Heme oxygenase-1 gene delivery for altering high mobility group box-1 protein in pancreatic islet


Type 1 diabetes is a chronic condition in which the pancreas produces little or no insulin. It is also known as juvenile diabetes or insulin-dependent diabetes. Insulin is a hormone required to allow sugar (glucose) to enter cells to produce energy. Usually, the body’s own immune system which normally fights harmful bacteria and viruses mistakenly destroys the insulin-producing cells (islet, or islets of Langerhans) in pancreas. Once a significant number of islet cells are destroyed, it produces little or no insulin. Glucose is the main source of energy for cells that make up muscles and other tissues. Sugar is absorbed into the bloodstream where it enters cells with the help of insulin. In type 1 diabetes, there’s no insulin to let glucose into the cells, so sugar builds up in the bloodstream. This can cause life-threatening complications. Over time, type 1 diabetes complications can affect major organs in the body including heart, blood vessels, nerves, eyes and kidneys. Maintaining a normal blood sugar level can dramatically reduce the risk of many complications. Pancreatic islet transplantation is a promising strategy for the treatment of type I diabetes. Pancreatic islets have significant amount of high mobility group box-1 (HMGB1), a nuclear transcription factor molecule, compared with other cells; HMGB1 is highly expressed in islet cells and is a potent immune stimulator in immune rejection. Extracellular HMGB1 has been extensively studied for its prototypical alarmin functions activating innate immunity, after being actively released from cells or passively released upon cell death. Loss of HMGB1 in the pancreas is associated with oxidative DNA damage and chromosomal instability characterized by chromosome rearrangements and telomere abnormalities.

In a new study published in Journal of Controlled Release by Min Jun Kim, Yong Hwa Hwang, Jin Wook Hwang, Zahid Alam and led by Professor Dong Yun Lee from Hanyang University in South Korea investigated whether it could protect islets from hypoxic stress by attenuating HMGB1 release. In their experiments, they delivered the adenovirally-encoded HO1 gene (Adv-HO1) in pancreatic islets and evaluated the effect of HO1 gene delivery on HMGB1 release in pancreatic islets. They also identified the mechanism of HMGB1 translocation and its release in hypoxia-exposed islets.

The research team showed that after transduction of Adv-HO1-eGFP, the transduced islets changed into green fluorescence, indicative that AdvHO1-eGFP was well diffused inside area of islets. In addition, expression of HO1 protein was confirmed by using western blot. When isolated islets were transduced with Adv-HO1, the band of HO1 protein was clearly detected. To further confirm the expression of HO1 after Adv-HO1 transduction, the HO1 protein from the cell extract was detected. The HO1 protein was only detected in the Adv-HO1-transduced islets. Afterward, the researchers evaluated the effect of HO1 under the hypoxic condition and showed that the structure of untransduced islets and Adv-Mock-transduced islets were severely destroyed and lost their viability. Based on these findings, the authors suggested that the overexpression of HO1 protected islets from hypoxia. Researchers further investigated whether islets maintain their ability to secrete insulin after exposure to hypoxia, the glucose-stimulated insulin secretion (GSIS) assay was performed. They observed that hypoxic culture for 4 h is optimal for studying the mechanism of HMGB1 active release because this duration does not affect the viability, morphology, or insulin secretion ability of islets. Based on the findings, they found that HO1 gene delivery could prevent translocation of HMGB1 under the hypoxic conditions, and that this effect might be attributed to prevention of extracellular Ca2+ influx to the cytosol. Their findings suggested that HO1 gene delivery could markedly inhibit Ca2+ influx in islets with cooperation with nifedipine under hypoxia condition. Based on their findings, they demonstrated that HO1 gene delivery could decrease HMGB1 translocation to the cytosol via inhibition of HAT activity although they were exposed under the hypoxic condition.

Furthermore, Professor Dong Yun Lee and his research team reported that HO1 gene delivery could suppress the PARP-1 activity for inhibition of HMGB1 translocation in islet. They also found that HO1 gene delivery could protect transplanted islets in mice from hypoxic environment at subcutaneous site and help normal glucose responsiveness of them. Researchers also found that insulin protein was strongly expressed in Adv-HO1-transduced islets, which is likely due to HO1-mediated hypoxia resistance.

In summary, Professor Dong Yun Lee and colleagues concluded that delivering the HO1 gene via adenovirus (Adv-HO1) can protect transplanted islets from hypoxic stress. They also found that expressed HO1 inhibited HMGB1 translocation and release in hypoxia-exposed islets. Reduced Ca2+ content in the cytosol and dephosphorylation of NFAT via reduced calcineurin activity were the mechanisms of expressed HO1, which might alter HAT and PARP-1 activity. Altogether, their new findings suggest that HO1 gene transfer can be used for successful islet transplantation by altering the activity of intracellular signal molecules and reducing HMGB1 release.

About the author

Dong Yun Lee, Ph.D.

Advanced Nanobioengineering & Confluence (ANBC) Lab.
Department of Bioengineering, Hanyang University
Institute of Nano Science & Technology (INST)
Institute for Bioengineering and Biopharmaceutical Research (IBBR)
Seoul 04763, Republic of Korea
CEO & Founder
Elixir Pharmatech Inc., Seoul 04763, Republic of Korea

Prof. Dong Yun Lee is currently a professor of department of bioengineering at the Hanyang University, Seoul, Republic of Korea. Dr. Lee’s research focuses on the immunomodulatory cell engineering (PEGylation to live cell, first-mover in worldwide with global patents), implantable cellular device with 3D bioprinting, molecular imaging with nanomedicine, oral drug delivery system for gene/peptide/cell therapy, as well as designing contact lens-based biosensor with developing software algorism for diagnosis of tear on eye. Dr. Lee’s research has led to 115 peer-reviewed publications (>43 H-index), including papers in Science Advances, Journal of the American Chemical Society, Bioactive Materials, Nano Letters, Journal of Nanobiotechnology, Clinical Cancer Research, Biomaterials, Journal of Controlled Release, etc. Dr. Lee currently holds more than 45 domestic and international patents. Dr. Lee’s research has been recognized with the HYU Outstanding Professor Award by the Hanyang University (2014 & 2016), the Mid-Career Scientist Award by the Polymer Society of Korea (2018), the 2018 National R&D Excellence Achievement 100-selected Award by the Republic of Korea Government (Very Best Research Project) (2018), the ENF Creative Innovation Award by the Korean Society of Industrial and Engineering Chemistry (2022)and the ‘Commendation of Prime Minister’ Award by the Republic of Korea Government (2018).

Dr. Lee is a member of Tissue Engineering and Regenerative Medicine International Society (TERMIS), International Controlled Release Society (CRS) and International Biomedical Engineering Society (BMES), and now serves as a council member for the Korean Society for Biomaterials (KSBM), the Polymer Society of Korea (PSK), the Korean Society of Pharmaceutical Sciences and Technology (KSPST), Tissue Engineering and Regenerative Medicine International Society (TERMIS), and Korean Society of Industrial and Engineering Chemistry (KSIEC). From 2009 to present, Dr. Lee serves as an Associate Editor (currently Editorial Board member) of the ‘Molecular and Cellular Toxicology’ and a member of the Editorial Board of the ‘Quantitative Imaging in Medicine and Surgery’ and ‘Polymer (Korea)’, Journal of Pharmaceutical Investigation, and serves as a reviewer for scientific journals (e.g., Biomaterials, Tissue Engineering, Journal of Controlled Release, ACS Nano, Advanced Materials, Advanced Functional Materials, and so on).


Kim MJ, Hwang YH, Hwang JW, Alam Z, Lee DY. Heme oxygenase-1 gene delivery for altering high mobility group box-1 protein in pancreatic islet. Journal of Controlled Release 2022 Jan 24.

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