Department of Bioengineering, College of Engineering, and BK FOUR Biopharmaceutical Innovation Leader for Education and Research Group, Hanyang University, Seoul 04763, Republic of Korea.
Department of Bioengineering, College of Engineering, and BK FOUR Biopharmaceutical Innovation Leader for Education and Research Group, Hanyang University, Seoul 04763, Republic of Korea; Institute of Nano Science & Technology (INST), Hanyang University, Seoul 04763, Republic of Korea; Elixir Pharmatech Inc., Seoul 04763, Republic of Korea.
J Control Release. 2022 Mar;343:326-337. doi: 10.1016/j.jconrel.2022.01.031. Epub 2022 Jan 24.
Pancreatic islet transplantation is a promising strategy for the treatment of type I diabetes. High-mobility group box-1 (HMGB1), highly expressed in islet cells, is a potent immune stimulator in immune rejection. Heme oxygenase-1 (HO1) gene therapy can modulate the release of HMGB1 by altering intracellular molecules for successful cell transplantation. After delivery of the heme oxygenase-1 (HO1) gene to islet cells using an adeno-associated viral vector (AAV), it was evaluated the changes in cytoplasmic Ca ions and calcineurin activity as well as histone acetyltransferase (HAT) and Poly(ADP) ribose polymerase-1 (PARP-1). Inhibition of HMGB1 release was evaluated through altering these intracellular molecules. Then, after transplantation of HO1-transduced islets, the therapeutic effect of them was evaluated through measuring blood glucose level to diabetic mice and through immunohistochemical analysis. The transduced HO1 gene significantly inhibited HMGB1 release in islets that was under the cell damage by hypoxia exposure. It was confirmed that this result was initially due to the decrease in cytoplasmic Ca ion concentration and calcineurin activity. In addition, the delivered HO1 gene simultaneously reduced the activity of HAT and PARP-1, which are involved in the translocation of HMGB1 from the nucleus to the cytoplasm. As a result, when the HO1 gene-transduced islets were transplanted into diabetic mice, the treatment efficiency of diabetes was effectively improved by increasing the survival rate of the islets. Collectively, these results suggest that HO1 gene transfer can be used for successful islet transplantation by altering the activity of intracellular signal molecules and reducing HMGB1 release.
胰岛细胞移植是治疗 1 型糖尿病的一种很有前途的策略。高迁移率族蛋白 B1（HMGB1）在胰岛细胞中高表达，是免疫排斥反应中的一种强烈免疫刺激物。血红素加氧酶-1（HO1）基因治疗可以通过改变细胞内分子来调节 HMGB1 的释放，从而成功进行细胞移植。使用腺相关病毒载体（AAV）将血红素加氧酶-1（HO1）基因递送到胰岛细胞后，评估了细胞质钙离子和钙调神经磷酸酶活性以及组蛋白乙酰转移酶（HAT）和多聚（ADP-核糖）聚合酶-1（PARP-1）的变化。通过改变这些细胞内分子来评估 HMGB1 释放的抑制情况。然后，在转导 HO1 的胰岛细胞移植后，通过测量糖尿病小鼠的血糖水平并进行免疫组织化学分析来评估它们的治疗效果。转导的 HO1 基因可显著抑制缺氧暴露下胰岛细胞损伤导致的 HMGB1 释放。结果证实，这最初是由于细胞质钙离子浓度和钙调神经磷酸酶活性的降低。此外，所递送的 HO1 基因同时降低了 HAT 和 PARP-1 的活性，HAT 和 PARP-1 参与 HMGB1 从细胞核到细胞质的易位。结果，当将 HO1 基因转导的胰岛细胞移植到糖尿病小鼠中时，通过增加胰岛细胞的存活率，有效地改善了糖尿病的治疗效果。总之，这些结果表明，通过改变细胞内信号分子的活性和减少 HMGB1 的释放，HO1 基因转移可用于成功的胰岛细胞移植。
