Lung regeneration: diverse cell types and the therapeutic potential

Abstract

Lung tissue has a certain regenerative ability and triggers repair procedures after injury. Under controllable conditions, lung tissue can restore normal structure and function. Disruptions in this process can lead to respiratory system failure and even death, causing substantial medical burden. The main types of respiratory diseases are chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and acute respiratory distress syndrome (ARDS). Multiple cells, such as lung epithelial cells, endothelial cells, fibroblasts, and immune cells, are involved in regulating the repair process after lung injury. Although the mechanism that regulates the process of lung repair has not been fully elucidated, clinical trials targeting different cells and signaling pathways have achieved some therapeutic effects in different respiratory diseases. In this review, we provide an overview of the cell type involved in the process of lung regeneration and repair, research models, and summarize molecular mechanisms involved in the regulation of lung regeneration and fibrosis. Moreover, we discuss the current clinical trials of stem cell therapy and pharmacological strategies for COPD, IPF, and ARDS treatment. This review provides a reference for further research on the molecular and cellular mechanisms of lung regeneration, drug development, and clinical trials.

Keywords

cellular composition / lung regeneration / molecular mechanisms / research models / therapeutic potential

References

[1] Chen Y, Klein SL, Garibaldi BT, et al. Aging in COVID-19: vulnerability, immunity and intervention. Ageing Res Rev. 2021;65:101205.

[2] Schneider JL, Rowe JH, Garcia-de-Alba C, Kim CF, Sharpe AH, Haigis MC. The aging lung: physiology, disease, and immunity. Cell. 2021;184(8):1990-2019.

[3] O'Driscoll M, Ribeiro Dos Santos G, Wang L, et al. Age-specific mortality and immunity patterns of SARS-CoV-2. Nature. 2021;590(7844):140-145.

[4] Sudre CH, Murray B, Varsavsky T, et al. Attributes and predictors of long COVID. Nat Med. 2021;27(4):626-631.

[5] Rendeiro AF, Ravichandran H, Bram Y, et al. The spatial landscape of lung pathology during COVID-19 progression. Nature. 2021;593(7860):564-569.

[6] GBD 2019 Chronic Respiratory Diseases Collaborators. Global burden of chronic respiratory diseases and risk factors, 1990–2019: an update from the Global Burden of Disease Study 2019. eClinicalMedicine. 2023;59:101936.

[7] Wijsenbeek M, Suzuki A, Maher TM. Interstitial lung diseases. Lancet (London, England). 2022;400(10354):769-786.

[8] Joy GM, Arbiv OA, Wong CK, et al. Prevalence, imaging patterns and risk factors of interstitial lung disease in connective tissue disease: a systematic review and meta-analysis. Eur Respir Rev. 2023;32(167):220210.

[9] Neupane AS, Willson M, Chojnacki AK, et al. Patrolling alveolar macrophages conceal bacteria from the immune system to maintain homeostasis. Cell. 2020;183(1):110-125.e11.

[10] Shenderov K, Collins SL, Powell JD, Horton MR. Immune dysregulation as a driver of idiopathic pulmonary fibrosis. J Clin Invest. 2021;131(2):e143226.

[11] Cho SJ, Stout-Delgado HW. Aging and lung disease. Annu Rev Physiol. 2020;82:433-459.

[12] Raghu G, Remy-Jardin M, Richeldi L, et al. Idiopathic pulmonary fibrosis (an update) and progressive pulmonary fibrosis in adults: an official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2022;205(9):e18-e47.

[13] Fournier D, Jouneau S, Bouzillé G, Polard E, Osmont M-N, Scailteux L-M. Real-world safety profiles of pirfenidone and nintedanib in idiopathic pulmonary fibrosis patients. Pulm Pharmacol Ther. 2022;76:102149.

[14] Amati F, Stainer A, Polelli V, et al. Efficacy of pirfenidone and nintedanib in interstitial lung diseases other than idiopathic pulmonary fibrosis: a systematic review. Int J Mol Sci. 2023;24(9):7849.

[15] Renzoni EA, Poletti V, Mackintosh JA. Disease pathology in fibrotic interstitial lung disease: is it all about usual interstitial pneumonia? Lancet (London, England). 2021;398(10309):1437-1449.

[16] Kadota T, Fujita Y, Araya J, et al. Human bronchial epithelial cell-derived extracellular vesicle therapy for pulmonary fibrosis via inhibition of TGF-β-WNT crosstalk. J Extracell Vesicles. 2021;10(10):e12124.

[17] Brody SL, Gunsten SP, Luehmann HP, et al. Chemokine receptor 2-targeted molecular imaging in pulmonary fibrosis. A clinical trial. Am J Respir Crit Care Med. 2021;203(1):78-89.

[18] Habermann AC, Gutierrez AJ, Bui LT, et al. Single-cell RNA sequencing reveals profibrotic roles of distinct epithelial and mesenchymal lineages in pulmonary fibrosis. Sci Adv. 2020;6(28):eaba1972.

[19] Strunz M, Simon LM, Ansari M, et al. Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis. Nat Commun. 2020;11(1):3559.

[20] Chen Q, Liu Y. Heterogeneous groups of alveolar type II cells in lung homeostasis and repair. Am J Physiol Cell Physiol. 2020;319(6):C991-C996.

[21] Choi J, Park J-E, Tsagkogeorga G, et al. Inflammatory signals induce AT2 cell-derived damage-associated transient progenitors that mediate alveolar regeneration. Cell Stem Cell. 2020;27(3):366-382.e7.

[22] Kobayashi Y, Tata A, Konkimalla A, et al. Persistence of a regeneration-associated, transitional alveolar epithelial cell state in pulmonary fibrosis. Nat Cell Biol. 2020;22(8):934-946.

[23] Chan M, Liu Y. Function of epithelial stem cell in the repair of alveolar injury. Stem Cell Res Ther. 2022;13(1):170.

[24] Kadur Lakshminarasimha Murthy P, Sontake V, Tata A, et al. Human distal lung maps and lineage hierarchies reveal a bipotent progenitor. Nature. 2022;604(7904):111-119.

[25] Dost AFM, Moye AL, Vedaie M, et al. Organoids model transcriptional hallmarks of oncogenic KRAS activation in lung epithelial progenitor cells. Cell Stem Cell. 2020;27(4):663-678.e8.

[26] Jiang P, Gil de Rubio R, Hrycaj SM, et al. Ineffectual type 2-to-type 1 alveolar epithelial cell differentiation in idiopathic pulmonary fibrosis: persistence of the KRT8(hi) transitional state. Am J Respir Crit Care Med. 2020;201(11):1443-1447.

[27] Wang F, Ting C, Riemondy KA, et al. Regulation of epithelial transitional states in murine and human pulmonary fibrosis. J Clin Invest. 2023;133(22):e165612.

[28] Katzen J, Beers MF. Contributions of alveolar epithelial cell quality control to pulmonary fibrosis. J Clin Invest. 2020;130(10):5088-5099.

[29] Ruaro B, Salton F, Braga L, et al. The history and mystery of alveolar epithelial type II cells: focus on their physiologic and pathologic role in lung. Int J Mol Sci. 2021;22(5):2566.

[30] Basil MC, Katzen J, Engler AE, et al. The cellular and physiological basis for lung repair and regeneration: past, present, and future. Cell Stem Cell. 2020;26(4):482-502.

[31] Frank DB, Penkala IJ, Zepp JA, et al. Early lineage specification defines alveolar epithelial ontogeny in the murine lung. Proc Natl Acad Sci USA. 2019;116(10):4362-4371.

[32] Basil MC, Cardenas-Diaz FL, Kathiriya JJ, et al. Human distal airways contain a multipotent secretory cell that can regenerate alveoli. Nature. 2022;604(7904):120-126.

[33] Peisker F, Halder M, Nagai J, et al. Mapping the cardiac vascular niche in heart failure. Nat Commun. 2022;13(1):3027.

[34] Zhang H, Ma Y, Cheng X, et al. Targeting epigenetically maladapted vascular niche alleviates liver fibrosis in nonalcoholic steatohepatitis. Sci Transl Med. 2021;13(614):eabd1206.

[35] Hoffmann J, Luxán G, Abplanalp WT, et al. Post-myocardial infarction heart failure dysregulates the bone vascular niche. Nat Commun. 2021;12(1):3964.

[36] Termini CM, Pang A, Fang T, et al. Neuropilin 1 regulates bone marrow vascular regeneration and hematopoietic reconstitution. Nat Commun. 2021;12(1):6990.

[37] Yip RKH, Rimes JS, Capaldo BD, et al. Mammary tumour cells remodel the bone marrow vascular microenvironment to support metastasis. Nat Commun. 2021;12(1):6920.

[38] Singhal M, Gengenbacher N, Abdul Pari AA, et al. Temporal multi-omics identifies LRG1 as a vascular niche instructor of metastasis. Sci Transl Med. 2021;13(609):eabe6805.

[39] Rafii S, Butler JM, Ding B-S. Angiocrine functions of organ-specific endothelial cells. Nature. 2016;529(7586):316-325.

[40] Ding BS, Nolan DJ, Guo P, et al. Endothelial-derived angiocrine signals induce and sustain regenerative lung alveolarization. Cell. 2011;147(3):539-553.

[41] Schupp JC, Adams TS, Cosme CJ, et al. Integrated single-cell atlas of endothelial cells of the human lung. Circulation. 2021;144(4):286-302.

[42] Dharmadhikari AV, Szafranski P, Kalinichenko VV, Stankiewicz P. Genomic and epigenetic complexity of the FOXF1 locus in 16q24.1: implications for development and disease. Curr Genomics. 2015;16(2):107-116.

[43] Pradhan A, Dunn A, Ustiyan V, et al. The S52F FOXF1 mutation inhibits STAT3 signaling and causes alveolar capillary dysplasia. Am J Respir Crit Care Med. 2019;200(8):1045-1056.

[44] Kolesnichenko OA, Whitsett JA, Kalin TV, Kalinichenko VV. Therapeutic potential of endothelial progenitor cells in pulmonary diseases. Am J Respir Cell Mol Biol. 2021;65(5):473-488.

[45] Wang G, Wen B, Deng Z, et al. Endothelial progenitor cells stimulate neonatal lung angiogenesis through FOXF1-mediated activation of BMP9/ACVRL1 signaling. Nat Commun. 2022;13(1):2080.

[46] Chen Q, Rehman J, Chan M, et al. Angiocrine sphingosine-1-phosphate activation of S1PR2-YAP signaling axis in alveolar type II cells is essential for lung repair. Cell Rep. 2020;31(13):107828.

[47] Finn J, Sottoriva K, Pajcini KV, et al. Dlk1-mediated temporal regulation of notch signaling is required for differentiation of alveolar type II to type I cells during repair. Cell Rep. 2019;26(11):2942-2954.e5.

[48] Volpe MC, Ciucci G, Zandomenego G, et al. Flt1 produced by lung endothelial cells impairs ATII cell transdifferentiation and repair in pulmonary fibrosis. Cell Death Dis. 2023;14(7):437.

[49] Lechartier B, Humbert M. Pulmonary arterial hypertension in systemic sclerosis. Presse Med. 2021;50(1):104062.

[50] Wu Z, Zhu L, Nie X, Wei L, Qi Y. USP15 promotes pulmonary vascular remodeling in pulmonary hypertension in a YAP1/TAZ-dependent manner. Exp Mol Med. 2023;55(1):183-195.

[51] Gillich A, Zhang F, Farmer CG, et al. Capillary cell-type specialization in the alveolus. Nature. 2020;586(7831):785-789.

[52] Fan H, Goodwin AJ, Chang E, et al. Endothelial progenitor cells and a stromal cell-derived factor-1α analogue synergistically improve survival in sepsis. Am J Respir Crit Care Med. 2014;189(12):1509-1519.

[53] Mao M, Wang S-N, Lv X-J, Wang Y, Xu J-C. Intravenous delivery of bone marrow-derived endothelial progenitor cells improves survival and attenuates lipopolysaccharide-induced lung injury in rats. Shock. 2010;34(2):196-204.

[54] Zhou Y, Li P, Goodwin AJ, et al. Exosomes from endothelial progenitor cells improve the outcome of a murine model of sepsis. Mol Ther. 2018;26(5):1375-1384.

[55] Zhou Y, Li P, Goodwin AJ, et al. Exosomes from endothelial progenitor cells improve outcomes of the lipopolysaccharide-induced acute lung injury. Crit Care. 2019;23(1):44.

[56] Chen Y, Ding B-S. Comprehensive review of the vascular niche in regulating organ regeneration and fibrosis. Stem Cells Transl Med. 2022;11(11):1135-1142.

[57] Mercer RR, Russell ML, Roggli VL, Crapo JD. Cell number and distribution in human and rat airways. Am J Respir Cell Mol Biol. 1994;10(6):613-624.

[58] Kathiriya JJ, Brumwell AN, Jackson JR, Tang X, Chapman HA. Distinct airway epithelial stem cells hide among club cells but mobilize to promote alveolar regeneration. Cell Stem Cell. 2020;26(3):346-358.e4.

[59] Shivaraju M, Chitta UK, Grange RMH, et al. Airway stem cells sense hypoxia and differentiate into protective solitary neuroendocrine cells. Science. 2021;371(6524):52-57.

[60] Smirnova NF, Schamberger AC, Nayakanti S, Hatz R, Behr J, Eickelberg O. Detection and quantification of epithelial progenitor cell populations in human healthy and IPF lungs. Respir Res. 2016;17(1):83.

[61] Prasse A, Binder H, Schupp JC, et al. BAL cell gene expression is indicative of outcome and airway basal cell involvement in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2019;199(5):622-630.

[62] Hewitt RJ, Puttur F, Gaboriau DCA, et al. Lung extracellular matrix modulates KRT5(+) basal cell activity in pulmonary fibrosis. Nat Commun. 2023;14(1):6039.

[63] Kathiriya JJ, Wang C, Zhou M, et al. Human alveolar type 2 epithelium transdifferentiates into metaplastic KRT5(+) basal cells. Nat Cell Biol. 2022;24(1):10-23.

[64] Xi Y, Kim T, Brumwell AN, et al. Local lung hypoxia determines epithelial fate decisions during alveolar regeneration. Nat Cell Biol. 2017;19(8):904-914.

[65] Vaughan AE, Brumwell AN, Xi Y, et al. Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury. Nature. 2015;517(7536):621-625.

[66] Ray S, Chiba N, Yao C, et al. Rare SOX2(+) airway progenitor cells generate KRT5(+) cells that repopulate damaged alveolar parenchyma following influenza virus infection. Stem Cell Rep. 2016;7(5):817-825.

[67] Yang Y, Riccio P, Schotsaert M, et al. Spatial-temporal lineage restrictions of embryonic p63(+) progenitors establish distinct stem cell pools in adult airways. Dev Cell. 2018;44(6):752-761.e4.

[68] Yu W, Moninger TO, Thurman AL, et al. Cellular and molecular architecture of submucosal glands in wild-type and cystic fibrosis pigs. Proc Natl Acad Sci USA. 2022;119(4):e2119759119.

[69] Montoro DT, Haber AL, Biton M, et al. A revised airway epithelial hierarchy includes CFTR-expressing ionocytes. Nature. 2018;560(7718):319-324.

[70] Plasschaert LW, Žilionis R, Choo-Wing R, et al. A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte. Nature. 2018;560(7718):377-381.

[71] Hinz B, Lagares D. Evasion of apoptosis by myofibroblasts: a hallmark of fibrotic diseases. Nat Rev Rheumatol. 2020;16(1):11-31.

[72] Ptasinski VA, Stegmayr J, Belvisi MG, Wagner DE, Murray LA. Targeting alveolar repair in idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol. 2021;65(4):347-365.

[73] Gong Z, Li Q, Shi J, et al. Lung fibroblasts facilitate pre-metastatic niche formation by remodeling the local immune microenvironment. Immunity. 2022;55(8):1483-1500.e9.

[74] El Agha E, Moiseenko A, Kheirollahi V, et al. Two-way conversion between lipogenic and myogenic fibroblastic phenotypes marks the progression and resolution of lung fibrosis. Cell Stem Cell. 2017;20(2):261-273.e3.

[75] 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(6380):1118-1123.

[76] Tsukui T, Sun K-H, Wetter JB, et al. Collagen-producing lung cell atlas identifies multiple subsets with distinct localization and relevance to fibrosis. Nat Commun. 2020;11(1):1920.

[77] Hinz B, Phan SH, Thannickal VJ, et al. Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. Am J Pathol. 2012;180(4):1340-1355.

[78] Moore MW, Herzog EL. Regulation and relevance of myofibroblast responses in idiopathic pulmonary fibrosis. Curr Pathobiol Rep. 2013;1(3):199-208.

[79] Hinz B. The extracellular matrix and transforming growth factor-β1: tale of a strained relationship. Matrix Biol. 2015;47:54-65.

[80] Guan R, Yuan L, Li J, et al. Bone morphogenetic protein 4 inhibits pulmonary fibrosis by modulating cellular senescence and mitophagy in lung fibroblasts. Eur Respir J. 2022;60(6):2102307.

[81] Yamaguchi M, Hirai S, Tanaka Y, et al. Pericyte-myofibroblast transition in the human lung. Biochem Biophys Res Commun. 2020;528(2):269-275.

[82] Reilkoff RA, Bucala R, Herzog EL. Fibrocytes: emerging effector cells in chronic inflammation. Nat Rev Immunol. 2011;11(6):427-435.

[83] Dupin I, Contin-Bordes C, Berger P. Fibrocytes in asthma and chronic obstructive pulmonary disease: variations on the same theme. Am J Respir Cell Mol Biol. 2018;58(3):288-298.

[84] Wendisch D, Dietrich O, Mari T, et al. SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis. Cell. 2021;184(26):6243-6261.e27.

[85] Gao R, Peng X, Perry C, et al. Macrophage-derived netrin-1 drives adrenergic nerve-associated lung fibrosis. J Clin Invest. 2021;131(1):e136542.

[86] Ogger PP, Albers GJ, Hewitt RJ, et al. Itaconate controls the severity of pulmonary fibrosis. Sci Immunol. 2020;5(52):eabc1884.

[87] Bernardes JP, Mishra N, Tran F, et al. Longitudinal multi-omics analyses identify responses of megakaryocytes, erythroid cells, and plasmablasts as hallmarks of severe COVID-19. Immunity. 2020;53(6):1296-1314.e9.

[88] Tian Y, Lv J, Su Z, et al. LRRK2 plays essential roles in maintaining lung homeostasis and preventing the development of pulmonary fibrosis. Proc Natl Acad Sci USA. 2021;118(35):e2106685118.

[89] Fabre T, Barron AMS, Christensen SM, et al. Identification of a broadly fibrogenic macrophage subset induced by type 3 inflammation. Sci Immunol. 2023;8(82):eadd8945.

[90] Wang Y, Zhang L, Wu G-R, et al. MBD2 serves as a viable target against pulmonary fibrosis by inhibiting macrophage M2 program. Sci Adv. 2021;7(1):eabb6075.

[91] Westphalen K, Gusarova GA, Islam MN, et al. Sessile alveolar macrophages communicate with alveolar epithelium to modulate immunity. Nature. 2014;506(7489):503-506.

[92] Jardine L, Wiscombe S, Reynolds G, et al. Lipopolysaccharide inhalation recruits monocytes and dendritic cell subsets to the alveolar airspace. Nat Commun. 2019;10(1):1999.

[93] Branchett WJ, Cook J, Oliver RA, et al. Airway macrophage-intrinsic TGF-β1 regulates pulmonary immunity during early-life allergen exposure. J Allergy Clin Immunol. 2021;147(5):1892-1906.

[94] Hogg JC, Doerschuk CM, Wiggs B, Minshall D. Neutrophil retention during a single transit through the pulmonary circulation. J Appl Physiol. 1992;73(4):1683-1685.

[95] Sibille Y, Reynolds HY. Macrophages and polymorphonuclear neutrophils in lung defense and injury. Am Rev Respir Dis. 1990;141(2):471-501.

[96] Giacalone VD, Margaroli C, Mall MA, Tirouvanziam R. Neutrophil adaptations upon recruitment to the lung: new concepts and implications for homeostasis and disease. Int J Mol Sci. 2020;21(3).

[97] Schulte-Schrepping J, Reusch N, Paclik D, et al. Severe COVID-19 is marked by a dysregulated myeloid cell compartment. Cell. 2020;182(6):1419-1440.e23.

[98] Zhang T, Yin C, Boyd DF, et al. Influenza virus Z-RNAs induce ZBP1-mediated necroptosis. Cell. 2020;180(6):1115-1129.e13.

[99] Negreros M, Flores-Suárez LF. A proposed role of neutrophil extracellular traps and their interplay with fibroblasts in ANCA-associated vasculitis lung fibrosis. Autoimmun Rev. 2021;20(4):102781.

[100] Suzuki M, Ikari J, Anazawa R, et al. PAD4 deficiency improves bleomycin-induced neutrophil extracellular traps and fibrosis in mouse lung. Am J Respir Cell Mol Biol. 2020;63(6):806-818.

[101] Thiam HR, Wong SL, Wagner DD, Waterman CM. Cellular mechanisms of NETosis. Annu Rev Cell Dev Biol. 2020;36:191-218.

[102] Lin W-C, Fessler MB. Regulatory mechanisms of neutrophil migration from the circulation to the airspace. Cell Mol Life Sci. 2021;78(9):4095-4124.

[103] Pernet E, Sun S, Sarden N, et al. Neonatal imprinting of alveolar macrophages via neutrophil-derived 12-HETE. Nature. 2023;614(7948):530-538.

[104] Grieshaber-Bouyer R, Radtke FA, Cunin P, et al. The neutrotime transcriptional signature defines a single continuum of neutrophils across biological compartments. Nat Commun. 2021;12(1):2856.

[105] Rao W, Wang S, Duleba M, et al. Regenerative metaplastic clones in COPD lung drive inflammation and fibrosis. Cell. 2020;181(4):848-864.e18.

[106] Zhao X, Alibhai D, Walsh TG, et al. Highly efficient platelet generation in lung vasculature reproduced by microfluidics. Nat Commun. 2023;14(1):4026.

[107] Koupenova M, Livada AC, Morrell CN. Platelet and megakaryocyte roles in innate and adaptive immunity. Circ Res. 2022;130(2):288-308.

[108] Lefrançais E, Ortiz-Muñoz G, Caudrillier A, et al. The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors. Nature. 2017;544(7648):105-109.

[109] Pariser DN, Hilt ZT, Ture SK, et al. Lung megakaryocytes are immune modulatory cells. J Clin Invest. 2021;131(1):e137377.

[110] Rafii S, Cao Z, Lis R, et al. Platelet-derived SDF-1 primes the pulmonary capillary vascular niche to drive lung alveolar regeneration. Nat Cell Biol. 2015;17(2):123-136.

[111] Saito S, Chung CHH, Jacob A, et al. Hematopoietic and lung platelet biogenesis as a prognostic indicator in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2022;206(9):1174-1177.

[112] Delaney C, Davizon-Castillo P, Allawzi A, et al. Platelet activation contributes to hypoxia-induced inflammation. Am J Physiol Lung Cell Mol Physiol. 2021;320(3):L413-L421.

[113] Kim S-J, Carestia A, McDonald B, et al. Platelet-mediated NET release amplifies coagulopathy and drives lung pathology during severe influenza infection. Front Immunol. 2021;12:772859.

[114] Wang Y, Tang N. The diversity of adult lung epithelial stem cells and their niche in homeostasis and regeneration. Sci China Life Sci. 2021;64(12):2045-2059.

[115] Zhao F, Ma Q, Yue Q, Chen H. SARS-CoV-2 infection and lung regeneration. Clin Microbiol Rev. 2022;35(2):e0018821.

[116] Jones-Freeman B, Starkey MR. Bronchioalveolar stem cells in lung repair, regeneration and disease. J Pathol. 2020;252(3):219-226.

[117] Sun X, Perl A-K, Li R, et al. A census of the lung: cellCards from LungMAP. Dev Cell. 2022;57(1):112-145.e2.

[118] Carraro G, Langerman J, Sabri S, et al. Transcriptional analysis of cystic fibrosis airways at single-cell resolution reveals altered epithelial cell states and composition. Nat Med. 2021;27(5):806-814.

[119] Adams TS, Schupp JC, Poli S, et al. Single-cell RNA-seq reveals ectopic and aberrant lung-resident cell populations in idiopathic pulmonary fibrosis. Sci Adv. 2020;6(28):eaba1983.

[120] Morse C, Tabib T, Sembrat J, et al. Proliferating SPP1/MERTK-expressing macrophages in idiopathic pulmonary fibrosis. Eur Respir J. 2019;54(2):1802441.

[121] Liu Q, Liu K, Cui G, et al. Lung regeneration by multipotent stem cells residing at the bronchioalveolar-duct junction. Nat Genet. 2019;51(4):728-738.

[122] Hillel-Karniel C, Rosen C, Milman-Krentsis I, et al. Multi-lineage lung regeneration by stem cell transplantation across major genetic barriers. Cell Rep. 2020;30(3):807-819.e4.

[123] Cao Z, Ye T, Sun Y, et al. Targeting the vascular and perivascular niches as a regenerative therapy for lung and liver fibrosis. Sci Transl Med. 2017;9(405):eaai8710.

[124] Ding BS, Nolan DJ, Butler JM, et al. Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration. Nature. 2010;468(7321):310-315.

[125] Wang L, Zhao Y, Yang F, et al. Biomimetic collagen biomaterial induces in situ lung regeneration by forming functional alveolar. Biomaterials. 2020;236:119825.

[126] Conlon TM, John-Schuster G, Heide D, et al. Inhibition of LTβR signalling activates WNT-induced regeneration in lung. Nature. 2020;588(7836):151-156.

[127] Dinnon KH, Leist SR, Okuda K, et al. SARS-CoV-2 infection produces chronic pulmonary epithelial and immune cell dysfunction with fibrosis in mice. Sci Transl Med. 2022;14(664):eabo5070.

[128] Regard L, Martin C, Teillaud J-L, et al. Effective control of Staphylococcus aureus lung infection despite tertiary lymphoid structure disorganisation. Eur Respir J. 2021;57(4):2000768.

[129] Polverino F, Cosio BG, Pons J, et al. B cell-activating factor. An orchestrator of lymphoid follicles in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2015;192(6):695-705.

[130] Brunet M, Crombé A, Cousin S, et al. Mature tertiary lymphoid structure is a specific biomarker of cancer immunotherapy and does not predict outcome to chemotherapy in non-small-cell lung cancer. Ann Oncol. 2022;33(10):1084-1085.

[131] Ng KW, Boumelha J, Enfield KSS, et al. Antibodies against endogenous retroviruses promote lung cancer immunotherapy. Nature. 2023;616(7957):563-573.

[132] Sun X, Liu W, Sun L, et al. Maturation and abundance of tertiary lymphoid structures are associated with the efficacy of neoadjuvant chemoimmunotherapy in resectable non-small cell lung cancer. J Immunother Cancer. 2022;10(11):e005531.

[133] Macchi F, Sadler KC. Unraveling the epigenetic basis of liver development, regeneration and disease. Trends Genet. 2020;36(8):587-597.

[134] Tao L, Yu HV, Llamas J, et al. Enhancer decommissioning imposes an epigenetic barrier to sensory hair cell regeneration. Dev Cell. 2021;56(17):2471-2485.e5.

[135] Paris AJ, Hayer KE, Oved JH, et al. STAT3-BDNF-TrkB signalling promotes alveolar epithelial regeneration after lung injury. Nat Cell Biol. 2020;22(10):1197-1210.

[136] Melms JC, Biermann J, Huang H, et al. A molecular single-cell lung atlas of lethal COVID-19. Nature. 2021;595(7865):114-119.

[137] Zhu J, Fan Y, Xiong Y, et al. Delineating the dynamic evolution from preneoplasia to invasive lung adenocarcinoma by integrating single-cell RNA sequencing and spatial transcriptomics. Exp Mol Med. 2022;54(11):2060-2076.

[138] Sinjab A, Han G, Treekitkarnmongkol W, et al. Resolving the spatial and cellular architecture of lung adenocarcinoma by multiregion single-cell sequencing. Cancer Discov. 2021;11(10):2506-2523.

[139] Zhang Q, Abdo R, Iosef C, et al. The spatial transcriptomic landscape of non-small cell lung cancer brain metastasis. Nat Commun. 2022;13(1):5983.

[140] Vandereyken K, Sifrim A, Thienpont B, Voet T. Methods and applications for single-cell and spatial multi-omics. Nat Rev Genet. 2023;24(8):494-515.

[141] Moffitt JR, Lundberg E, Heyn H. The emerging landscape of spatial profiling technologies. Nat Rev Genet. 2022;23(12):741-759.

[142] Chen Y, Pu Q, Ma Y, et al. Aging reprograms the hematopoietic-vascular niche to impede regeneration and promote fibrosis. Cell Metab. 2021;33(2):395-410.e4.

[143] Singh A, Chakraborty S, Wong SW, et al. Nanoparticle targeting of de novo profibrotic macrophages mitigates lung fibrosis. Proc Natl Acad Sci USA. 2022;119(15):e2121098119.

[144] Chilosi M, Caliò A, Rossi A, et al. Epithelial to mesenchymal transition-related proteins ZEB1, β-catenin, and β-tubulin-III in idiopathic pulmonary fibrosis. Mod Pathol. 2017;30(1):26-38.

[145] Baek AR, Hong J, Song KS, et al. Spermidine attenuates bleomycin-induced lung fibrosis by inducing autophagy and inhibiting endoplasmic reticulum stress (ERS)-induced cell death in mice. Exp Mol Med. 2020;52(12):2034-2045.

[146] Yao C, Guan X, Carraro G, et al. Senescence of alveolar type 2 cells drives progressive pulmonary fibrosis. Am J Respir Crit Care Med. 2021;203(6):707-717.

[147] Spagnolo P, Kropski JA, Jones MG, et al. Idiopathic pulmonary fibrosis: disease mechanisms and drug development. Pharmacol Ther. 2021;222:107798.

[148] Richeldi L, Collard HR, Jones MG. Idiopathic pulmonary fibrosis. Lancet (London, England). 2017;389(10082):1941-1952.

[149] Lederer DJ, Martinez FJ. Idiopathic pulmonary fibrosis. N Engl J Med. 2018;378(19):1811-1823.

[150] Wu H, Yu Y, Huang H, et al. Progressive pulmonary fibrosis is caused by elevated mechanical tension on alveolar stem cells. Cell. 2020;180(1):107-121.e17.

[151] Lee S, Islam MN, Boostanpour K, et al. Molecular programs of fibrotic change in aging human lung. Nat Commun. 2021;12(1):6309.

[152] Vukmirovic M, Kaminski N. Impact of transcriptomics on our understanding of pulmonary fibrosis. Front Med. 2018;5:87.

[153] Lunney JK, Van Goor A, Walker KE, Hailstock T, Franklin J, Dai C. Importance of the pig as a human biomedical model. Sci Transl Med. 2021;13(621):eabd5758.

[154] Sun S-H, Chen Q, Gu H-J, et al. A mouse model of SARS-CoV-2 infection and pathogenesis. Cell Host Microbe. 2020;28(1):124-133.e4.

[155] Pang I-H, Clark AF. Inducible rodent models of glaucoma. Prog Retin Eye Res. 2020;75:100799.

[156] Stener-Victorin E, Padmanabhan V, Walters KA, et al. Animal models to understand the etiology and pathophysiology of polycystic ovary syndrome. Endocr Rev. 2020;41(4):bnaa010.

[157] Allen RJ, Guillen-Guio B, Oldham JM, et al. Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2020;201(5):564-574.

[158] Peljto AL, Blumhagen RZ, Walts AD, et al. Idiopathic pulmonary fibrosis is associated with common genetic variants and limited rare variants. Am J Respir Crit Care Med. 2023;207(9):1194-1202.

[159] Alysandratos K-D, Russo SJ, Petcherski A, et al. Patient-specific iPSCs carrying an SFTPC mutation reveal the intrinsic alveolar epithelial dysfunction at the inception of interstitial lung disease. Cell Rep. 2021;36(9):109636.

[160] Radicioni G, Ceppe A, Ford AA, et al. Airway mucin MUC5AC and MUC5B concentrations and the initiation and progression of chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort. Lancet Respir Med. 2021;9(11):1241-1254.

[161] Sundarakrishnan A, Chen Y, Black LD, Aldridge BB, Kaplan DL. Engineered cell and tissue models of pulmonary fibrosis. Adv Drug Deliv Rev. 2018;129:78-94.

[162] Tanner L, Single AB, Bhongir RKV, et al. Small-molecule-mediated OGG1 inhibition attenuates pulmonary inflammation and lung fibrosis in a murine lung fibrosis model. Nat Commun. 2023;14(1):643.

[163] Savin IA, Zenkova MA, Sen'kova AV. Pulmonary fibrosis as a result of acute lung inflammation: molecular mechanisms, relevant in vivo models, prognostic and therapeutic approaches. Int J Mol Sci. 2022;23(23):14959.

[164] Della Latta V, Cecchettini A, Del Ry S, Morales MA. Bleomycin in the setting of lung fibrosis induction: from biological mechanisms to counteractions. Pharmacol Res. 2015;97:122-130.

[165] Chin C, Ravichandran R, Sanborn K, et al. Loss of IGFBP2 mediates alveolar type 2 cell senescence and promotes lung fibrosis. Cell Rep Med. 2023;4(3):100945.

[166] Degryse AL, Tanjore H, Xu XC, et al. Repetitive intratracheal bleomycin models several features of idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2010;299(4):L442-L452.

[167] Chung MP, Monick MM, Hamzeh NY, Butler NS, Powers LS, Hunninghake GW. Role of repeated lung injury and genetic background in bleomycin-induced fibrosis. Am J Respir Cell Mol Biol. 2003;29(3):375-380. Pt 1.

[168] Kolb P, Upagupta C, Vierhout M, et al. The importance of interventional timing in the bleomycin model of pulmonary fibrosis. Eur Respir J. 2020;55(6):1901105.

[169] Tashiro J, Rubio GA, Limper AH, et al. Exploring animal models that resemble idiopathic pulmonary fibrosis. Front Med. 2017;4:118.

[170] Jenkins RG, Moore BB, Chambers RC, et al. An official american thoracic society workshop report: use of animal models for the preclinical assessment of potential therapies for pulmonary fibrosis. Am J Respir Cell Mol Biol. 2017;56(5):667-679.

[171] Chua F, Gauldie J, Laurent GJ. Pulmonary fibrosis: searching for model answers. Am J Respir Cell Mol Biol. 2005;33(1):9-13.

[172] George PM, Wells AU, Jenkins RG. Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy. Lancet Respir Med. 2020;8(8):807-815.

[173] Matute-Bello G, Frevert CW, Martin TR. Animal models of acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2008;295(3):L379-L399.

[174] Geilen J, Kainz M, Zapletal B, et al. Unilateral acute lung injury in pig: a promising animal model. J Transl Med. 2022;20(1):548.

[175] Naikawadi RP, Disayabutr S, Mallavia B, et al. Telomere dysfunction in alveolar epithelial cells causes lung remodeling and fibrosis. JCI Insight. 2016;1(14):e86704.

[176] Povedano JM, Martinez P, Flores JM, Mulero F, Blasco MA. Mice with pulmonary fibrosis driven by telomere dysfunction. Cell Rep. 2015;12(2):286-299.

[177] Zhou Y, Mohsenin A, Morschl E, et al. Enhanced airway inflammation and remodeling in adenosine deaminase-deficient mice lacking the A2B adenosine receptor. J Immunol. 2009;182(12):8037-8046.

[178] Rodriguez L, Tomer Y, Carson P, et al. Chronic expression of a clinical SFTPC mutation causes murine lung fibrosis with idiopathic pulmonary fibrosis features. Am J Respir Cell Mol Biol. 2023;68(4):358-365.

[179] Tirelli C, Pesenti C, Miozzo M, Mondoni M, Fontana L, Centanni S. The genetic and epigenetic footprint in idiopathic pulmonary fibrosis and familial pulmonary fibrosis: a state-of-the-art review. Diagnostics (Basel, Switzerland). 2022;12(12):3107.

[180] Kurche JS, Stancil IT, Michalski JE, Yang IV, Schwartz DA. Dysregulated cell-cell communication characterizes pulmonary fibrosis. Cells. 2022;11(20):3319.

[181] Liegeois MA, Fahy JV. The mucin gene MUC5B is required for normal lung function. Am J Respir Crit Care Med. 2022;205(7):737-739.

[182] Paisley D, Bevan L, Choy KJ, Gross C. The pneumonectomy model of compensatory lung growth: insights into lung regeneration. Pharmacol Ther. 2014;142(2):196-205.

[183] Stevenson CS, Birrell MA. Moving towards a new generation of animal models for asthma and COPD with improved clinical relevance. Pharmacol Ther. 2011;130(2):93-105.

[184] Miller AJ, Spence JR. In vitro models to study human lung development, disease and homeostasis. Physiology (Bethesda). 2017;32(3):246-260.

[185] Mulay A, Konda B, Garcia GJ, et al. SARS-CoV-2 infection of primary human lung epithelium for COVID-19 modeling and drug discovery. Cell Rep. 2021;35(5):109055.

[186] Tang X-Y, Wu S, Wang D, et al. Human organoids in basic research and clinical applications. Signal Transduct Target Ther. 2022;7(1):168.

[187] Hendriks D, Artegiani B, Hu H, Chuva de Sousa Lopes S, Clevers H. Establishment of human fetal hepatocyte organoids and CRISPR-Cas9-based gene knockin and knockout in organoid cultures from human liver. Nat Protoc. 2021;16(1):182-217.

[188] Lancaster MA, Renner M, Martin C-A, et al. Cerebral organoids model human brain development and microcephaly. Nature. 2013;501(7467):373-379.

[189] Liberti DC, Morrisey EE. Organoid models: assessing lung cell fate decisions and disease responses. Trends Mol Med. 2021;27(12):1159-1174.

[190] Tindle C, Fuller M, Fonseca A, et al. Adult stem cell-derived complete lung organoid models emulate lung disease in COVID-19. eLife. 2021;10:e66417.

[191] Chen Y-W, Huang SX, de Carvalho ALRT, et al. A three-dimensional model of human lung development and disease from pluripotent stem cells. Nat Cell Biol. 2017;19(5):542-549.

[192] Cunniff B, Druso JE, van der Velden JL. Lung organoids: advances in generation and 3D-visualization. Histochem Cell Biol. 2021;155(2):301-308.

[193] Baptista D, Moreira Teixeira L, Barata D, et al. 3D lung-on-chip model based on biomimetically microcurved culture membranes. ACS Biomater Sci Eng. 2022;8(6):2684-2699.

[194] 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(5):1800876.

[195] Sucre JMS, Jetter CS, Loomans H, et al. Successful establishment of primary type II alveolar epithelium with 3D organotypic coculture. Am J Respir Cell Mol Biol. 2018;59(2):158-166.

[196] Silva S, Bicker J, Falcão A, Fortuna A. Air-liquid interface (ALI) impact on different respiratory cell cultures. Eur J Pharm Biopharm. 2023;184:62-82.

[197] Gamage AM, Sen Tan K, Chan WOY, et al. Infection of human nasal epithelial cells with SARS-CoV-2 and a 382-nt deletion isolate lacking ORF8 reveals similar viral kinetics and host transcriptional profiles. PLoS Pathog. 2020;16(12):e1009130.

[198] Hatton CF, Botting RA, Dueñas ME, et al. Delayed induction of type I and III interferons mediates nasal epithelial cell permissiveness to SARS-CoV-2. Nat Commun. 2021;12(1):7092.

[199] Baldassi D, Ambike S, Feuerherd M, et al. Inhibition of SARS-CoV-2 replication in the lung with siRNA/VIPER polyplexes. J Control Release. 2022;345:661-674.

[200] Viana F, O'Kane CM, Schroeder GN. Precision-cut lung slices: a powerful ex vivo model to investigate respiratory infectious diseases. Mol Microbiol. 2022;117(3):578-588.

[201] Liu Y, Wu P, Wang Y, et al. Application of precision-cut lung slices as an in vitro model for research of inflammatory respiratory diseases. Bioeng (Basel, Switzerland). 2022;9(12):767.

[202] Alsafadi HN, Uhl FE, Pineda RH, et al. Applications and approaches for three-dimensional precision-cut lung slices. disease modeling and drug discovery. Am J Respir Cell Mol Biol. 2020;62(6):681-691.

[203] Clair G, Bramer LM, Misra R, et al. Proteomic analysis of human lung development. Am J Respir Crit Care Med. 2022;205(2):208-218.

[204] Leiphrakpam PD, Weber HR, Ogun T, Buesing KL. Rat model of smoke inhalation-induced acute lung injury. BMJ Open Respir Res. 2021;8(1):e000879.

[205] Dasgupta Q, Jiang A, Wen AM, et al. A human lung alveolus-on-a-chip model of acute radiation-induced lung injury. Nat Commun. 2023;14(1):6506.

[206] Li S, Shi J, Tang H. Animal models of drug-induced pulmonary fibrosis: an overview of molecular mechanisms and characteristics. Cell Biol Toxicol. 2022;38(5):699-723.

[207] Vats A, Chaturvedi P. The regenerative power of stem cells: treating bleomycin-induced lung fibrosis. Stem Cells Cloning. 2023;16:43-59.

[208] Taha A, Bobi J, Dammers R, et al. Comparison of large animal models for acute ischemic stroke: which model to use? Stroke. 2022;53(4):1411-1422.

[209] Yang IA, Jenkins CR, Salvi SS. Chronic obstructive pulmonary disease in never-smokers: risk factors, pathogenesis, and implications for prevention and treatment. Lancet Respir Med. 2022;10(5):497-511.

[210] Labaki WW, Rosenberg SR. Chronic obstructive pulmonary disease. Ann Intern Med. 2020;173(3):ITC17-ITC32.

[211] Wang C, Zhou J, Wang J, et al. Progress in the mechanism and targeted drug therapy for COPD. Signal Transduct Target Ther. 2020;5(1):248.

[212] Halpin DM, Miravitlles M, Metzdorf N, Celli B. Impact and prevention of severe exacerbations of COPD: a review of the evidence. Int J Chron Obstruct Pulmon Dis. 2017;12:2891-2908.

[213] Ferrera MC, Labaki WW, Han MK. Advances in chronic obstructive pulmonary disease. Annu Rev Med. 2021;72:119-134.

[214] Weng C-F, Wu C-C, Wu M-H, Lin F-J. Comparison of clinical outcomes among different fixed-dose combinations of long-acting muscarinic antagonists and long-acting β(2)-agonists in patients with COPD. Chest. 2023;163(4):799-814.

[215] Ismaila AS, Haeussler K, Czira A, et al. Fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy compared with other therapies for the treatment of COPD: a network meta-analysis. Adv Ther. 2022;39(9):3957-3978.

[216] Rabe KF, Martinez FJ, Ferguson GT, et al. Triple inhaled therapy at two glucocorticoid doses in moderate-to-very-severe COPD. N Engl J Med. 2020;383(1):35-48.

[217] Calzetta L, Aiello M, Frizzelli A, et al. Stem cell-based regenerative therapy and derived products in COPD: a systematic review and meta-analysis. Cells. 2022;11(11):1797.

[218] Ridzuan N, Zakaria N, Widera D, 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(1):54.

[219] Broekman W, Khedoe PPSJ, Schepers K, Roelofs H, Stolk J, Hiemstra PS. Mesenchymal stromal cells: a novel therapy for the treatment of chronic obstructive pulmonary disease? Thorax. 2018;73(6):565-574.

[220] Ribeiro-Paes JT, Bilaqui A, Greco OT, et al. Unicentric study of cell therapy in chronic obstructive pulmonary disease/pulmonary emphysema. Int J Chron Obstruct Pulmon Dis. 2011;6:63-71.

[221] Weiss DJ, Casaburi R, Flannery R, LeRoux-Williams M, Tashkin DP. A placebo-controlled, randomized trial of mesenchymal stem cells in COPD. Chest. 2013;143(6):1590-1598.

[222] de Oliveira HG, Cruz FF, Antunes MA, et al. Combined bone marrow-derived mesenchymal stromal cell therapy and one-way endobronchial valve placement in patients with pulmonary emphysema: a phase I clinical trial. Stem Cells Transl Med. 2017;6(3):962-969.

[223] Chen Y-T, Miao K, Zhou L, Xiong W-N. Stem cell therapy for chronic obstructive pulmonary disease. Chin Med J (Engl). 2021;134(13):1535-1545.

[224] Martinez FJ, Collard HR, Pardo A, et al. Idiopathic pulmonary fibrosis. Nat Rev Dis Prim. 2017;3:17074.

[225] Raghu G, van den Blink B, Hamblin MJ, et al. Effect of recombinant human pentraxin 2 vs placebo on change in forced vital capacity in patients with idiopathic pulmonary fibrosis: a randomized clinical trial. JAMA. 2018;319(22):2299-2307.

[226] Martinez FJ, Yow E, Flaherty KR, et al. Effect of antimicrobial therapy on respiratory hospitalization or death in adults with idiopathic pulmonary fibrosis: the cleanUP-IPF randomized clinical trial. JAMA. 2021;325(18):1841-1851.

[227] Wolters PJ, Blackwell TS, Eickelberg O, et al. Time for a change: is idiopathic pulmonary fibrosis still idiopathic and only fibrotic? Lancet Respir Med. 2018;6(2):154-160.

[228] Mora AL, Rojas M, Pardo A, Selman M. Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease. Nat Rev Drug Discov. 2017;16(11):755-772.

[229] Rangarajan S, Bone NB, Zmijewska AA, et al. Metformin reverses established lung fibrosis in a bleomycin model. Nat Med. 2018;24(8):1121-1127.

[230] Liu GY, Budinger GRS, Dematte JE. Advances in the management of idiopathic pulmonary fibrosis and progressive pulmonary fibrosis. BMJ. 2022;377:e066354.

[231] Somogyi V, Chaudhuri N, Torrisi SE, Kahn N, Müller V, Kreuter M. The therapy of idiopathic pulmonary fibrosis: what is next? Eur Respir Rev. 2019;28(153):190021.

[232] van den Bosch L, Luppi F, Ferrara G, Mura M. Immunomodulatory treatment of interstitial lung disease. Ther Adv Respir Dis. 2022;16:17534666221117002.

[233] Reyfman PA, Walter JM, Joshi N, et al. Single-cell transcriptomic analysis of human lung provides insights into the pathobiology of pulmonary fibrosis. Am J Respir Crit Care Med. 2019;199(12):1517-1536.

[234] Bonella F, Spagnolo P, Ryerson C. Current and future treatment landscape for idiopathic pulmonary fibrosis. Drugs. 2023;83(17):1581-1593.

[235] Averyanov A, Koroleva I, Konoplyannikov M, et al. First-in-human high-cumulative-dose stem cell therapy in idiopathic pulmonary fibrosis with rapid lung function decline. Stem Cells Transl Med. 2020;9(1):6-16.

[236] Bellani G, Laffey JG, Pham T, et al. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA. 2016;315(8):788-800.

[237] Matthay MA, Zemans RL, Zimmerman GA, et al. Acute respiratory distress syndrome. Nat Rev Dis Prim. 2019;5(1):18.

[238] Hu B, Guo H, Zhou P, Shi Z-L. Characteristics of SARS-CoV-2 and COVID-19. Nat Rev Micro. 2021;19(3):141-154.

[239] Poissy J, Goutay J, Caplan M, et al. Pulmonary embolism in patients with COVID-19: awareness of an increased prevalence. Circulation. 2020;142(2):184-186.

[240] Léonard-Lorant I, Delabranche X, Séverac F, et al. Acute pulmonary embolism in patients with COVID-19 at CT angiography and relationship to d-dimer levels. Radiology. 2020;296(3):E189-E191.

[241] Mehandru S, Merad M. Pathological sequelae of long-haul COVID. Nat Immunol. 2022;23(2):194-202.

[242] Mousavizadeh L, Ghasemi S. Genotype and phenotype of COVID-19: their roles in pathogenesis. J Microbiol Immunol Infect. 2021;54(2):159-163.

[243] Herridge MS, Tansey CM, Matté A, et al. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med. 2011;364(14):1293-1304.

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

[245] Laffey JG, Matthay MA. Fifty years of research in ARDS. Cell-based therapy for acute respiratory distress syndrome. biology and potential therapeutic value. Am J Respir Crit Care Med. 2017;196(3):266-273.

[246] Matthay MA, Arabi YM, Siegel ER, et al. Phenotypes and personalized medicine in the acute respiratory distress syndrome. Intensive Care Med. 2020;46(12):2136-2152.

[247] Ashburn TT, Thor KB. Drug repositioning: identifying and developing new uses for existing drugs. Nat Rev Drug Discov. 2004;3(8):673-683.

[248] Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a Review. JAMA. 2020;324(8):782-793.

[249] Li J, Deng X, Ji X, et al. Mesenchymal stem cell exosomes reverse acute lung injury through Nrf-2/ARE and NF-κB signaling pathways. PeerJ. 2020;8:e9928.

[250] He Y, Xu W, Xiao Y-T, Huang H, Gu D, Ren S. Targeting signaling pathways in prostate cancer: mechanisms and clinical trials. Signal Transduct Target Ther. 2022;7(1):198.

[251] Weatherald J, Boucly A, Peters A, et al. The evolving landscape of pulmonary arterial hypertension clinical trials. Lancet (London, England). 2022;400(10366):1884-1898.

[252] Kim JY, Nam Y, Rim YA, Ju JH. Review of the current trends in clinical trials involving induced pluripotent stem cells. Stem Cell Rev Rep. 2022;18(1):142-154.

[253] Zhu Y, Ge J, Huang C, Liu H, Jiang H. Application of mesenchymal stem cell therapy for aging frailty: from mechanisms to therapeutics. Theranostics. 2021;11(12):5675-5685.

[254] Cen J, Zhang Y, Bai Y, et al. Research progress of stem cell therapy for endometrial injury. Mater Today Bio. 2022;16:100389.

[255] Nowak B, Rogujski P, Janowski M, Lukomska B, Andrzejewska A. Mesenchymal stem cells in glioblastoma therapy and progression: how one cell does it all. Biochim Biophys Acta Rev Cancer. 2021;1876(1):188582.

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