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Our previous work showed that mesenchymal stem\/stromal cells (MSCs) and MSCs overexpressing alpha\u20101 antitrypsin (AAT\u2010MSCs) could be therapeutic tools for CP. However, primary MSCs are predisposed to undergo senescence during culture expansion, which limits their therapeutic applications. We generated and characterized immortalized human MSCs (iMSCs) and AAT\u2010MSCs (iAAT\u2010MSCs) and tested their protective effect on 2,4,6\u2010Trinitrobenzenesulfonic acid (TNBS)\u2010induced acinar cell death in an in\u00a0vitro cell culture system. Primary MSCs were immortalized by transduction with simian virus 40 large T antigen (SV40LT), and the resulting iMSC and iAAT\u2010MSC lines were analysed for proliferation, senescence, phenotype and multi\u2010differentiation potential. Subsequently, apoptosis and ferroptosis pathways were investigated by assessing changes before and after TNBS treatment. Coculture of iMSCs and iAAT\u2010MSCs with acinar cell lines inhibited early cell death induced by TNBS, reduced ER stress and reversed TNBS\u2010induced protein reduction at tight junctions. Additionally, iMSCs and iAAT\u2010MSCs exerted such protection by regulating mitochondrial respiration, ATP content and ROS production in TNBS\u2010induced acinar cells. Furthermore, iMSCs and iAAT\u2010MSCs ameliorated TNBS\u2010induced ferroptosis by modulating iron generation and ROS production and regulating the ferritin heavy chain 1 (FTH1)\/protein disulfide isomerase (PDI)\/glutathione peroxide 4 (GPX4) signalling pathways in acinar cells. These findings identify ferroptosis as an unrecognized mechanism that leads to TNBS\u2010induced cell death and offer mechanistic insights relevant to using stem cell therapy to treat acinar cell death associated with CP.<\/jats:p>","DOI":"10.1111\/jcmm.70093","type":"journal-article","created":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T04:41:37Z","timestamp":1730176897000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Immortalized mesenchymal stromal cells overexpressing alpha\u20101 antitrypsin protect acinar cells from apoptotic and ferroptotic cell death"],"prefix":"10.1111","volume":"28","author":[{"given":"Sara","family":"Shoeibi","sequence":"first","affiliation":[{"name":"Department of Surgery Medical University of South Carolina  Charleston South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Green","sequence":"additional","affiliation":[{"name":"Department of Surgery Medical University of South Carolina  Charleston South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Surgery Medical University of South Carolina  Charleston South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyu","family":"Gou","sequence":"additional","affiliation":[{"name":"Department of Surgery Medical University of South Carolina  Charleston South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlie","family":"Strange","sequence":"additional","affiliation":[{"name":"Department of Medicine Medical University of South Carolina  Charleston South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7421-1917","authenticated-orcid":false,"given":"Hongjun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Surgery Medical University of South Carolina  Charleston South Carolina USA"},{"name":"Ralph H. 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