{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T17:27:15Z","timestamp":1793899635880,"version":"4.8.0"},"reference-count":24,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"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. Vet. Sci."],"abstract":"<jats:p>Advances in genetic engineering have enabled the development of highly modified porcine models for xenotransplantation. Among available technologies, somatic cell nuclear transfer (SCNT) remains the most reliable method for generating multi-genic pigs carrying complex genetic modifications, including the knockout of porcine xenoantigens and the insertion of human immune regulatory genes. Despite these advances, the physiological viability of highly engineered cloned animals remains a major challenge. In our previous study, we generated cloned pigs carrying a knockout of \u03b1-1,3-galactosyltransferase (\u03b1-gal) and knock-in of five human immune-related genes: human decay-accelerating factor (hDAF), CD39 (hCD39), tissue factor pathway inhibitor (hTFPI), C1 inhibitor (hC1INH), and TNF-\u03b1-induced protein 3 (hTNFAIP3). Although genomic integration and cellular expression of these transgenes were confirmed, all piglets in this cohort died within 48 h after birth. Necropsy revealed no evidence of external trauma or systemic abnormalities in major organs. However, hemorrhagic lesions were observed in the left ventricular myocardium of all necropsied piglets, and histological examination confirmed localized intramyocardial hemorrhage without ventricular rupture or pericardial effusion. We propose that incomplete epigenetic reprogramming associated with SCNT, combined with the physiological burden of multi-gene expression, may have compromised myocardial microvascular integrity. Under the abrupt hemodynamic transition that occurs after birth, this structural vulnerability may predispose the left ventricle to intramyocardial hemorrhage and rapid cardiogenic collapse. These findings suggest that left ventricular hemorrhage may represent a previously underrecognized cause of early neonatal death in highly engineered SCNT-derived pigs.<\/jats:p>","DOI":"10.3389\/fvets.2026.1833278","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T15:36:14Z","timestamp":1781105774000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Case Report: Left ventricular hemorrhage associated with early neonatal mortality in multi-gene engineered cloned pigs"],"prefix":"10.3389","volume":"13","author":[{"given":"Dong-Hwan","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Animal Science, College of Natural Resources and Life Science, Pusan National University","place":["Miryang, Republic of Korea"]},{"name":"Green Bio Science Major, School of Applied Life and Convergence Science, Pusan National University","place":["Yangsan, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-Eon","family":"Kim","sequence":"additional","affiliation":[{"name":"Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology","place":["Daejeon, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bumseok","family":"Kim","sequence":"additional","affiliation":[{"name":"Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University","place":["Iksan, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In-Sul","family":"Hwang","sequence":"additional","affiliation":[{"name":"Columbia Center for Translational Immunology, Columbia University Irving Medical Center, Columbia University, New York","place":["NY, United States"]},{"name":"National Institute of Animal Science, Rural Development Administration","place":["Wanju, Jeollabuk-do, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geumyoung","family":"Sok","sequence":"additional","affiliation":[{"name":"Department of Animal Science, College of Natural Resources and Life Science, Pusan National University","place":["Miryang, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seongsoo","family":"Hwang","sequence":"additional","affiliation":[{"name":"National Institute of Animal Science, Rural Development Administration","place":["Wanju, Jeollabuk-do, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeongwoong","family":"Lee","sequence":"additional","affiliation":[{"name":"Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology","place":["Daejeon, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1089","DOI":"10.1126\/science.1068228","article-title":"Production of alpha-1,3-galactosyltransferase knockout pigs by nuclear transfer cloning","volume":"295","author":"Lai","year":"2002","journal-title":"Science (1979)."},{"key":"B2","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1097\/00007890-199809150-00001","article-title":"Discordant organ xenotransplantation in primates: world experience and current status","volume":"66","author":"Lambrigts","year":"1998","journal-title":"Transplantation."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1171","DOI":"10.1097\/00007890-199311000-00024","article-title":"Prevention of complement-mediated activation of xenogeneic endothelial cells in an in vitro model of xenograft hyperacute rejection by C1 inhibitor","volume":"56","author":"Dalmasso","year":"1993","journal-title":"Transplantation."},{"key":"B4","doi-asserted-by":"publisher","first-page":"958","DOI":"10.1016\/j.yjmcc.2012.01.002","article-title":"d'Apice AJF, et al. 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