Pancreatic Transdifferentiation in Porcine Liver Following Lentiviral Delivery of Human Furin–Cleavable Insulin

Gerace, Dario; Ren, Bin; Hawthorne, Wayne J.; Byrne, M; Phillips, Peta; O’Brien, Bronwyn A.; Nassif, Najah T.; Alexander, Ian E.; Simpson, Ann M.

doi:10.1016/j.transproceed.2013.01.051

Cited by 17 publications

(26 citation statements)

References 18 publications

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“…Hepatocytes and pancreatic β‐cells are both derived from endoderm during organogenesis and share common progenitors (Luo et al ., ). Therefore, interesting results in the reversal of diabetes have been obtained by transdifferentiation of cells in other organs and induction of islet neogenesis (i.e,, in the liver) (Ber et al ., ; Gerace et al ., ; Kojima et al ., ). Other approaches have involved allogenic islet cell transplantation and differentiation of stem cells in vitro into insulin‐producing cells followed by their implantation (Lenzen, ).…”

Section: Resultsmentioning

confidence: 98%

Differentiation of stem cells into insulin‐producing cells under the influence of nanostructural polyoxometalates

Bâlici

Şuşman

Rusu

et al. 2015

J of Applied Toxicology

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Two polyoxometalates (POMs) with W were synthesized by a two-step, self-assembling method. They were used for stimulation of mesenchymal stem cell differentiation into insulin-producing cells. The nanocompounds (tris(vanadyl)-substituted tungsto-antimonate(III) anions [POM1] and tris-butyltin-21-tungsto-9-antimonate(III) anions [POM2]) were characterized by analytical techniques, including ultraviolet-visible, Fourier transform infrared, nuclear magnetic resonance spectroscopy, and transmission electron microscopy. We found that these polyoxotungstates, with 2-4 nm diameters, did not present toxic effects at the tested concentrations. In vitro, POM1 stimulated differentiation of a greater number of dithizone-positive cells (also organized in clusters) than the second nanocompound (POM2). Based on our in vitro studies, we have concluded that both the POMs tested had significant biological activity acting as active stimuli for differentiation of stem cells into insulin-producing cells. Copyright

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Section: Resultsmentioning

confidence: 98%

Differentiation of stem cells into insulin‐producing cells under the influence of nanostructural polyoxometalates

Bâlici

Şuşman

Rusu

et al. 2015

J of Applied Toxicology

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“…We are sceptical that normal glucose tolerance would have been seen at 24 h, even if the animals could have survived an intravenous glucose tolerance test (IVGTT) so soon after the operation. In a porcine model, in which we have repeated the FFO technique, normal glucose tolerance was observed at 30 days even though normalisation of blood glucose was not seen until after 10 days in this large animal model .…”

mentioning

confidence: 76%

Response to the letter to the editor by M. Elsner et al: “Comment on Binhai Ren et al (2013;15:28–41). Long term reversal of diabetes in non‐obese diabetic mice by liver‐directed gene therapy”

Simpson

Ren

O’Brien

et al. 2013

The Journal of Gene Medicine

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“…Numerous studies have shown pancreatic transdifferentiation of liver cells upon expression of β-cell transcription factors and we have shown spontaneous expression of β-cell transcription factors, pancreatic transdifferentiation, and reversal of diabetes in several animal models following the lentiviral delivery of furin cleavable insulin. 9 , 11 , 30 We have previously described the presence of GLUT2, liver glucokinase, PC1 and PC2, and the pancreatic β-cell transcription factors, Pdx1 , NeuroD1, Neurogenin 3 , Pax4, Pax6, Nkx6.1 , in Huh7ins cells. 4 , 29 As expected, human islet glucokinase was expressed in the Melligen cells, at both the RNA and protein levels, but was not expressed by the parental cell lines.…”

Section: Discussionmentioning

confidence: 99%

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

Lawandi

Tao

Ren

et al. 2015

Molecular Therapy - Methods & Clinical Development

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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.

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Pancreatic Transdifferentiation in Porcine Liver Following Lentiviral Delivery of Human Furin–Cleavable Insulin

Cited by 17 publications

References 18 publications

Differentiation of stem cells into insulin‐producing cells under the influence of nanostructural polyoxometalates

Differentiation of stem cells into insulin‐producing cells under the influence of nanostructural polyoxometalates

Response to the letter to the editor by M. Elsner et al: “Comment on Binhai Ren et al (2013;15:28–41). Long term reversal of diabetes in non‐obese diabetic mice by liver‐directed gene therapy”

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

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