Generation and Characterization of Human Heme Oxygenase-1 Transgenic Pigs

Hye Jung Yeom, Ok Jae Koo, Jaeseok Yang, Bumrae Cho, Jong Ik Hwang, Sol Ji Park, Sunghoon Hurh, Hwajung Kim, Eun Mi Lee, Han Ro, Jung Taek Kang, Su Jin Kim, Jae Kyung Won, Philip J. O'Connell, Hyunil Kim, Charles D. Surh, Byeong Chun Lee, Curie Ahn

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43 Citations (Scopus)

Abstract

Xenotransplantation using transgenic pigs as an organ source is a promising strategy to overcome shortage of human organ for transplantation. Various genetic modifications have been tried to ameliorate xenograft rejection. In the present study we assessed effect of transgenic expression of human heme oxygenase-1 (hHO-1), an inducible protein capable of cytoprotection by scavenging reactive oxygen species and preventing apoptosis caused by cellular stress during inflammatory processes, in neonatal porcine islet-like cluster cells (NPCCs). Transduction of NPCCs with adenovirus containing hHO-1 gene significantly reduced apoptosis compared with the GFP-expressing adenovirus control after treatment with either hydrogen peroxide or hTNF-α and cycloheximide. These protective effects were diminished by co-treatment of hHO-1 antagonist, Zinc protoporphyrin IX. We also generated transgenic pigs expressing hHO-1 and analyzed expression and function of the transgene. Human HO-1 was expressed in most tissues, including the heart, kidney, lung, pancreas, spleen and skin, however, expression levels and patterns of the hHO-1 gene are not consistent in each organ. We isolate fibroblast from transgenic pigs to analyze protective effect of the hHO-1. As expected, fibroblasts derived from the hHO-1 transgenic pigs were significantly resistant to both hydrogen peroxide damage and hTNF-α and cycloheximide-mediated apoptosis when compared with wild-type fibroblasts. Furthermore, induction of RANTES in response to hTNF-α or LPS was significantly decreased in fibroblasts obtained from the hHO-1 transgenic pigs. These findings suggest that transgenic expression of hHO-1 can protect xenografts when exposed to oxidative stresses, especially from ischemia/reperfusion injury, and/or acute rejection mediated by cytokines. Accordingly, hHO-1 could be an important candidate molecule in a multi-transgenic pig strategy for xenotransplantation.

Original languageEnglish
Article numbere46646
JournalPloS one
Volume7
Issue number10
DOIs
Publication statusPublished - 2012 Oct 5

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Yeom, H. J., Koo, O. J., Yang, J., Cho, B., Hwang, J. I., Park, S. J., Hurh, S., Kim, H., Lee, E. M., Ro, H., Kang, J. T., Kim, S. J., Won, J. K., O'Connell, P. J., Kim, H., Surh, C. D., Lee, B. C., & Ahn, C. (2012). Generation and Characterization of Human Heme Oxygenase-1 Transgenic Pigs. PloS one, 7(10), [e46646]. https://doi.org/10.1371/journal.pone.0046646