{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T15:56:59Z","timestamp":1785254219316,"version":"3.55.0"},"reference-count":45,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T00:00:00Z","timestamp":1670803200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81772085"],"award-info":[{"award-number":["81772085"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82072176"],"award-info":[{"award-number":["82072176"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: As a fibrotic disease with a high incidence, the pathogenesis of hypertrophic scarring is still not fully understood, and the treatment of this disease is also challenging. In recent years, human adipose-derived mesenchymal stem cells (AD-MSCs) have been considered an effective treatment for hypertrophic scars. This study mainly explored whether the therapeutic effect of AD-MSCs on hypertrophic scars is associated with oxidative-stress-related proteins. Methods: AD-MSCs were isolated from adipose tissues and characterized through flow cytometry and a differentiation test. Afterwards, coculture, cell proliferation, apoptosis, and migration were detected. Western blotting and a quantitative real-time polymerase chain reaction (qRT\u2013PCR) were used to detect oxidative stress-related genes and protein expression in hypertrophic scar fibroblasts (HSFs). Flow cytometry was used to detect reactive oxygen species (ROS). A nude mouse animal model was established; the effect of AD-MSCs on hypertrophic scars was observed; and hematoxylin and eosin staining, Masson\u2019s staining, and immunofluorescence staining were performed. Furthermore, the content of oxidative-stress-related proteins, including nuclear factor erythroid-2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), B-cell lymphoma 2(Bcl2), Bcl2-associated X(BAX) and caspase 3, was detected. Results: Our results showed that AD-MSCs inhibited HSFs\u2019 proliferation and migration and promoted apoptosis. Moreover, after coculture, the expression of antioxidant enzymes, including HO-1, in HSFs decreased; the content of reactive oxygen species increased; and the expression of Nrf2 decreased significantly. In animal experiments, we found that, at 14 days after injection of AD-MSCs into human hypertrophic scar tissue blocks that were transplanted onto the dorsum of nude mice, the weight of the tissue blocks decreased significantly. Hematoxylin and eosin staining and Masson\u2019s staining demonstrated a rearrangement of collagen fibers. We also found that Nrf2 and antioxidant enzymes decreased significantly, while apoptotic cells increased after AD-MSC treatment. Conclusions: Our results demonstrated that AD-MSCs efficiently cured hypertrophic scars by promoting the apoptosis of HSFs and by inhibiting their proliferation and migration, which may be related to the inhibition of Nrf2 expression in HSFs, suggesting that AD-MSCs may provide an alternative therapeutic approach for the treatment of hypertrophic scars.<\/jats:p>","DOI":"10.3390\/cells11244024","type":"journal-article","created":{"date-parts":[[2022,12,13]],"date-time":"2022-12-13T02:59:01Z","timestamp":1670900341000},"page":"4024","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Adipose-Derived Mesenchymal Stem Cells Alleviate Hypertrophic Scar by Inhibiting Bioactivity and Inducing Apoptosis in Hypertrophic Scar Fibroblasts"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6635-8529","authenticated-orcid":false,"given":"Shiyi","family":"Li","sequence":"first","affiliation":[{"name":"Senior Department of Burns and Plastic Surgery, The Fourth Medical Center of Chinese PLA General Hospital, Beijing 100038, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinxiu","family":"Yang","sequence":"additional","affiliation":[{"name":"Senior Department of Burns and Plastic Surgery, The Fourth Medical Center of Chinese PLA General Hospital, Beijing 100038, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiachen","family":"Sun","sequence":"additional","affiliation":[{"name":"Senior Department of Burns and Plastic Surgery, The Fourth Medical Center of Chinese PLA General Hospital, Beijing 100038, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minliang","family":"Chen","sequence":"additional","affiliation":[{"name":"Senior Department of Burns and Plastic Surgery, The Fourth Medical Center of Chinese PLA General Hospital, Beijing 100038, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/S0305-4179(03)00067-6","article-title":"What is the prevalence of hypertrophic scarring following burns?","volume":"29","author":"Bombaro","year":"2003","journal-title":"Burns"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Lee, H.J., and Jang, Y.J. (2018). Recent Understandings of Biology, Prophylaxis and Treatment Strategies for Hypertrophic Scars and Keloids. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19030711"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1007\/s00403-018-1856-2","article-title":"Expression of inflammatory and fibrogenetic markers in acne hypertrophic scar formation: Focusing on role of TGF-\u03b2 and IGF-1R","volume":"310","author":"Yang","year":"2018","journal-title":"Arch. Dermatol. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1007\/s00403-019-01960-7","article-title":"Effect of artesunate and relation with TGF-\u03b21 and SMAD3 signaling on experimental hypertrophic scar model in rabbit ear","volume":"311","author":"Nong","year":"2019","journal-title":"Arch. Dermatol. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1177\/1535370216669839","article-title":"Upregulation of microRNA-205 suppresses vascular endothelial growth factor expression-mediated PI3K\/Akt signaling transduction in human keloid fibroblasts","volume":"242","author":"An","year":"2017","journal-title":"Exp. Biol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1097\/SAP.0000000000001784","article-title":"The Effect of Chyle Fat Injection on Human Hypertrophic Scars in an Animal Model: A New Strategy for the Treatment of Hypertrophic Scars","volume":"82","author":"Chen","year":"2019","journal-title":"Ann. Plast. Surg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.redox.2015.01.002","article-title":"Oxidative stress: A concept in redox biology and medicine","volume":"4","author":"Sies","year":"2015","journal-title":"Redox Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6465","DOI":"10.1073\/pnas.85.17.6465","article-title":"Normal oxidative damage to mitochondrial and nuclear DNA is extensive","volume":"85","author":"Richter","year":"1988","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1152\/physrev.00018.2001","article-title":"Free radicals in the physiological control of cell function","volume":"82","author":"Droge","year":"2002","journal-title":"Physiol. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.17219\/acem\/105852","article-title":"NFE2L2 is associated with NQO1 expression and low stage of hepatic fibrosis in patients with chronic hepatitis C","volume":"28","author":"Wojcik","year":"2019","journal-title":"Adv. Clin. Exp. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.mrfmmm.2004.05.023","article-title":"Contribution of NAD(P)H:quinone oxidoreductase 1 to protection against carcinogenesis, and regulation of its gene by the Nrf2 basic-region leucine zipper and the arylhydrocarbon receptor basic helix-loop-helix transcription factors","volume":"555","author":"Nioi","year":"2004","journal-title":"Mutat. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"26882","DOI":"10.1074\/jbc.M114.567685","article-title":"Nuclear heme oxygenase-1 (HO-1) modulates subcellular distribution and activation of Nrf2, impacting metabolic and anti-oxidant defenses","volume":"289","author":"Biswas","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"9873","DOI":"10.1074\/jbc.M111.312694","article-title":"Nrf2 protein up-regulates antiapoptotic protein Bcl-2 and prevents cellular apoptosis","volume":"287","author":"Niture","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1146\/annurev.pharmtox.46.120604.141046","article-title":"Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway","volume":"47","author":"Kensler","year":"2007","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"637","DOI":"10.14336\/AD.2018.0513","article-title":"The Anti-Inflammatory and Anti-Oxidant Mechanisms of the Keap1\/Nrf2\/ARE Signaling Pathway in Chronic Diseases","volume":"10","author":"Tu","year":"2019","journal-title":"Aging Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3577","DOI":"10.1002\/jcb.26097","article-title":"Mechanism of Generation of Oxidative Stress and Pathophysiology of Type 2 Diabetes Mellitus: How Are They Interlinked?","volume":"118","author":"Rehman","year":"2017","journal-title":"J. Cell. Biochem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1007\/s11010-009-0057-x","article-title":"Differential apoptosis markers in human keloids and hypertrophic scars fibroblasts","volume":"327","author":"Garbi","year":"2009","journal-title":"Mol. Cell. Biochem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"507","DOI":"10.5021\/ad.2015.27.5.507","article-title":"Oxidative Damage and Nuclear Factor Erythroid 2-Related Factor 2 Protein Expression in Normal Skin and Keloid Tissue","volume":"27","author":"Lee","year":"2015","journal-title":"Ann. Dermatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.jss.2019.06.006","article-title":"Reactive Oxygen Species Scavenging Potential Contributes to Hypertrophic Scar Formation","volume":"244","author":"Carney","year":"2019","journal-title":"J. Surg. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s13287-020-02061-3","article-title":"Combination of lyophilized adipose-derived stem cell concentrated conditioned medium and polysaccharide hydrogel in the inhibition of hypertrophic scarring","volume":"12","author":"Zhang","year":"2021","journal-title":"Stem Cell Res. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1186\/s13287-021-02290-0","article-title":"Exosomes derived from human adipose mesenchymal stem cells attenuate hypertrophic scar fibrosis by miR-192-5p\/IL-17RA\/Smad axis","volume":"12","author":"Li","year":"2021","journal-title":"Stem Cell Res. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1186\/s13287-015-0133-y","article-title":"Intralesional injection of adipose-derived stem cells reduces hypertrophic scarring in a rabbit ear model","volume":"6","author":"Zhang","year":"2015","journal-title":"Stem Cell Res. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4057","DOI":"10.1002\/jcb.27689","article-title":"Adipose tissue-derived stem cells inhibit hypertrophic scar (HS) fibrosis via p38\/MAPK pathway","volume":"120","author":"Chai","year":"2019","journal-title":"J. Cell. Biochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1159\/000075030","article-title":"Elevated vascular endothelial growth factor in keloids: Relevance to tissue fibrosis","volume":"176","author":"Le","year":"2004","journal-title":"Cells Tissues Organs"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1046\/j.1523-1755.2001.00469.x","article-title":"Hydrogen peroxide increases extracellular matrix mRNA through TGF-beta in human mesangial cells","volume":"59","author":"Chen","year":"2001","journal-title":"Kidney Int."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"565","DOI":"10.6061\/clinics\/2014(08)11","article-title":"Update on hypertrophic scar treatment","volume":"69","author":"Rabello","year":"2014","journal-title":"Clinics"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1186\/s13287-016-0356-6","article-title":"Adipose tissue-derived stem cells suppress hypertrophic scar fibrosis via the p38\/MAPK signaling pathway","volume":"7","author":"Li","year":"2016","journal-title":"Stem Cell Res. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1097\/SAP.0000000000001932","article-title":"Chyle Fat-Derived Stem Cells Conditioned Medium Inhibits Hypertrophic Scar Fibroblast Activity","volume":"83","author":"Chen","year":"2019","journal-title":"Ann. Plast. Surg."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Ogawa, R. (2017). Keloid and Hypertrophic Scars Are the Result of Chronic Inflammation in the Reticular Dermis. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18030606"},{"key":"ref_30","first-page":"793","article-title":"Heterogeneity of human fibroblasts isolated from hypertrophic scar","volume":"60","author":"Florea","year":"2019","journal-title":"Rom. J. Morphol. Embryol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s13287-018-0786-4","article-title":"Human adipose-derived stem cells inhibit bioactivity of keloid fibroblasts","volume":"9","author":"Wang","year":"2018","journal-title":"Stem Cell Res. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.burns.2017.08.017","article-title":"Human adipose tissue-derived stem cells inhibit the activity of keloid fibroblasts and fibrosis in a keloid model by paracrine signaling","volume":"44","author":"Liu","year":"2018","journal-title":"Burns"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"tkab020","DOI":"10.1093\/burnst\/tkab020","article-title":"Adipose-derived stem cells inhibit dermal fibroblast growth and induce apoptosis in keloids through the arachidonic acid-derived cyclooxygenase-2\/prostaglandin E2 cascade by paracrine","volume":"9","author":"Yang","year":"2021","journal-title":"Burn. Trauma"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1023\/A:1009616228304","article-title":"Role of reactive oxygen species (ROS) in apoptosis induction","volume":"5","author":"Simon","year":"2000","journal-title":"Apoptosis"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"641308","DOI":"10.3389\/fphar.2021.641308","article-title":"rhKGF-2 Attenuates Smoke Inhalation Lung Injury of Rats via Activating PI3K\/Akt\/Nrf2 and Repressing FoxO1-NLRP3 Inflammasome","volume":"12","author":"Fu","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1038\/aps.2017.143","article-title":"Ulinastatin attenuates LPS-induced inflammation in mouse macrophage RAW264.7 cells by inhibiting the JNK\/NF-\u03baB signaling pathway and activating the PI3K\/Akt\/Nrf2 pathway","volume":"39","author":"Li","year":"2018","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1111\/j.1524-475X.2011.00672.x","article-title":"Human hypertrophic scar-like nude mouse model: Characterization of the molecular and cellular biology of the scar process","volume":"19","author":"Wang","year":"2011","journal-title":"Wound Repair Regen."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1111\/j.1600-0625.2005.00362.x","article-title":"Learning from nudity: Lessons from the nude phenotype","volume":"14","author":"Mecklenburg","year":"2005","journal-title":"Exp. Dermatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1111\/j.1524-475X.2012.00856.x","article-title":"A nude mouse model of hypertrophic scar shows morphologic and histologic characteristics of human hypertrophic scar","volume":"21","author":"Momtazi","year":"2013","journal-title":"Wound Repair Regen."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"136","DOI":"10.5021\/ad.2012.24.2.136","article-title":"Paracrine effects of adipose-derived stem cells on keratinocytes and dermal fibroblasts","volume":"24","author":"Lee","year":"2012","journal-title":"Ann. Dermatol."},{"key":"ref_41","first-page":"15739","article-title":"Protective effects of adipose-derived stem cells secretome on human dermal fibroblasts from ageing damages","volume":"8","author":"Wang","year":"2015","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"BSR20192549","DOI":"10.1042\/BSR20192549","article-title":"ADSC-Exos containing MALAT1 promotes wound healing by targeting miR-124 through activating Wnt\/\u03b2-catenin pathway","volume":"40","author":"He","year":"2020","journal-title":"Biosci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"10847","DOI":"10.1002\/jcb.28376","article-title":"Adipose mesenchymal stem cell-derived exosomes promote cell proliferation, migration, and inhibit cell apoptosis via Wnt\/\u03b2-catenin signaling in cutaneous wound healing","volume":"120","author":"Ma","year":"2019","journal-title":"J. Cell. Biochem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.yexcr.2018.06.035","article-title":"Cell-free therapy based on adipose tissue stem cell-derived exosomes promotes wound healing via the PI3K\/Akt signaling pathway","volume":"370","author":"Zhang","year":"2018","journal-title":"Exp. Cell Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"108531","DOI":"10.1016\/j.abb.2020.108531","article-title":"Adipose-derived stem cells promote diabetic wound healing via the recruitment and differentiation of endothelial progenitor cells into endothelial cells mediated by the VEGF-PLC\u03b3-ERK pathway","volume":"692","author":"Chen","year":"2020","journal-title":"Arch. Biochem. Biophys."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/24\/4024\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:40:08Z","timestamp":1760146808000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/24\/4024"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,12]]},"references-count":45,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["cells11244024"],"URL":"https:\/\/doi.org\/10.3390\/cells11244024","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,12]]}}}