{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:37:54Z","timestamp":1790789874272,"version":"4.1.0"},"reference-count":115,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T00:00:00Z","timestamp":1681776000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R01EY023242"],"award-info":[{"award-number":["R01EY023242"]}]},{"name":"NIH","award":["R21EY033961"],"award-info":[{"award-number":["R21EY033961"]}]},{"name":"NIH","award":["R01EY032960"],"award-info":[{"award-number":["R01EY032960"]}]},{"name":"NIH","award":["R21EY028671"],"award-info":[{"award-number":["R21EY028671"]}]},{"name":"NIH","award":["P30EY031631"],"award-info":[{"award-number":["P30EY031631"]}]},{"name":"NIH","award":["R01EY028888"],"award-info":[{"award-number":["R01EY028888"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Biomechanical and molecular stresses may contribute to the pathogenesis of keratoconus (KC). We aimed to profile the transcriptomic changes in healthy primary human corneal (HCF) and KC-derived cells (HKC) combined with TGF\u03b21 treatment and cyclic mechanical stretch (CMS), mimicking the pathophysiological condition in KC. HCFs (n = 4) and HKCs (n = 4) were cultured in flexible-bottom collagen-coated 6-well plates treated with 0, 5, and 10 ng\/mL of TGF\u03b21 with or without 15% CMS (1 cycle\/s, 24 h) using a computer-controlled Flexcell FX-6000T Tension system. We used stranded total RNA-Seq to profile expression changes in 48 HCF\/HKC samples (100 bp PE, 70\u201390 million reads per sample), followed by bioinformatics analysis using an established pipeline with Partek Flow software. A multi-factor ANOVA model, including KC, TGF\u03b21 treatment, and CMS, was used to identify differentially expressed genes (DEGs, |fold change| \u2265 1.5, FDR \u2264 0.1, CPM \u2265 10 in \u22651 sample) in HKCs (n = 24) vs. HCFs (n = 24) and those responsive to TGF\u03b21 and\/or CMS. PANTHER classification system and the DAVID bioinformatics resources were used to identify significantly enriched pathways (FDR \u2264 0.05). Using multi-factorial ANOVA analyses, 479 DEGs were identified in HKCs vs. HCFs including TGF\u03b21 treatment and CMS as cofactors. Among these DEGs, 199 KC-altered genes were responsive to TGF\u03b21, thirteen were responsive to CMS, and six were responsive to TGF\u03b21 and CMS. Pathway analyses using PANTHER and DAVID indicated the enrichment of genes involved in numerous KC-relevant functions, including but not limited to degradation of extracellular matrix, inflammatory response, apoptotic processes, WNT signaling, collagen fibril organization, and cytoskeletal structure organization. TGF\u03b21-responsive KC DEGs were also enriched in these. CMS-responsive KC-altered genes such as OBSCN, CLU, HDAC5, AK4, ITGA10, and F2RL1 were identified. Some KC-altered genes, such as CLU and F2RL1, were identified to be responsive to both TGF\u03b21 and CMS. For the first time, our multi-factorial RNA-Seq study has identified many KC-relevant genes and pathways in HKCs with TGF\u03b21 treatment under CMS, suggesting a potential role of TGF\u03b21 and biomechanical stretch in KC development.<\/jats:p>","DOI":"10.3390\/ijms24087437","type":"journal-article","created":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T05:18:13Z","timestamp":1681795093000},"page":"7437","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Unravelling the Impact of Cyclic Mechanical Stretch in Keratoconus\u2014A Transcriptomic Profiling Study"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2408-2800","authenticated-orcid":false,"given":"Theresa","family":"Akoto","sequence":"first","affiliation":[{"name":"Department of Cellular Biology & Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingwen","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology & Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Nicholas","sequence":"additional","affiliation":[{"name":"North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"},{"name":"Department of Pharmaceutical Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayden","family":"McCord","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology & Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy J.","family":"Estes","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Augusta University, Augusta, GA 30912, USA"},{"name":"James & Jean Culver Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Population Health Sciences, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8761-3824","authenticated-orcid":false,"given":"Dimitrios","family":"Karamichos","sequence":"additional","affiliation":[{"name":"North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"},{"name":"Department of Pharmaceutical Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"},{"name":"Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2870-4504","authenticated-orcid":false,"given":"Yutao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology & Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"},{"name":"James & Jean Culver Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"},{"name":"Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1097\/ICO.0000000000001083","article-title":"Trends in Corneal Transplantation in Keratoconus","volume":"36","author":"Sarezky","year":"2017","journal-title":"Cornea"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7","DOI":"10.4103\/ijmr.IJMR_141_19","article-title":"Corneal transplantation in the modern era","volume":"150","author":"Singh","year":"2019","journal-title":"Indian J. 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