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The annulus fibrosus (AF) plays a critical role in maintaining IVD structure\/function and undergoes degenerative changes such as matrix catabolism and inflammation. Thus, therapies targeting the AF are crucial to fully restore IVD function. Previously, we have shown nonviral delivery of transcription factors to push diseased nucleus pulposus cells to a healthy phenotype. As a next step in a proof\u2010of\u2010concept study, we report the use of Scleraxis (<jats:italic>SCX<\/jats:italic>) and Mohawk (<jats:italic>MKX<\/jats:italic>), which are critical for the development, maintenance, and regeneration of the AF and may have therapeutic potential to induce a healthy, pro\u2010anabolic phenotype in diseased AF cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p><jats:italic>MKX<\/jats:italic> and <jats:italic>SCX<\/jats:italic> plasmids were delivered via electroporation into diseased human AF cells from autopsy specimens and patients undergoing surgery for LBP. Transfected cells were cultured over 14\u2009days and assessed for cell morphology, viability, density, gene expression of key phenotypic, inflammatory, matrix, pain markers, and collagen accumulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>AF cells demonstrated a fibroblastic phenotype posttreatment. Moreover, transfection of <jats:italic>SCX<\/jats:italic> and <jats:italic>MKX<\/jats:italic> resulted in significant upregulation of the respective genes, as well as <jats:italic>SOX9<\/jats:italic>. Transfected autopsy cells demonstrated upregulation of core extracellular matrix markers; however, this was observed to a lesser effect in surgical cells. Matrix\u2010degrading enzymes and inflammatory cytokines were downregulated, suggesting a push toward a pro\u2010anabolic, anti\u2010inflammatory phenotype. Similarly, pain markers were downregulated over time in autopsy cells. At the protein level, collagen content was increased in both <jats:italic>MKX<\/jats:italic> and <jats:italic>SCX<\/jats:italic> transfected cells compared to controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This exploratory study demonstrates the potential of <jats:italic>MKX<\/jats:italic> or <jats:italic>SCX<\/jats:italic> to drive reprogramming in mild to moderately degenerate AF cells from autopsy and severely degenerate AF cells from surgical patients toward a healthy phenotype and may be a potential nonviral gene therapy for LBP.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jsp2.1270","type":"journal-article","created":{"date-parts":[[2023,6,28]],"date-time":"2023-06-28T04:43:16Z","timestamp":1687927396000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Nonviral overexpression of Scleraxis or Mohawk drives reprogramming of degenerate human annulus fibrosus cells from a diseased to a healthy phenotype"],"prefix":"10.1002","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8807-2348","authenticated-orcid":false,"given":"Shirley","family":"Tang","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering The Ohio State University  Columbus Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Connor","family":"Gantt","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering The Ohio State University  Columbus Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana","family":"Salazar Puerta","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering The Ohio State University  Columbus Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucy","family":"Bodine","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering The Ohio State University  Columbus Ohio 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