Human liver‐derived cells stably modified for regulated proinsulin secretion function as bioimplants <i>in vivo</i>

Chen, Xiang; Patil, Jawahar G.; Lok, Serene H. L.; Kon, Oi Lian

doi:10.1002/jgm.263

Cited by 7 publications

(6 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…12 In our studies of regulated insulin expression, promoter constructs with Diabetic C57BL/6J mice were implanted with B8 Â 10 5 viable transfected hepatocytes in regenerating liver. Glucose solution (75 mg/ml; 1.5 mg/g body weight) was administered to three mice as a single intravenous bolus 3 days after hepatocyte implantation, while two control mice received an identical volume of glucose-free saline.…”

Section: Discussionmentioning

confidence: 99%

“…The ability of the bifunctional promoter to increase insulin secretion in response to glucose, zinc or both stimuli 12 provides a means of maintaining adequate basal interprandial insulin secretion, with the additional capacity of stimulating insulin secretion in response to post-prandial increase in blood glucose. The threshold concentrations of glucose and zinc that stimulated insulin secretion from transfected hepatocytes of 2.5 mM and between 10 and 15 mM, respectively (Figure 2a), are physiological.…”

Section: Hepatocyte-mediated Therapy Of Murine Diabetes Nkf Chen Et Almentioning

confidence: 99%

“…10 Our study is the first to show that primary adult hepatocytes can be genetically modified to secrete insulin with rapid kinetics in response to high extracellular glucose concentrations. The gene vector in this study was an expression plasmid that placed human proinsulin cDNA, modified for furin cleavage and encoding the HisB10Asp variant, 11 under the control of a bifunctional promoter 12 comprising the human metallothionein IIA promoter and a single copy of the carbohydrate response element (ChoRE) from the L-type pyruvate kinase (LPK) gene. While all other studies to date have used viral vectors, calcium phosphate or liposomes to deliver insulin transgenes into cells, we have achieved efficient transgene delivery into primary hepatocytes by electroporation.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Plasmid-electroporated primary hepatocytes acquire quasi-physiological secretion of human insulin and restore euglycemia in diabetic mice

et al. 2005

View full text Add to dashboard Cite

We describe the durable correction of streptozotocin-induced murine diabetes by in vivo implantation of primary mouse hepatocytes electroporated ex vivo with a human proinsulin cDNA plasmid construct controlled by glucose and zinc regulatory elements. Transfected hepatocytes increased insulin transgene transcription and secretion within 10-20 min of exposure to 25 mM glucose or 60 mM zinc. Insulin release did not occur from secretory granules. Electroporated Rosa26 hepatocytes (B8 Â 10 5 viable cells) were implanted in C57BL/6J diabetic mice in one of three sites: unresected liver, regenerating liver or mesentery. Control diabetic mice were implanted with untransfected hepatocytes. At 30 days after implantation, 8/15 control mice were alive, while 19/19 treated mice were alive. The ratio of body weight on day 30/nadir body weight was significantly higher for all treated groups compared with controls. All eight surviving control mice were hyperglycemic 30 days postimplantation, while 16/19 treated diabetic mice remained normoglycemic. Treated mice had lower mean glucose values (Pp0.001) without fasting hypoglycemia and better glucose tolerance (Pp0.0003) than untreated controls. All (6/6) diabetic mice implanted in regenerating liver and 71% (5/7) implanted in unresected liver were alive 77 days after implantation. Engrafted hepatocytes were identified, mainly around central veins, by staining for b-galactosidase activity and with anti-human insulin antibody. Gene Therapy (2005) 12, 655-667.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Hepatocyte-mediated Therapy Of Murine Diabetes Nkf Chen Et Almentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Plasmid-electroporated primary hepatocytes acquire quasi-physiological secretion of human insulin and restore euglycemia in diabetic mice

et al. 2005

View full text Add to dashboard Cite

show abstract

“…However, transplantation is limited by the availability of suitable donors [19][20][21]. This lack of available islets for transplantation has led investigators to experiment with in vitro production of glucoregulating, insulin-secreting cells [22][23][24][25][26][27][28][29], with limited success. Stem cell therapy provides a potential solution to the afore-described problems.…”

Section: Discussionmentioning

confidence: 99%

Treatment of Type I Diabetes in the NOD Mouse with Syngeneic Cord Blood Stem Cells

Harris¹,

Badowski²,

Harman³

2009

TOSCJ

View full text Add to dashboard Cite

Human type 1 diabetes mellitus occurs due to chronic inflammation with lymphocytic infiltration and (usually) the presence of antibodies against insulin and characteristic islet cell proteins (e.g., GAD). This autoimmune process destroys the islets of Langerhans (including the beta cells) leading to insulin insufficiency. In several studies to date diabetes in the non-obese diabetic (NOD) mouse model of human type 1 diabetes has either been prevented or reversed by allogeneic transplantation of stem cells derived from mouse bone marrow or spleen. Immunosuppressive regimens have been ablative in some studies, but non-ablative regimes have been used in others. With non-ablative regimens, recipient mice develop chimeric immune systems. In addition, two recent clinical trials using stem cells have shown similar benefit for human patients with type 1 diabetes. We investigated whether stem cells isolated from genetically identical, but non-diabetic neonatal mouse pups (i.e., the mouse equivalent of human cord blood stem cells) would reverse diabetes when transfused into NOD mouse recipients which have already developed hyperglycemia. It was observed that cord blood stem cell infusion after diabetic conversion resulted in reversal of hyperglycemia whether given with or without the immune ablative drug, cytoxan. However, cytoxan alone had no beneficial effect. Stem cell-treated mice also lived longer than untreated mice. In these studies it was not possible to demonstrate islet cell regeneration resulting from the infused stem cells. These experiments provide evidence that cord blood stem cells may be suitable for improving or eliminating the autoimmune process in human type 1 diabetes patients, and thereby modulating their disease. However, additional studies are needed to clarify the mechanisms behind these observations.

show abstract

“…The device was implanted into the mouse’s abdomen under the skin, where the biosensor unit can directly contact with the mouse blood. The edges of the device were connected with two electrode poles to receive the outputting piezoelectric voltage generated by the device [ 40 ]. After that, we slowly injected 5 mL of glucose solution (0.045 g L −1 ) into the mouse abdomen using a medical syringe within about 5 s. All of the procedures in this study conformed to the regulations for the administration of affairs concerning experimental animals and were approved by Northeastern University.…”

Section: Methodsmentioning

confidence: 99%

Self-Powered Implantable Skin-Like Glucometer for Real-Time Detection of Blood Glucose Level In Vivo

Zhang

Gao

et al. 2018

Nano-Micro Lett.

View full text Add to dashboard Cite

Implantable bioelectronics for analyzing physiological biomarkers has recently been recognized as a promising technique in medical treatment or diagnostics. In this study, we developed a self-powered implantable skin-like glucometer for real-time detection of blood glucose level in vivo. Based on the piezo-enzymatic-reaction coupling effect of GOx@ZnO nanowire, the device under an applied deformation can actively output piezoelectric signal containing the glucose-detecting information. No external electricity power source or battery is needed for this device, and the outputting piezoelectric voltage acts as both the biosensing signal and electricity power. A practical application of the skin-like glucometer implanted in mouse body for detecting blood glucose level has been simply demonstrated. These results provide a new technique path for diabetes prophylaxis and treatment. Electronic supplementary materialThe online version of this article (10.1007/s40820-017-0185-x) contains supplementary material, which is available to authorized users.

show abstract

Human liver‐derived cells stably modified for regulated proinsulin secretion function as bioimplants in vivo

Abstract: These results are the first to demonstrate stable proinsulin production in a human liver-derived cell line with activity in vitro and in vivo and provide a basis for engineering hepatocytes as in vivo bioimplants for future diabetes treatment.

Cited by 7 publications

References 50 publications

Plasmid-electroporated primary hepatocytes acquire quasi-physiological secretion of human insulin and restore euglycemia in diabetic mice

Plasmid-electroporated primary hepatocytes acquire quasi-physiological secretion of human insulin and restore euglycemia in diabetic mice

Treatment of Type I Diabetes in the NOD Mouse with Syngeneic Cord Blood Stem Cells

Self-Powered Implantable Skin-Like Glucometer for Real-Time Detection of Blood Glucose Level In Vivo

Contact Info

Product

Resources

About