title: HMGB1 modulation in pancreatic islets using a cell-permeable A-box fragment.
abstract: Although pancreatic islet implantation is an attractive strategy for curing diabetes mellitus, implanted cells are immunologically eliminated due to early islet graft loss. One of main issues in early islet graft loss is the secretion of high-mobility group-box-1 (HMGB1) protein from the damaged islet cells, which is known as a cytokine-like factor. Therefore, regulating the activity of HMGB1 protein offers an alternative strategy for improving outcomes of islet cell therapy. To this end, we first demonstrated that HMGB1 protein could be bound to its A-box fragment (HMGB1 A-box) with higher binding affinity, resembling anti-HMGB1 antibody. To be used as a pharmaceutical protein ex vivo, TAT-labeled HMGB1 A-box-His6(TAT-HMGB1A) was structurally modified for cellular membrane penetration. TAT-HMGB1A significantly reduced secretion of endogenous HMGB1 protein through interaction in the cytosol without any damage to the viability or functionality of the islets. When TAT-HMGB1A-treated islets were implanted into diabetic nude mice, they completely cured diabetes, as evidenced by stable blood glucose level. TAT-HMGB1A treatment could also reduce the marginal islet mass needed to cure diabetes. Furthermore, TAT-HMGB1A positively protected xenotransplanted islets from xenogeneic immune reactions. Collectively, cell-penetrable TAT-HMGB1A could be used to modulate HMGB1 activity to increase successful outcomes of ex vivo pancreatic islet cell therapy.
authors.affiliation: Department of Bioengineering, College of Engineering, and BK21 PLUS Future Biopharmaceutical Human Resources Training and Research Team, Hanyang University, Seoul 04763, Republic of Korea.
authors.forename: Yong Hwa
authors.initials: YH
authors.lastname: Hwang
authors.affiliation: Department of Bioengineering, College of Engineering, and BK21 PLUS Future Biopharmaceutical Human Resources Training and Research Team, Hanyang University, Seoul 04763, Republic of Korea.
authors.forename: Min Jun
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Department of Chemical and Biological Engineering, Korea National University of Transportation, Chungju 27469, Republic of Korea.
authors.forename: Yong-Kyu
authors.initials: YK
authors.lastname: Lee
authors.affiliation: Department of Bioengineering, College of Engineering, and BK21 PLUS Future Biopharmaceutical Human Resources Training and Research Team, Hanyang University, Seoul 04763, Republic of Korea.
authors.forename: Minhyung
authors.initials: M
authors.lastname: Lee
authors.affiliation: Department of Bioengineering, College of Engineering, and BK21 PLUS Future Biopharmaceutical Human Resources Training and Research Team, Hanyang University, Seoul 04763, Republic of Korea; Institute of Nano Science & Technology (INST), Hanyang University, Seoul 04763, Republic of Korea. Electronic address: dongyunlee@hanyang.ac.kr.
authors.forename: Dong Yun
authors.initials: DY
authors.lastname: Lee
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000628:therapy*; D057809:HEK293 Cells; D024243:HMGB1 Protein / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism* / Q000648:ultrastructure; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D008297:Male; D008819:Mice, Nude; D017207:Rats, Sprague-Dawley
chemical_list: D024243:HMGB1 Protein
keywords: Diabetes; HMGB1; HMGB1 A-box; Inflammation; Pancreatic islet; Transplantation