{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T23:52:54Z","timestamp":1785196374455,"version":"3.55.0"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T00:00:00Z","timestamp":1660089600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Ligamentum flavum hypertrophy (LFH) is a common cause of spinal stenosis. The aim of the current study was to identify the differentially expressed genes (DEGs) in LFH and the molecular mechanisms underlying the development of and immune responses to LFH. The gene expression omnibus (GEO) database was used to obtain the GSE113212 dataset, and the DEGs were derived from microarray data. To identify critical genes and signaling pathways, gene ontology enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and protein-protein interaction (PPI) network analyses were performed, followed by immune cell infiltration and Friends analyses using the retrieved datasets. The results were validated using quantitative real-time PCR. The 1530 DEGs identified comprised 971 upregulated and 559 downregulated genes. KEGG analysis revealed that DEGs were mostly enriched in the PI3K-Akt signaling pathway, while PPI network analysis identified tumor necrosis factor, interleukin (IL)-6, IL-10, epidermal growth factor receptor, and leptin as important nodes, which was validated by qPCR and IHC in human LFH tissues <jats:italic>in vitro<\/jats:italic>. A significant positive correlation was found between key LFH immune-related DEGs and several immune cell types, including T and B cells. The findings of the present study might lead to novel therapeutic targets and clinical approaches, as they provide insights into the molecular mechanisms of LFH.<\/jats:p>","DOI":"10.3389\/fcell.2022.914781","type":"journal-article","created":{"date-parts":[[2022,9,22]],"date-time":"2022-09-22T16:29:54Z","timestamp":1663864194000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":24,"title":["Immune cell infiltration and the genes associated with ligamentum flavum hypertrophy: Identification and validation"],"prefix":"10.3389","volume":"10","author":[{"given":"Yang","family":"Duan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songjia","family":"Ni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyue","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,8,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2036","DOI":"10.1177\/0300060517711308","article-title":"Hypertrophy of the ligamentum flavum and expression of transforming growth factor beta","volume":"45","author":"Amudong","year":"2017","journal-title":"J. Int. Med. Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"4941","DOI":"10.1096\/fj.201701455RR","article-title":"Cardiac fibroblast-specific p38\u03b1 MAP kinase promotes cardiac hypertrophy via a putative paracrine interleukin-6 signaling mechanism","volume":"32","author":"Bageghni","year":"2018","journal-title":"Faseb J."},{"key":"B3","doi-asserted-by":"publisher","first-page":"D760","DOI":"10.1093\/nar\/gkl887","article-title":"NCBI GEO: Mining tens of millions of expression profiles--database and tools update","volume":"35","author":"Barrett","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"B4","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1007\/s12026-014-8516-1","article-title":"ImmPort: Disseminating data to the public for the future of immunology","volume":"58","author":"Bhattacharya","year":"2014","journal-title":"Immunol. Res."},{"key":"B5","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1007\/978-1-4939-7493-1_12","article-title":"Profiling tumor infiltrating immune cells with CIBERSORT","volume":"1711","author":"Chen","year":"2018","journal-title":"Methods Mol. Biol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"6025","DOI":"10.18632\/aging.202536","article-title":"SIRT6 enhances telomerase activity to protect against DNA damage and senescence in hypertrophic ligamentum flavum cells from lumbar spinal stenosis patients","volume":"13","author":"Chen","year":"2021","journal-title":"Aging (Albany NY)"},{"key":"B7","doi-asserted-by":"publisher","first-page":"8630","DOI":"10.1021\/jacs.6b04910","article-title":"A fluorescence polarization assay for binding to macrophage migration inhibitory factor and crystal structures for complexes of two potent inhibitors","volume":"138","author":"Cisneros","year":"2016","journal-title":"J. Am. Chem. Soc."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1846","DOI":"10.1093\/bioinformatics\/btm254","article-title":"GEOquery: A bridge between the gene expression omnibus (GEO) and BioConductor","volume":"23","author":"Davis","year":"2007","journal-title":"Bioinformatics"},{"key":"B9","doi-asserted-by":"publisher","first-page":"98","DOI":"10.3389\/fchem.2018.00098","article-title":"Design, synthesis, and evaluation of dihydrobenzo[cd]indole-6-sulfonamide as TNF-\u03b1 inhibitors","volume":"6","author":"Deng","year":"2018","journal-title":"Front. Chem."},{"key":"B10","doi-asserted-by":"publisher","first-page":"258","DOI":"10.3892\/ijo.2019.4918","article-title":"Protein- and growth-modulatory effects of carcinoma-associated fibroblasts on breast cancer cells: Role of interleukin-6","volume":"56","author":"Dittmer","year":"2020","journal-title":"Int. J. Oncol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/1471-2105-14-7","article-title":"GSVA: Gene set variation analysis for microarray and RNA-seq data","volume":"14","author":"H\u00e4nzelmann","year":"2013","journal-title":"BMC Bioinforma."},{"key":"B12","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1177\/1535370217746611","article-title":"MiR-145 regulates osteogenic differentiation of human adipose-derived mesenchymal stem cells through targeting FoxO1","volume":"243","author":"Hao","year":"2018","journal-title":"Exp. Biol. Med."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1326","DOI":"10.3389\/fphar.2020.01326","article-title":"Hesperetin promotes cisplatin-induced apoptosis of gastric cancer in vitro and in vivo by upregulating PTEN expression","volume":"11","author":"He","year":"2020","journal-title":"Front. Pharmacol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1001\/archneur.1971.00490030082009","article-title":"Hypertrophy of the ligamentum flavum. Secondary cord syndrome in an acromegalic","volume":"25","author":"Kaufman","year":"1971","journal-title":"Arch. Neurol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"14805","DOI":"10.1038\/ncomms14805","article-title":"Constitutive smooth muscle tumour necrosis factor regulates microvascular myogenic responsiveness and systemic blood pressure","volume":"8","author":"Kroetsch","year":"2017","journal-title":"Nat. Commun."},{"key":"B16","doi-asserted-by":"publisher","first-page":"105738","DOI":"10.1016\/j.intimp.2019.105738","article-title":"Inhibition of COX-2 alleviates lumbar spinal stenosis-induced chronic mechanical allodynia in rats","volume":"75","author":"Lee","year":"2019","journal-title":"Int. Immunopharmacol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The Molecular Signatures Database (MSigDB) hallmark gene set collection","volume":"1","author":"Liberzon","year":"2015","journal-title":"Cell Syst."},{"key":"B18","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1016\/j.stem.2018.05.009","article-title":"Modulating cell fate as a therapeutic strategy","volume":"23","author":"Lin","year":"2018","journal-title":"Cell Stem Cell"},{"key":"B19","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1007\/s00701-010-0839-7","article-title":"Hypertrophy of the lumbar ligamentum flavum is associated with inflammation-related TGF-\u03b2 expression","volume":"153","author":"L\u00f6hr","year":"2011","journal-title":"Acta Neurochir."},{"key":"B20","doi-asserted-by":"publisher","first-page":"730","DOI":"10.7507\/1002-1892.201811140","article-title":"Mechanism of p38 mitogen activated protein kinase signaling pathway on promoting the hypertrophy of human lumbar ligamentum flavum via transforming growth factor \u03b2 (1)\/connective tissue growth factor","volume":"33","author":"Lu","year":"2019","journal-title":"Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi"},{"key":"B21","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.bioactmat.2022.03.042","article-title":"Amelioration of ligamentum flavum hypertrophy using umbilical cord mesenchymal stromal cell-derived extracellular vesicles","volume":"19","author":"Ma","year":"2023","journal-title":"Bioact. Mat."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1413","DOI":"10.1007\/s00586-019-05994-3","article-title":"Molecular alterations of human lumbar yellow ligament related to the process of intervertebral disk degeneration and stenosis","volume":"28","author":"Martins","year":"2019","journal-title":"Eur. Spine J."},{"key":"B23","doi-asserted-by":"publisher","first-page":"385","DOI":"10.5483\/bmbrep.2019.52.6.189","article-title":"Leptin stimulates IGF-1 transcription by activating AP-1 in human breast cancer cells","volume":"52","author":"Min","year":"2019","journal-title":"BMB Rep."},{"key":"B24","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.atherosclerosis.2019.05.030","article-title":"Subjects with diffuse idiopathic skeletal hyperostosis have an increased burden of coronary artery disease: An evaluation in the COPDGene cohort","volume":"287","author":"Oudkerk","year":"2019","journal-title":"Atherosclerosis"},{"key":"B25","doi-asserted-by":"publisher","first-page":"688","DOI":"10.3892\/ijmm.2020.4809","article-title":"ADAM10 promotes the proliferation of ligamentum flavum cells by activating the PI3K\/AKT pathway","volume":"47","author":"Pan","year":"2021","journal-title":"Int. J. Mol. Med."},{"key":"B26","doi-asserted-by":"publisher","first-page":"2750","DOI":"10.2106\/JBJS.E.00251","article-title":"Hypertrophy of ligamentum flavum in lumbar spinal stenosis associated with increased proteinase inhibitor concentration","volume":"87","author":"Park","year":"2005","journal-title":"J. Bone Jt. Surg. Am."},{"key":"B27","doi-asserted-by":"publisher","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"Limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"2872","DOI":"10.1016\/j.jacc.2019.04.003","article-title":"Transthyretin amyloid cardiomyopathy: JACC state-of-the-art review","volume":"73","author":"Ruberg","year":"2019","journal-title":"J. Am. Coll. Cardiol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"2831","DOI":"10.1016\/j.ajpath.2017.08.020","article-title":"Macrophage infiltration is a causative factor for ligamentum flavum hypertrophy through the activation of collagen production in fibroblasts","volume":"187","author":"Saito","year":"","journal-title":"Am. J. Pathol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"e0169717","DOI":"10.1371\/journal.pone.0169717","article-title":"Experimental mouse model of lumbar ligamentum flavum hypertrophy","volume":"12","author":"Saito","year":"","journal-title":"PLoS One"},{"key":"B31","doi-asserted-by":"publisher","first-page":"3940","DOI":"10.1093\/bioinformatics\/bti623","article-title":"ROCR: Visualizing classifier performance in R","volume":"21","author":"Sing","year":"2005","journal-title":"Bioinformatics"},{"key":"B32","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B33","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1186\/s40425-019-0534-z","article-title":"Intralymphatic histiocytosis in a patient with lung adenocarcinoma treated with pembrolizumab: A case report","volume":"7","author":"Sugano","year":"2019","journal-title":"J. Immunother. Cancer"},{"key":"B34","doi-asserted-by":"publisher","first-page":"BSR20171214","DOI":"10.1042\/BSR20171214","article-title":"Leptin-induced inflammation by activating IL-6 expression contributes to the fibrosis and hypertrophy of ligamentum flavum in lumbar spinal canal stenosis","volume":"38","author":"Sun","year":"2018","journal-title":"Biosci. Rep."},{"key":"B35","doi-asserted-by":"publisher","first-page":"D607","DOI":"10.1093\/nar\/gky1131","article-title":"STRING v11: Protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets","volume":"47","author":"Szklarczyk","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"B36","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1080\/21623945.2020.1770525","article-title":"Elastin-derived peptide VGVAPG decreases differentiation of mouse embryo fibroblast (3T3-L1) cells into adipocytes","volume":"9","author":"Szychowski","year":"2020","journal-title":"Adipocyte"},{"key":"B37","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/s13018-020-1552-8","article-title":"Posterolateral fusion combined with posterior decompression shows superiority in the treatment of severe lumbar spinal stenosis without lumbar disc protrusion or prolapse: A retrospective cohort study","volume":"15","author":"Wang","year":"2020","journal-title":"J. Orthop. Surg. Res."},{"key":"B38","doi-asserted-by":"publisher","first-page":"e128","DOI":"10.1016\/j.wneu.2021.03.147","article-title":"The role of Smad2 in transforming growth factor \u03b2(1)-induced hypertrophy of ligamentum flavum","volume":"151","author":"Wang","year":"2021","journal-title":"World Neurosurg."},{"key":"B39","first-page":"3398","article-title":"High-throughput sequencing analysis of the expression profile of microRNAs and target genes in mechanical force-induced osteoblastic\/cementoblastic differentiation of human periodontal ligament cells","volume":"11","author":"Wu","year":"2019","journal-title":"Am. J. Transl. Res."},{"key":"B40","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1097\/BRS.0000000000001226","article-title":"MicroRNA-221 regulates hypertrophy of ligamentum flavum in lumbar spinal stenosis by targeting TIMP-2","volume":"41","author":"Xu","year":"2016","journal-title":"Spine (Phila Pa 1976)"},{"key":"B41","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1007\/978-1-0716-0301-7_11","article-title":"Gene ontology semantic similarity analysis using GOSemSim","volume":"2117","author":"Yu","year":"2020","journal-title":"Methods Mol. Biol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"Omics"},{"key":"B43","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1186\/s12943-020-01170-0","article-title":"m(6 A regulator-mediated methylation modification patterns and tumor microenvironment infiltration characterization in gastric cancer","volume":"19","author":"Zhang","year":"2020","journal-title":"Mol. Cancer"},{"key":"B44","doi-asserted-by":"publisher","first-page":"858","DOI":"10.3389\/fcell.2020.00858","article-title":"CRLF1 is a key regulator in the ligamentum flavum hypertrophy","volume":"8","author":"Zheng","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1016\/j.ijid.2020.04.041","article-title":"Clinical value of immune-inflammatory parameters to assess the severity of coronavirus disease 2019","volume":"95","author":"Zhu","year":"2020","journal-title":"Int. J. Infect. Dis."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2022.914781\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,22]],"date-time":"2022-09-22T16:29:59Z","timestamp":1663864199000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2022.914781\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,10]]},"references-count":45,"alternative-id":["10.3389\/fcell.2022.914781"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2022.914781","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,10]]},"article-number":"914781"}}