From scarring to healing: Emerging regenerative therapies for pulmonary fibrosis using MSCs and exosomes

Abstract

Background: Pulmonary fibrosis is a progressive and often fatal disease featuring the disruption of lung architecture by excessive extracellular matrix deposition.

Main Body: Mesenchymal stem cells (MSCs) have strong immunomodulatory, anti-inflammatory and regenerative capacities that enable them to restore lung function through the targeting of key fibrotic mechanisms. Their migration into sites of injury and interaction with immune and structural cells through cytokines and growth factors underlines their therapeutic value. Recently, exosomes derived from MSCs have emerged as a promising cell-free treatment option capable of crossing biological barriers and delivering anti-fibrotic molecules like miRNAs, siRNAs, and proteins directly to fibrotic tissues. These vesicles enhance therapeutic precision and safety compared with cell therapy. Despite challenges in standardization, large-scale production, and heterogeneity among MSCs sources, ongoing advances in biotechnology and clinical trial design are rapidly bridging the gap between preclinical promise and clinical application.

Conclusion: This present review discusses the pathogenesis and modelling of pulmonary fibrosis and underlines MSCs and exosome-based regenerative strategies as an effective and transforming approach in the future therapy of pulmonary fibrosis.

Keywords

cell-based therapy / exosome / mesenchymal stem cell / modification / pulmonary fibrosis

References

[1] Chanda A, Singh G, Chanda A, Singh G. Lung Tissue Simulants, in Soft Tissue Simulants. Springer Nature Singapore; 2024: 59-70.

[2] Whitsett J, Kalin T, Xu Y, Kalinichenko V. Building and regenerating the lung cell by cell. Physiol Rev. 2019; 99(1): 513-554.

[3] Block E, Stalcup S. Metabolic functions of the lung: of what clinical relevance? Chest. 1982; 81(2): 215-223.

[4] Hill D, Button B, Rubinstein M, Boucher R. Physiology and pathophysiology of human airway mucus. Physiol Rev. 2022; 102(4): 1757-1836.

[5] Blanc PD, Annesi-Maesano I, Balmes JR, et al. The occupational burden of nonmalignant respiratory diseases. An official American Thoracic Society and European Respiratory Society statement. Am J Respir Crit Care Med. 2019; 199(11): 1312-1334.

[6] Huh D, Chae W, Choi Y, Kang M, Lee Y, Moon K. Disease latency according to asbestos exposure characteristics among malignant mesothelioma and asbestos-related lung cancer cases in South Korea. Int J Environ Res Public Health. 2022; 19(23): 15934.

[7] Savin I, Zenkova M, Sen'kova A. 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.

[8] Rafati F, Ghorbani Z, Manoochehrabadi T, et al. Smart integrated biomaterial systems for precision and optimized delivery of MSCs and their exosomes: transforming wound healing and organ regeneration. Regen Ther. 2026; 31: 101045.

[9] Jia M, Rosas L, Kapetanaki MG, et al. Early events marking lung fibroblast transition to profibrotic state in idiopathic pulmonary fibrosis. Respir Res. 2023; 24(1): 116.

[10] Jiang M, Bu W, Wang X, et al. Pulmonary fibrosis: from mechanisms to therapies. J Transl Med. 2025; 23(1): 515.

[11] Wilson M, Wynn T. Pulmonary fibrosis: pathogenesis, etiology and regulation. Mucosal Immunol. 2009; 2(2): 103-121.

[12] Cabral-Pacheco GA, Garza-Veloz I, Castruita-De la Rosa C, et al. The roles of matrix metalloproteinases and their inhibitors in human diseases. Int J Mol Sci. 2020; 21(24): 9739.

[13] Zhidu S, Ying T, Rui J, Chao Z. Translational potential of mesenchymal stem cells in regenerative therapies for human diseases: challenges and opportunities. Stem Cell Res Ther. 2024; 15(1): 266.

[14] Nie Y, Wu S, Xuan Y, Yan G. Role of IL-17 family cytokines in the progression of IPF from inflammation to fibrosis. Mil Med Res. 2022; 9(1): 21.

[15] Todd N, Luzina I, Atamas S. Molecular and cellular mechanisms of pulmonary fibrosis. Fibrogenes Tissue Repair. 2012; 5(1): 11.

[16] Chuliá-Peris L, Carreres-Rey C, Gabasa M, Alcaraz J, Carretero J, Pereda J. Matrix metalloproteinases and their inhibitors in pulmonary fibrosis: eMMPRIN/CD147 comes into play. Int J Mol Sci. 2022; 23(13): 6894.

[17] Pardo A, Cabrera S, Maldonado M, Selman M. Role of matrix metalloproteinases in the pathogenesis of idiopathic pulmonary fibrosis. Respir Res. 2016; 17(1): 23.

[18] Freeberg MA, Camus SV, Robila V, Perelas A, Thatcher TH, Sime PJ. Piezo2 is a key mechanoreceptor in lung fibrosis that drives myofibroblast differentiation. Am J Pathol. 2025; 195(4): 626-638..

[19] Prior TS, Hoyer N, Davidsen JR, et al. Fibroblast activation protein and disease severity, progression, and survival in idiopathic pulmonary fibrosis. Scand J Immunol. 2024; 100(3): e13392.

[20] D'Agnano V, Mariniello DF, Ruotolo M, et al. Targeting progression in pulmonary fibrosis: an overview of underlying mechanisms, molecular biomarkers, and therapeutic Intervention. Life. 2024; 14(2): 229.

[21] Meltzer E, Noble P. Idiopathic pulmonary fibrosis. Orphanet J Rare Dis. 2008; 3(1): 8.

[22] Murtha LA, Schuliga MJ, Mabotuwana NS, et al. The processes and mechanisms of cardiac and pulmonary fibrosis. Front Physiol. 2017; 8: 2017.

[23] He A, He L, Chen T, Li X, Cao C. Biomechanical properties and cellular responses in pulmonary fibrosis. Bioengineering. 2024; 11(8): 747.

[24] Martin P, Nunan R. Cellular and molecular mechanisms of repair in acute and chronic wound healing. Br J Dermatol. 2015; 173(2): 370-378.

[25] Chanda D, Otoupalova E, Smith SR, Volckaert T, De Langhe SP, Thannickal VJ. Developmental pathways in the pathogenesis of lung fibrosis. Mol Asp Med. 2019; 65: 56-69.

[26] Miles T, Hoyne GF, Knight DA, Fear MW, Mutsaers SE, Prêle CM. The contribution of animal models to understanding the role of the immune system in human idiopathic pulmonary fibrosis. Clin Transl Immunol. 2020; 9(7): e1153.

[27] Russo RC, Togbe D, Couillin I, et al. Ozone-induced lung injury and inflammation: pathways and therapeutic targets for pulmonary diseases caused by air pollutants. Environ Int. 2025; 198: 109391.

[28] Yoon H, Kim S, Kim O, Song J. Nitrogen dioxide increases the risk of disease progression in idiopathic pulmonary fibrosis. Respirology. 2023; 28(3): 254-261.

[29] Hams E, Armstrong ME, Barlow JL, et al. IL-25 and type 2 innate lymphoid cells induce pulmonary fibrosis. PNAS. 2014; 111(1): 367-372.

[30] 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: 699-723.

[31] Ogawa T, Shichino S, Ueha S, Ogawa S, Matsushima K. Complement protein C1q activates lung fibroblasts and exacerbates silica-induced pulmonary fibrosis in mice. Biochem Biophys Res Commun. 2022; 603: 88-93.

[32] Sun W, Li Y, Ma D, et al. ALKBH5 promotes lung fibroblast activation and silica-induced pulmonary fibrosis through miR-320a-3p and FOXM1. Cell Mol Biol Lett. 2022; 27: 26.

[33] Shen J, Feng J, Wu Z, et al. Apelin prevents and alleviates crystalline silica-induced pulmonary fibrosis via inhibiting transforming growth factor beta 1-triggered fibroblast activation. Int J Biol Sci. 2023; 19(13): 4004-4019.

[34] Hayashi S, Mitsumori K, Imaida K, Imazawa T, Yasuhara K, Uneyama C, Hayashi Y. Establishment of an animal model for pulmonary fibrosis in mice using monocrotaline. Toxicol Pathol. 1995; 23: 63-71.

[35] Lin C, Hsieh N, Liou H, Chen H. Niacinamide mitigated the acute lung injury induced by phorbol myristate acetate in isolated rat's lungs. J Biomed Sci. 2012; 19(1): 27.

[36] Taylor R, McCall CE, Thrall RS, Woodruff RD, O'Flaherty JT. Histopathologic features of phorbol myristate acetate-induced lung injury. Lab Investig. 1985; 52(1): 61-70.

[37] Chen Z, Wu Z, Ning W. Advances in molecular mechanisms and treatment of radiation-induced pulmonary fibrosis. Transl Oncol. 2019; 12(1): 162-169.

[38] Jarzebska N, Karetnikova ES, Markov AG, Kasper M, Rodionov RN, Spieth PM. Scarred lung. An update on radiation-induced pulmonary fibrosis. Front Med (Lausanne). 2020; 7: 585756.

[39] Fox J, Bergeron M, Haston C. Genetic deficiency in complement component 4b does not alter radiation-induced lung disease in mice. Radiat Res. 2013; 179(2): 146-150.

[40] Kolodsick JE, Toews GB, Jakubzick C, et al. Protection from fluorescein isothiocyanate-induced fibrosis in IL-13-deficient, but not IL-4-deficient, mice results from impaired collagen synthesis by fibroblasts1. J Immunol. 2004; 172(7): 4068-4076.

[41] Ochi N, Abidi A, Taamalli W, Ayedi A, Sebai H. Ameliorative effects of avocado oil on bleomycin-induced lung fibrosis and oxidative stress in rats. Physiol Rep. 2025; 13(3): e70228.

[42] Redente EF, Black BP, Backos DS, et al. Persistent, progressive pulmonary fibrosis and epithelial remodeling in mice. Am J Respir Cell Mol Biol. 2021; 64(6): 669-676.

[43] Nuovo GJ, Hagood JS, Magro CM, et al. The distribution of immunomodulatory cells in the lungs of patients with idiopathic pulmonary fibrosis. Mod Pathol. 2012; 25(3): 416-433.

[44] Elshamy AM, El Tantawy AF, Basha EH, et al. Ganoderic acid a potential protective impact on bleomycin (BLM) -induced lung fibrosis in albino mice: targeting caveolin 1/TGF-β/Smad and P38MAPK signaling pathway. Arch Biochem Biophys. 2025; 764: 110284.

[45] Li J, Shu R, Peng T, et al. Targeted imaging of pulmonary fibrosis by a cyclic peptide LyP-1. Sci Rep. 2025; 15(1): 8098.

[46] Watanabe T, Nishimoto T, Mlakar L, et al. Optimization of a murine and human tissue model to recapitulate dermal and pulmonary features of systemic sclerosis. PLoS One. 2017; 12(6): e0179917.

[47] Ravanetti F, Ragionieri L, Ciccimarra R, et al. Modeling pulmonary fibrosis through bleomycin delivered by osmoticminipump: a new histomorphometric method of evaluation. Am J Physiol Lung Cell Mol Physiol. 2020; 318: L376-L385.

[48] 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: 667-679.

[49] Roman J, Brown KK, Olson A, Corcoran BM, Williams KJ. An official American thoracic society workshop report: comparative pathobiology of fibrosing lung disorders in humans and domestic animals. Ann Am Thorac Soc. 2013; 10: S224-S229.

[50] Clercx C, Fastrès A, Roels E. Idiopathic pulmonary fibrosis in West Highland white terriers: an update. Vet J. 2018; 242: 53-58.

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

[52] Murray RE, Gibson JE. A comparative study of paraquat intoxication in rats, guinea pigs and monkeys. Exp Mol Pathol. 1972; 17: 317-325.

[53] Kimura R, Hu H, Stein-Streilein J. Delayed-type hypersensitivity responses regulate collagen deposition in the lung. Immunology. 1992; 77: 550-555.

[54] Gharaee-Kermani M, Hatano K, Nozaki Y, Phan S. Gender-based differences in bleomycin-induced pulmonary fibrosis. Am J Pathol. 2005; 166(6): 1593-1606.

[55] Grainger DJ, Witchell CM, Metcalfe JC. Tamoxifen elevates transforming growth factor-β and suppresses diet-induced formation of lipid lesions in mouse aorta. Nat Med.1995; 1:: 1067-1073.

[56] Hadi DD, Marsool MDM, Marsool ADM, et al. Idiopathic pulmonary fibrosis: addressing the current and future therapeutic advances along with the role of Sotatercept in the management of pulmonary hypertension. Immun Inflamm Dis. 2023; 11(11): e1079.

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

[58] Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014; 370(22): 2071-2082.

[59] Horowitz J, Thannickal V. Mechanisms for the resolution of organ fibrosis. Physiol (Bethesda). 2019; 34(1): 43-55.

[60] Cojocaru E, Cojocaru T, Pînzariu GM, Vasiliu I, Armașu I, Cojocaru C. Perspectives on post-COVID-19 pulmonary fibrosis treatment. J Pers Med. 2024; 14(1): 51.

[61] Vancheri C, Sciacca E, Muscato G, et al. Pharmacological treatment in idiopathic pulmonary fibrosis: current issues and future perspectives. Multidiscip Respir Med. 2024; 19(1): 982.

[62] Shanaki M, Ehteram H, Nasiri H, et al. Assessment of liver and kidney functional parameters along with oxidative stress and inflammatory biomarker in patients with β-thalassemia major. Iran J Ped Hematol Oncol. 2016; 6(4): 249-260.

[63] Inamdar A, Inamdar A. Mesenchymal stem cell therapy in lung disorders: pathogenesis of lung diseases and mechanism of action of mesenchymal stem cell. Exp Lung Res. 2013; 39(8): 315-327.

[64] D'souza N, Rossignoli F, Golinelli G, et al. Mesenchymal stem/stromal cells as a delivery platform in cell and gene therapies. BMC Med. 2015; 13(1): 186.

[65] Alizadeh S, Mahboobi L, Nasiri M, et al. Decellularized placental sponge seeded with human mesenchymal stem cells improves deep skin wound healing in the animal model. ACS Appl Bio Mater. 2024; 7(4): 2140-2152.

[66] Li D, Li R, Sun D, Pu D, Zhang Y. Mesenchymal stem cell therapy in pulmonary fibrosis: a meta-analysis of preclinical studies. Stem Cell Res Ther. 2021; 12(1): 461.

[67] Hass R, Kasper C, Böhm S, Jacobs R. Different populations and sources of human mesenchymal stem cells (MSC): a comparison of adult and neonatal tissue-derived MSC. Cell Commun Signal. 2011; 9(1): 12.

[68] Mobarra N, Soleimani M, Kouhkan F, et al. Efficient differentiation of human induced pluripotent stem cell (hiPSC) derived hepatocyte-like cells on hMSCs feeder. Int J Hematol Oncol Stem Cell Res. 2014; 8(4): 20-29.

[69] Maldonado VV, Patel NH, Smith EE, et al. Clinical utility of mesenchymal stem/stromal cells in regenerative medicine and cellular therapy. J Biol Eng. 2023; 17(1): 44.

[70] Jones EA, English A, Kinsey SE, et al. Optimization of a flow cytometry-based protocol for detection and phenotypic characterization of multipotent mesenchymal stromal cells from human bone marrow. Cytom B Clin cytom. 2006; 70(6): 391-399.

[71] Sahar T, Eskandari F, Kohandani M, Manoochehrabadi T, Nasiri H. Genetic engineering in hematopoietic stem cells for β-hemoglobinopathies treatment: advances, challenges, and clinical translation. Int J Hematol Oncol Stem Cell Res. 2025; 19(4): 399-423.

[72] Mohammadi S, Norooznezhad AH, Mohammadi AM, et al. Optimizing peripheral blood stem cells transplantation outcome through amend relapse and graft failure: a review of current literature. Exp Hematol Oncol. 2017; 6(1): 24.

[73] Nasiri H, Manoochehrabadi T, Eskandari F, Majidi J, Gholipourmalekabadi M. Genetic modification of mesenchymal stem cells (MSCs): novel strategy to expand their naïve applications in critical illness. Mol Biol Rep. 2025; 52(1): 501.

[74] Schraufstatter I, DiScipio R, Zhao M, Khaldoyanidi S. C3a and C5a are chemotactic factors for human mesenchymal stem cells, which cause prolonged ERK1/2 phosphorylation1. J Immunol. 2009; 182(6): 3827-3836.

[75] Qian X, An N, Ren Y, Yang C, Zhang X, Li L. Immunosuppressive effects of mesenchymal stem cells-derived exosomes. Stem Cell Rev Rep. 2021; 17(2): 411-427.

[76] Nikfarjam S, Rezaie J, Zolbanin N, Jafari R. Mesenchymal stem cell derived-exosomes: a modern approach in translational medicine. J Transl Med. 2020; 18(1): 449.

[77] Mohammadi S, Nikbakht M, Malek Mohammadi A, et al. Human platelet lysate as a xeno free alternative of fetal bovine serum for the in vitro expansion of human mesenchymal stromal cells. Int J Hematol Oncol Stem Cell Res. 2016; 10(3): 161-171.

[78] Wu X, Jiang J, Gu Z, Zhang J, Chen Y, Liu X. Mesenchymal stromal cell therapies: immunomodulatory properties and clinical progress. Stem Cell Res Ther. 2020; 11(1): 345.

[79] Saldaña L, Bensiamar F, Vallés G, Mancebo FJ, García-Rey E, Vilaboa N. Immunoregulatory potential of mesenchymal stem cells following activation by macrophage-derived soluble factors. Stem Cell Res Ther. 2019; 10(1): 58.

[80] Chen Q, Wu F, Liu L, et al. Mesenchymal stem cells regulate the Th17/Treg cell balance partly through hepatocyte growth factor in vitro. Stem Cell Res Ther. 2020; 11(1): 91.

[81] Engela AU, Baan CC, Dor F, Weimar W, Hoogduijn MJ, On the interactions between mesenchymal stem cells and regulatory T cells for immunomodulation in transplantation. Front Immunol. 2012; 3: 2012.

[82] Yang G, Fan X, Liu Y, et al. Immunomodulatory mechanisms and therapeutic potential of mesenchymal stem cells. Stem Cell Rev Rep. 2023; 19(5): 1214-1231.

[83] Ghannam S, Bouffi C, Djouad F, Jorgensen C, Noël D. Immunosuppression by mesenchymal stem cells: mechanisms and clinical applications. Stem Cell Res Ther. 2010; 1(1): 2.

[84] Claeys E, Vermeire K. Immunosuppressive drugs in organ transplantation to prevent allograft rejection: mode of action and side effects. J Immunol Sci. 2019; 3(4): 14-21.

[85] Stallone G, Infante B, Grandaliano G. Management and prevention of post-transplant malignancies in kidney transplant recipients. Clin Kidney J. 2015; 8(5): 637-644.

[86] Planat-Benard V, Varin A, Casteilla L. MSCs and inflammatory cells crosstalk in regenerative medicine: concerted actions for optimized resolution driven by energy metabolism. Front Immunol. 2021; 12; 2021.

[87] Lan T, Luo M, Wei X. Mesenchymal stem/stromal cells in cancer therapy. J Hematol Oncol. 2021; 14(1): 195.

[88] Condotta S, Richer M. The immune battlefield: the impact of inflammatory cytokines on CD8+ T-cell immunity. PLoS Pathog. 2017; 13(10): e1006618.

[89] Hazrati A, Malekpour K, Khorramdelazad H, Rajaei S, Hashemi SM. Therapeutic and immunomodulatory potentials of mesenchymal stromal/stem cells and immune checkpoints related molecules. Biomark Res. 2024; 12(1): 35.

[90] Margiana R, Markov A, Zekiy AO, et al. Clinical application of mesenchymal stem cell in regenerative medicine: a narrative review. Stem Cell Res Ther. 2022; 13(1): 366.

[91] Eskandari F, Zolfaghari S, Yazdanpanah A, et al. TLR3 stimulation improves the migratory potency of adipose-derived mesenchymal stem cells through the stress response pathway in the melanoma mouse model. Mol Biol Rep. 2023; 50(3): 2293-2304.

[92] Castro Ramos A, Widjaja Lomanto MY, Vuong CK, Ohneda O, Fukushige M. Antibacterial effects of human mesenchymal stem cells and their derivatives: a systematic review. Front Microbiol. 2024; 15: 2024.

[93] Yang S, Liu P, Jiang Y, Wang Z, Dai H, Wang C. Therapeutic applications of mesenchymal stem cells in idiopathic pulmonary fibrosis. Front Cell Dev Biol. 2021; 9: 639657.

[94] Chuang H, Shih TE, Lu K, Tsai S, Harn H, Ho L. Mesenchymal stem cell therapy of pulmonary fibrosis: improvement with target combination. Cell Transplant. 2018; 27(11): 1581-1587.

[95] Zhao Y, Yan Z, Liu Y, et al. Effectivity of mesenchymal stem cells for bleomycin-induced pulmonary fibrosis: a systematic review and implication for clinical application. Stem Cell Res Ther. 2021; 12(1): 470.

[96] Zhang C, Yin X, Zhang J, Ao Q, Gu Y, Liu Y. Clinical observation of umbilical cord mesenchymal stem cell treatment of severe idiopathic pulmonary fibrosis: a case report. Exp Ther Med. 2017; 13(5): 1922-1926.

[97] Yang Y, Chen Y, Liu Y, et al. Mesenchymal stem cells and pulmonary fibrosis: a bibliometric and visualization analysis of literature published between 2002 and 2021. Front Pharmacol. 2023; 14: 2023.

[98] Barczyk M, Schmidt M, Mattoli S. Stem cell-based therapy in idiopathic pulmonary fibrosis. Stem Cell Rev Rep. 2015; 11(4): 598-620.

[99] Levy O, Kuai R, Siren EMJ, et al. Shattering barriers toward clinically meaningful MSC therapies. Sci Adv. 2020; 6(30): eaba6884.

[100] Ocansey DKW, Pei B, Yan Y, et al. Improved therapeutics of modified mesenchymal stem cells: an update. J Transl Med. 2020; 18: 1-14.

[101] Noronha N, Mizukami A, Caliári-Oliveira C, et al. Priming approaches to improve the efficacy of mesenchymal stromal cell-based therapies. Stem Cell Res Ther. 2019; 10: 1-21.

[102] Jiang C, Liu J, Zhao J, et al. Effects of hypoxia on the immunomodulatory properties of human gingiva–derived mesenchymal stem cells. J Dent Res. 2015; 94(1): 69-77.

[103] Chen L, Xu Y, Zhao J, et al. Conditioned medium from hypoxic bone marrow-derived mesenchymal stem cells enhances wound healing in mice. PLoS One. 2014; 9(4): e96161.

[104] Lan Y, Choo K, Chen C, et al., Hypoxia-preconditioned mesenchymal stem cells attenuate bleomycin-induced pulmonary fibrosis. Stem Cell Res Ther. 2015; 6: 1-17.

[105] Lan Y, Theng S, Huang T, et al. Oncostatin M-preconditioned mesenchymal stem cells alleviate bleomycin-induced pulmonary fibrosis through paracrine effects of the hepatocyte growth factor. Stem Cells Transl Med. 2017; 6(3): 1006-1017.

[106] Mahmoudi T, Abdolmohammadi K, Bashiri H, et al. Hydrogen peroxide preconditioning promotes protective effects of umbilical cord vein mesenchymal stem cells in experimental pulmonary fibrosis. Adv Pharm Bull. 2019; 10(1): 72.

[107] Li D, Liu Q, Qi L, Dai X, Liu H, Wang Y. Low levels of TGF-β1 enhance human umbilical cord-derived mesenchymal stem cell fibronectin production and extend survival time in a rat model of lipopolysaccharide-induced acute lung injury. Mol Med Rep. 2016; 14(2): 1681-1692.

[108] Liu Y, Chiang C, Hung S, et al. Hypoxia-preconditioned mesenchymal stem cells ameliorate ischemia/reperfusion-induced lung injury. PLoS One. 2017; 12(11): e0187637.

[109] Kitajima Y, Ide T, Ohtsuka T, Miyazaki K. Induction of hepatocyte growth factor activator gene expression under hypoxia activates the hepatocyte growth factor/c-Met system via hypoxia inducible factor-1 in pancreatic cancer. Cancer Sci. 2008; 99(7): 1341-1347.

[110] Zhao F, Liu W, Yue S, et al. Pretreatment with G-CSF could enhance the antifibrotic effect of BM-MSCs on pulmonary fibrosis. Stem Cells Int. 2019; 2019(1): 1726743.

[111] Zhao F, Cheng T, Yang L, et al. G-CSF inhibits pulmonary fibrosis by promoting BMSC homing to the lungs via SDF-1/CXCR4 chemotaxis. Sci Rep. 2020; 10(1): 10515.

[112] Yao L, Liu C, Luo Q, et al. Protection against hyperoxia-induced lung fibrosis by KGF-induced MSC s mobilization in neonatal rats. Pediatr Transplant. 2013; 17(7): 676-682.

[113] Rozier P, Maumus M, Maria ATJ, et al. Lung fibrosis is improved by extracellular vesicles from IFNγ-primed mesenchymal stromal cells in murine systemic sclerosis. Cells. 2021; 10(10): 2727.

[114] Sheng H, Wang Y, Jin Y, et al. A critical role of IFNγ in priming MSC-mediated suppression of T cell proliferation through up-regulation of B7-H1. Cell Res. 2008; 18(8): 846-857.

[115] Liang C, Jiang E, Yao J, et al. Interferon-γ mediates the immunosuppression of bone marrow mesenchymal stem cells on T-lymphocytes in vitro. Hematology. 2018; 23(1): 44-49.

[116] Nassar S, Abdelmonsif D, Ali R, Badae N. Sodium hydrosulfide and bone marrow derived mesenchymal stem cells combined therapy for bleomycin induced pulmonary fibrosis in rats: implication of micro RNA-21 and Lnc GAS5. Life Sci. 2022; 309: 120988.

[117] Bashiri Z, Khosrowpour Z, Moghaddaszadeh A, et al. Optimizations of placenta extracellular matrix-loaded silk fibroin/alginate 3D-printed scaffolds structurally and functionally for bone tissue engineering. Eng Life Sci. 2025; 25(1): e202400085.

[118] Lopes-Pacheco M, Rocco P. Functional enhancement strategies to potentiate the therapeutic properties of mesenchymal stromal cells for respiratory diseases. Front Pharmacol. 2023; 14: 2023.

[119] Le B, Cressman A, Morales D, Fierro F. First Clinical experiences using preconditioning approaches to improve MSC-based therapies. Curr Stem Cell Rep. 2024; 10(1): 1-7.

[120] Mehrabani M, Mohammadyar S, Rajizadeh MA, et al. Boosting therapeutic efficacy of mesenchymal stem cells in pulmonary fibrosis: the role of genetic modification and preconditioning strategies. Iran J Basic Med Sci. 2023; 26(9): 1001.

[121] Li X, An G, Wang Y, et al. Anti-fibrotic effects of bone morphogenetic protein-7-modified bone marrow mesenchymal stem cells on silica-induced pulmonary fibrosis. Exp Mol Pathol. 2017; 102(1): 70-77.

[122] Antar S, Ashour N, Marawan M, Al-Karmalawy A. Fibrosis: types, effects, markers, mechanisms for disease progression, and its relation with oxidative stress, immunity, and inflammation. Int J Mol Sci. 2023; 24(4): 4004.

[123] Ono M, Ohkouchi S, Kanehira M, et al. Mesenchymal stem cells correct inappropriate epithelial–mesenchyme relation in pulmonary fibrosis using stanniocalcin-1. Mol Ther. 2015; 23(3): 549-560.

[124] Min F, Gao F, Li Q, Liu Z. Therapeutic effect of human umbilical cord mesenchymal stem cells modified by angiotensin-converting enzyme 2 gene on bleomycin-induced lung fibrosis injury. Mol Med Rep. 2015; 11(4): 2387-2396.

[125] Chen H, Luo Y, Zhu Y, et al. Enhanced secretion of hepatocyte growth factor in human umbilical cord mesenchymal stem cells ameliorates pulmonary fibrosis induced by bleomycin in rats. Front Pharmacol. 2023; 13: 1070736.

[126] Liu D, Kong F, Yuan Y, et al. Decorin-modified umbilical cord mesenchymal stem cells (MSCs) attenuate radiation-induced lung injuries via regulating inflammation, fibrotic factors, and immune responses. Int J Radiat Oncol Biol Phys. 2018; 101(4): 945-956.

[127] Shyamsundar M, McAuley DF, Ingram RJ, et al. 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.

[128] Aguilar S, Scotton CJ, McNulty K, et al. Bone marrow stem cells expressing keratinocyte growth factor via an inducible lentivirus protects against bleomycin-induced pulmonary fibrosis. PLoS One. 2009; 4(11): e8013.

[129] Kwon O, Kim K, Lee E, et al. Induction of MiR-21 by stereotactic body radiotherapy contributes to the pulmonary fibrotic response. PLoS One. 2016; 11(5): e0154942.

[130] Huleihel L, Sellares J, Cardenes N, et al. Modified mesenchymal stem cells using miRNA transduction alter lung injury in a bleomycin model. Am J Physiol-Lung Cell Mol Physiol. 2017; 313(1): L92-L103.

[131] Chen X, Shi C, Wang C, et al. The role of miR-497-5p in myofibroblast differentiation of LR-MSCs and pulmonary fibrogenesis. Sci Rep. 2017; 7(1): 40958.

[132] Shi L, Han Q, Hong Y, et al. Inhibition of miR-199a-5p rejuvenates aged mesenchymal stem cells derived from patients with idiopathic pulmonary fibrosis and improves their therapeutic efficacy in experimental pulmonary fibrosis. Stem Cell Res Ther. 2021; 12: 1-17.

[133] Wang P, Zhou Y, Richards A. Effective tools for RNA-derived therapeutics: siRNA interference or miRNA mimicry. Theranostics. 2021; 11(18): 8771.

[134] Shi C, Chen X, Yin W, Sun Z, Hou J, Han X. Wnt8b regulates myofibroblast differentiation of lung-resident mesenchymal stem cells via the activation of Wnt/β-catenin signaling in pulmonary fibrogenesis. Differentiation. 2022; 125: 35-44.

[135] Wu G, Chang F, Fang H, et al. Non-muscle myosin II knockdown improves survival and therapeutic effects of implanted bone marrow-derived mesenchymal stem cells in lipopolysaccharide-induced acute lung injury. Ann Transl Med. 2021; 9(3): 262.

[136] Ji Q, Hou J, Yong X, et al. Targeted dual small interfering ribonucleic acid delivery via non-viral polymeric vectors for pulmonary fibrosis therapy. Adv Mater. 2021; 33(12): 2007798.

[137] Chen X, Shi C, Cao H, et al. The hedgehog and Wnt/β-catenin system machinery mediate myofibroblast differentiation of LR-MSCs in pulmonary fibrogenesis. Cell death dis. 2018; 9(6): 639.

[138] Fang Y, Zhang C, Han M, et al. Engineered MSCs break endothelial-myofibroblast crosstalk in pulmonary fibrosis: reconstructing the vascular niche. Adv Mater. 2025; 37(13): 2414601.

[139] Long Y, Yang B, Lei Q, et al. Targeting senescent alveolar epithelial cells using engineered mesenchymal stem cell-derived extracellular vesicles to treat pulmonary fibrosis. ACS Nano. 2024; 18(9): 7046-7063.

[140] Xu X, Huang L, Hu S, et al. Genetic modification of mesenchymal stem cells overexpressing angiotensin II type 2 receptor increases cell migration to injured lung in LPS-induced acute lung injury mice. Stem Cells Transl Med. 2018; 7(10): 721-730.

[141] Han M, He X, Tang L, et al. Nanoengineered mesenchymal stem cell therapy for pulmonary fibrosis in young and aged mice. Sci adv. 2023; 9(29): eadg5358.

[142] Xu Y, Rahman M, Wang Z, et al. Glycogen engineering improves the starvation resistance of mesenchymal stem cells and their therapeutic efficacy in pulmonary fibrosis. Elife. 2025; 14: RP106023.

[143] Ouji-Sageshima N, Hiyama A, Kumamoto M, et al. Adipose-derived mesenchymal stem cells (ADSCs) have anti-fibrotic effects on lung fibroblasts from idiopathic pulmonary fibrosis (IPF) patients. Cells. 2024; 13(24): 2050.

[144] Bao H, Wu M, Xing J, et al. Enzyme-like nanoparticle–engineered mesenchymal stem cell secreting HGF promotes visualized therapy for idiopathic pulmonary fibrosis in vivo. Sci Adv. 2024; 10(34): eadq0703.

[145] Zhai Z, Cui T, Chen J, Mao X, Zhang T. Advancements in engineered mesenchymal stem cell exosomes for chronic lung disease treatment. J Transl Med. 2023; 21(1): 895.

[146] Cha S, Lee J, Jang J, et al. Exosomes from Human embryonic stem cell-derived mesenchymal stem cells protect lung epithelium and attenuate fibrosis. Int J Stem Cells. 2026; 19(1): 66-82.

[147] Chen Y, Li M, Yang J, Chen Y, Wang J. Engineerable mesenchymal stem cell-derived extracellular vesicles as promising therapeutic strategies for pulmonary fibrosis. Stem Cell Res Ther. 2025; 16(1): 367.

[148] Li S, Zhang J, Feng G, et al. The emerging role of extracellular vesicles from mesenchymal stem cells and macrophages in pulmonary fibrosis: insights into miRNA delivery. Pharmaceuticals. 2022; 15(10): 1276.

[149] Yuan Y, Wang J, Zhang Y, Li L, Reza A, Gurunathan S. Biogenesis, composition and potential therapeutic applications of mesenchymal stem cells derived exosomes in various diseases. Int J Nanomed. 2023; 183177-3210. eCollection 2023.

[150] Melo M, Cruz F, Rocco P. Mesenchymal stromal cell therapy for chronic lung diseases: experimental and clinical evidence. Expert Rev Respir Med. 2023; 17(3): 223-235.

[151] Harrell CR, Djonov V, Volarevic A, Arsenijevic A, Volarevic V. Molecular mechanisms responsible for the therapeutic potential of mesenchymal stem cell-derived exosomes in the treatment of lung fibrosis. Int J Mol Sci. 2024; 25(8): 4378.

[152] Harrell CR, Volarevic A, Djonov V, Arsenijevic A, Volarevic V. The role of microRNAs in mesenchymal stem cell–based modulation of pulmonary fibrosis. Cell Transplant. 2024; 33: 09636897241281026.

[153] Shen B, Liu J, Zhang F, et al. CCR2 positive exosome released by mesenchymal stem cells suppresses macrophage functions and alleviates ischemia/reperfusion-induced renal injury. Stem Cells Int. 2016; 2016(1): 1240301.

[154] Mansouri N, Willis GR, Fernandez-Gonzalez A, et al. Mesenchymal stromal cell exosomes prevent and revert experimental pulmonary fibrosis through modulation of monocyte phenotypes. JCI insight. 2019; 4(21): e128060.

[155] Lei L, Zhao C, Qin F, He ZY, Wang X, Zhong XN. Th17 cells and IL-17 promote the skin and lung inflammation and fibrosis process in a bleomycin-induced murine model of systemic sclerosis. Clin Exp Rheumatol. 2016; 34(Suppl 100): 14-22.

[156] Singh R, Alape D, de Lima A, Ascanio J, Majid A, Gangadharan SP. Regulatory T cells in respiratory health and diseases. Pulm Med. 2019; 2019(1): 1907807.

[157] Lai P, Chen X, Guo L, et al. A potent immunomodulatory role of exosomes derived from mesenchymal stromal cells in preventing cGVHD. J Hematol Oncol. 2018; 11: 1-15.

[158] Zhang E, Geng X, Shan S, et al. Exosomes derived from bone marrow mesenchymal stem cells reverse epithelial-mesenchymal transition potentially via attenuating Wnt/β-catenin signaling to alleviate silica-induced pulmonary fibrosis. Toxicol Mech Methods. 2021; 31(9): 655-666.

[159] Xu C, Hou L, Zhao J, et al. Exosomal let-7i-5p from three-dimensional cultured human umbilical cord mesenchymal stem cells inhibits fibroblast activation in silicosis through targeting TGFBR1. Ecotoxicol Environ Saf. 2022; 233: 113302.

[160] Zhao Y, Du L, Sun J, et al. Exosomal miR-218 derived from mesenchymal stem cells inhibits endothelial-to-mesenchymal transition by epigenetically modulating of BMP2 in pulmonary fibrosis. Cell Biol Toxicol. 2023; 39(6): 2919-2936.

[161] De Langhe E, Cailotto F, De Vooght V, et al. Enhanced endogenous bone morphogenetic protein signaling protects against bleomycin induced pulmonary fibrosis. Respir Res. 2015; 16: 1-10.

[162] Mou Y, Wu G, Wang Q, et al. Macrophage-targeted delivery of siRNA to silence Mecp2 gene expression attenuates pulmonary fibrosis. Bioeng Transl Med. 2022; 7(2): e10280.

[163] Xie L, Long X, Mo M, et al. Bone marrow mesenchymal stem cell-derived exosomes alleviate skin fibrosis in systemic sclerosis by inhibiting the IL-33/ST2 axis via the delivery of microRNA-214. Mol Immunol. 2023; 157: 146-157.

[164] Li Y, Shen Z, Jiang X, et al. Mouse mesenchymal stem cell-derived exosomal miR-466f-3p reverses EMT process through inhibiting AKT/GSK3β pathway via c-MET in radiation-induced lung injury. J Exp Clin Cancer Res. 2022; 41(1): 128.

[165] Wang Y, Li S, Zhao J, et al. Snail-mediated partial epithelial mesenchymal transition augments the differentiation of local lung myofibroblast. Chemosphere. 2021; 267: 128870.

[166] Gao Y, Liu M, Li Y, et al. Mesenchymal stem cells-extracellular vesicles alleviate pulmonary fibrosis by regulating immunomodulators. World J Stem Cells. 2024; 16(6): 670.

[167] Wan X, Chen S, Fang Y, Zuo W, Cui J, Xie S. Mesenchymal stem cell-derived extracellular vesicles suppress the fibroblast proliferation by downregulating FZD6 expression in fibroblasts via micrRNA-29b-3p in idiopathic pulmonary fibrosis. J Cell Physiol. 2020; 235(11): 8613-8625.

[168] Zhou J, Lin Y, Kang X, Liu Z, Zhang W, Xu F. microRNA-186 in extracellular vesicles from bone marrow mesenchymal stem cells alleviates idiopathic pulmonary fibrosis via interaction with SOX4 and DKK1. Stem Cell Res Ther. 2021; 12: 1-14.

[169] Shi L, Ren J, Li J, et al. Extracellular vesicles derived from umbilical cord mesenchymal stromal cells alleviate pulmonary fibrosis by means of transforming growth factor-β signaling inhibition. Stem Cell Res Ther. 2021; 12: 1-13.

[170] Xu C, Zhao J, Li Q, et al. Exosomes derived from three-dimensional cultured human umbilical cord mesenchymal stem cells ameliorate pulmonary fibrosis in a mouse silicosis model. Stem Cell Res Ther. 2020; 11: 1-12.

[171] Sun L, Zhu M, Feng W, et al. Exosomal miRNA Let-7 from menstrual blood-derived endometrial stem cells alleviates pulmonary fibrosis through regulating mitochondrial DNA damage. Oxidative Med Cell Longev. 2019; 2019(1): 4506303.

[172] Xu X, Zheng L, Yuan Q, et al. Transforming growth factor-β in stem cells and tissue homeostasis. Bone Res. 2018; 6(1): 2.

[173] Kadota T, Fujita Y, Araya J, Ochiya T, Kuwano K. Extracellular vesicle-mediated cellular crosstalk in lung repair, remodelling and regeneration. Eur Respir Rev. 2022; 31(163): 210106.

[174] Cho IJ, Lui PP, Obajdin J, et al. Mechanisms, hallmarks, and implications of stem cell quiescence. Stem Cell Rep. 2019; 12(6): 1190-1200.

[175] Dinh PC, Paudel D, Brochu H, et al. Inhalation of lung spheroid cell secretome and exosomes promotes lung repair in pulmonary fibrosis. Nat Commun. 2020; 11(1): 1064.

[176] Ren J, Liu Y, Yao Y, et al. Intranasal delivery of MSC-derived exosomes attenuates allergic asthma via expanding IL-10 producing lung interstitial macrophages in mice. Int Immunopharmacol. 2021; 91: 107288.

[177] 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.

[178] Campo A, González-Ruiz JM, Andreu E, et al. Endobronchial autologous bone marrow–mesenchymal stromal cells in idiopathic pulmonary fibrosis: a phase I trial. ERJ Open Res. 2021; 7(2): 00773-02020.

[179] Tzouvelekis A, Paspaliaris V, Koliakos G, et al. A prospective, non-randomized, no placebo-controlled, phase Ib clinical trial to study the safety of the adipose derived stromal cells-stromal vascular fraction in idiopathic pulmonary fibrosis. J Transl Med. 2013; 11: 1-13.

[180] Liu W, Wang H, Yu W, et al. Treatment of silicosis with hepatocyte growth factor-modified autologous bone marrow stromal cells: a non-randomized study with follow-up. Genet Mol Res. 2015; 14(3): 10672-10681.

[181] Vishnupriya M, Naveenkumar M, Manjima K, et al. Post-COVID pulmonary fibrosis: therapeutic efficacy using with mesenchymal stem cells-How the lung heals. Eur Rev Med Pharmacol Sci. 2021; 25(6): 2748-2751.

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