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Protection of human islets from induction of apoptosis and improved islet function with HO-1 gene transduction

Chinese Medical Journal 2006年第19期119卷 1639-1645页

作者： LI Yong-xiang LI Ge DONG Wei-ping LU Da-ru TAN Jian-ming Department of Urology and Center of Renal Transplantation Shanghai Organ Transplant and Research Center Shanghai First People＇s Hospital Shanghai 200085 China State Key Laboratory of Genetic Engineering Institute of Genetics School of Life Sciences Fudan University Shanghai 200433 China

Background Islet transplantation represents an ideal therapeutic approach for treatment of type 1 diabetes but islet function and regeneration may be influenced by necrosis or apoptosis induced by oxidative stress and other insults. Heme oxygenase-1 （HO-1） is the rate-limiting enzyme in the catabolism of heme into biliverdin, releasing free iron and carbon monoxide. It has also been reported to be an antioxidant enzyme which can improve the function of grafted islets by cytoprotection via free radical scavenging and apoptosis prevention. In the present study, we investigated whether transduction of HO-1 genes into human islets with an adenovirus vector has cytoprotective action on islets cultured in vitro and discuss this method of gene therapy for clinical islet transplantation. Methods Cadaveric pancreatic islets were isolated and purified in vitro. Transduction efficiency of islets was determined by infecting islets with adenovirus vector containing the enhanced green fluorescent protein gene （Ad-EGFP） at multiplicities of infection （MOI） of 2, 5, 10, or 20. Newly isolated islets were divided into three groups： EGFP group, islets transduced with Ad-EGFP using MOI=20; HO-1 group, transduced with adenovirus vectors containing the human HO-1 gene using MOI=20; and control group, mock transduced islets. Insulin release after glucose stimulation of the cell lines was determined by a radioimmunoassay kit and the stimulation index was calculated. Flow cytometry was used to detect apoptotic cells in the HO-1 group and in the control group after induction by recombinant human tumor necrosis factor-α （rTNFα） and cycloheximide （CHX） for 48 hours. Results Adenovirus vectors have a high efficiency of gene transduction into adult islet cells. Transduction of islets with the Ad-EGFP was most successful at MOI 20, at which MOI fluorescence was very intense on day 7 after transduction and EGFP was expressed in cultured islet cells for more than four weeks in vitro. The insulin re

关键词： transplantation islets of langerhans heme oxygenase-1 adenovirus apoptosis

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Regenerative medicine of pancreatic islets

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World Journal of Gastroenterology 2020年第22期26卷 2948-2966页

作者： Irina V Arutyunyan Timur Kh Fatkhudinov Andrey V Makarov Andrey V Elchaninov Gennady T Sukhikh National Medical Research Center for Obstetrics Gynecology and Perinatology named after Academician V.I.Kulakov of Ministry of Healthcare of Russian FederationMoscow 117997Russia Research Institute of Human Morphology Moscow 117418Russia Peoples Friendship University of Russia Moscow 117198Russia Pirogov Russian National Research Medical University Ministry of Healthcare of the Russian FederationMoscow 117997Russi

The pancreas became one of the first objects of regenerative medicine,since other possibilities of dealing with the pancreatic endocrine insufficiency were clearly *** number of people living with diabetes mellitus is currently approaching half a billion,hence the crucial relevance of new methods to stimulate regeneration of the insulin-secretingβ-cells of the islets of *** restrictions on the islet regeneration are very tight;nevertheless,the islets are capable of physiological regeneration viaβ-cell self-replication,direct differentiation of multipotent progenitor cells and spontaneousα-toβ-orδ-toβ-cell conversion(trans-differentiation).The existing preclinical models ofβ-cell dysfunction or ablation(induced surgically,chemically or genetically)have significantly expanded our understanding of reparative regeneration of the islets and possible ways of its *** ultimate goal,sufficient level of functional activity ofβ-cells or their substitutes can be achieved by two prospective broad strategies:β-cell replacement andβ-cell ***“regeneration”strategy aims to maintain a preserved population ofβ-cells through in situ exposure to biologically active substances that improveβ-cell survival,replication and insulin secretion,or to evoke the intrinsic adaptive mechanisms triggering the spontaneous non-β-toβ-cell ***“replacement”strategy implies transplantation ofβ-cells(as non-disintegrated pancreatic material or isolated donor islets)orβ-like cells obtained ex vivo from progenitors or mature somatic cells(for example,hepatocytes orα-cells)under the action of small-molecule inducers or by genetic *** believe that the huge volume of experimental and clinical studies will finally allow a safe and effective solution to a seemingly simple goal-restoration of the functionally activeβ-cells,the innermost hope of millions of people globally.

关键词： Pancreas islets of langerhans β-cells Regeneration Replacement Transplantation Reprogramming

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Islet cell transplantation as a cure for insulin dependent diabetes: current improvements in preserving islet cell mass and function

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Hepatobiliary & Pancreatic Diseases International 2003年第2期2卷 486-495页

作者： MagaliJ.Fontaine the Department of Pathology and Laboratory Medicine Medical University of South Carolina. Charleston SC 29425 USA

OBJECTIVE: To review the current progress of islet cell transplantation in patients with insulin-dependent diabetes, emphasizing on the difficulties with recovering and preserving islet cell mass and function, 30% of which is lost during the peri-transplantation period. RESULTS: The islet-cell isolation technique is perfected, but improvements are still progressing in two major directions: preservation of islet cells and tolerance induction. Optimum islet cell viability and function depends on appropriate revascularization of the islet graft and blockade of thrombus formation as well as cytokine and free radical release. Conditioning the islet cells in-vitro prior to transplantation to either upregulate VEGF expression or downregulate NF-kappa B transcription factor has proven to improve revascularization and to prevent islet cell apoptosis and cytokine-mediated damage. Tolerance induction is currently being best achieved by selecting and combining immunosuppressive agents such as monoclonal antibodies which target the major signaling molecules during immune activation, but which are least toxic to islet cells. CONCLUSIONS: Patients with insulin-dependent diabetes will greatly benefit from current developments in effective approaches to protect islets during the peritransplant period. Emerging interest in stem cell biology and differentiation may provide the ultimate solution to the problem of organ scarcity and islet cell protection from the peritransplant induced damage.

关键词： islets of langerhans transplantation graft function graft preservation type I diabetes

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Age-dependent changes in the exocytotic efficacy in Kir6.2 ablated mouse pancreatic β-cells

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Open Journal of Molecular and Integrative Physiology 2012年第3期2卷 51-60页

作者： Ernest Beaudelaire Tsiaze Ya-Chi Huang Lidija Krizancic Bombek Shi-Bing Yang Marko Jevsek Susumu Seino Marjan Slak Rupnik European Neuroscience Institute GottingenGermany Institute of Medical Science University of TorontoTorontoCanada Institute of Physiology Faculty of MedicineUniversity of MariborMariborSlovenia Howard Hughes Medical Institute San FranciscoUSA Division of Diabetes and Endocrinology Department of Internal MedicineKobe University Graduate School of MedicineKobeJapan

In this study, we aimed to examine the electrophysio- logical properties of β-cells in Kir6.2-/- mice using fresh pancreatic tissue slice preparation. This prepa-ration is advantageous since it preserves socio-cellular context of the β-cells. Using this novel approach we revisited basic morphology and used whole-cell patch-clamp to study electrical excitability as well as to assess the modulation of the late steps of the exocy-totic activity of β-cells by cytosolic [Ca2+] changes in control and Kir6.2-/- mice. We found that young Kir6.2-/- mice (2 - 4 weeks old) were hypoglycaemic while aged Kir6.2-/- mice (5 - 60 weeks old) were normo- or even hyper- glycaemic. Membrane ca-pacitance measurements show- ed more efficient Ca2+-secretion coupling in young Kir6.2-/- mice, but this coupling is significantly reduced in older Kir6.2-/- mice. We have found increased exo- cytotic efficacy induced by repetitive trains of depo- larization pulses which may result from higher cyto- solic [Ca2+] due to hyperexcitability in Kir6.2-/- mice. This condition in turn resulted in the reduced β-cell number and func-tion in the following weeks. Detailed assessment of the efficacy of Ca2+ dependent exocyto- sis in β-cell from Kir6.2-/- mice may contribute to our understanding of the pathophysiology of persistent hyperinsulinemia hypoglycemia of infancy (PHHI) and suggest potential alternative therapeutic approaches for PHHI patients.

关键词： islets of langerhans Insulin Hyperinsulinism Persistent Hyperinsulinemia Hypoglycemia of Infancy Ion Channels Patch-Clamp Techniques

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