al. Metformin induces lipogenic differentiation in myofibroblasts to reverse lung fibrosis. Nat. Commun. 2019, 10, 2987.

[179] Nasri A, Foisset F, Ahmed E, Lahmar Z, Vachier I, Jorgensen C, et al. Roles of Mesenchymal Cells in the Lung: From Lung Development to Chronic Obstructive Pulmonary Disease. Cells 2021, 10, 3467.

[180] Taghizadeh S, Heiner M, Vazquez-Armendariz AI, Wilhelm J, Herold S, Chen C, et al. Characterization in mice of the resident mesenchymal niche maintaining AT2 stem cell proliferation in homeostasis and disease. Stem Cells 2021, 39, 1382-1394.

[181] Fang Y, Chung SS, Xu L, Xue C, Liu X, Jiang D, et al. RUNX2 promotes fibrosis via an alveolar-to-pathological fibroblast transition. Nature 2025, 640, 221-230.