Reversal of diabetes following transplantation of an insulin-secreting human liver cell line: Melligen cells

• Published in: Molecular therapy. Methods & clinical development Vol. 2; p. 15011
• Main Authors: Lawandi, Janet, Tao, Chang, Ren, Binhai, Williams, Paul, Ling, Dora, Swan, M Anne, Nassif, Najah T, Torpy, Fraser R, O'Brien, Bronwyn A, Simpson, Ann M
• Format: Journal Article
• Language: English
• Published: United States Elsevier Limited 01-01-2015; Nature Publishing Group; Elsevier
• ISSN: 2329-0501; 2329-0501
• DOI: 10.1038/mtm.2015.11

As an alternative to the transplantation of islets, a human liver cell line has been genetically engineered to reverse type 1 diabetes (TID). The initial liver cell line (Huh7ins) commenced secretion of insulin in response to a glucose concentration of 2.5 mmol/l. After transfection of the Huh7ins cells with human islet glucokinase, the resultant Melligen cells secreted insulin in response to glucose within the physiological range; commencing at 4.25 mmol/l. Melligen cells exhibited increased glucokinase enzymatic activity in response to physiological glucose concentrations, as compared with Huh7ins cells. When transplanted into diabetic immunoincompetent mice, Melligen cells restored normoglycemia. Quantitative real-time polymerase chain reaction (qRT-PCR) revealed that both cell lines expressed a range of β-cell transcription factors and pancreatic hormones. Exposure of Melligen and Huh7ins cells to proinflammatory cytokines (TNF-α, IL-1β, and IFN-γ) affected neither their viability nor their ability to secrete insulin to glucose. Gene expression (microarray and qRT-PCR) analyses indicated the survival of Melligen cells in the presence of known β-cell cytotoxins was associated with the expression of NF-κB and antiapoptotic genes (such as BIRC3). This study describes the successful generation of an artificial β-cell line, which, if encapsulated to avoid allograft rejection, may offer a clinically applicable cure for T1D.