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:10.1097/00007890-201211271-00319

Cited by 4 publications

(7 citation statements)

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“…Hepatocytes and pancreatic β-cells are both derived from endoderm during organogenesis and share common progenitors (Luo et al, 2014). 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, 2003;Gerace et al, 2013;Kojima et al, 2003). Other approaches have involved allogenic islet cell transplantation and differentiation of stem cells in vitro into insulin-producing cells followed by their implantation (Lenzen, 2008).…”

Section: Polyoxometalates Stimulated Differentiation Of Stem Cells Inmentioning

confidence: 99%

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: Polyoxometalates Stimulated Differentiation Of Stem Cells Inmentioning

confidence: 99%

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 have successfully used a LV, HMD, which has a murine stem cell virus promoter to deliver furin-cleavable insulin (INS-FUR) to the livers of STZ-diabetic rats, 18 NOD mice, 19 and pancreatectomized Westran pigs. 20 In these animal models, we observed spontaneous expression of β-cell transcription factors, formation of storage granules, and permanent reversal of diabetes.…”

Section: Selecting a Suitable Vector For Gene Transfermentioning

confidence: 92%

“…20 However, reproducible results were problematic in the large animal due to the complexity of the surgical approach. Subsequently, viral delivery of INS-FUR has become a popular choice for gene therapy, with a number of studies showing amelioration of hyperglycemia in rodent models.…”

Section: -101mentioning

confidence: 99%

“…13,14 In addition, gene transfer of pancreatic transcription factors and insulin for the production of "artificial" β-cells that are capable of synthesizing and secreting insulin in response to metabolic signals is a promising alternative. Two common methods of generating surrogate β-cells are the dedifferentiation and directed transdifferentiation of autologous or allogeneic cells ex vivo [15][16][17] followed by transplantation, and the in vivo [18][19][20] transdifferentiation of target tissue via gene transfer of transcription factors or insulin within viral vectors. Animal models have been used in T1D research since the discovery of insulin by Banting and Best in 1922 21 for studying the pathogenesis of the disease and its complications and for the discovery of new treatments.…”

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confidence: 99%

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Diabetes reversal via gene transfer: building on successes in animal models

Gerace¹,

Martiniello‐Wilks²,

Simpson³

2015

RRED

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Type 1 diabetes (T1D) is caused by the autoimmune destruction of the insulinproducing pancreatic β-cells. People with T1D manage their hyperglycemia using daily insulin injections; however, this does not prevent the development of long-term diabetic complications such as retinopathy, nephropathy, neuropathy, and various macrovascular disorders. Currently, the only "cure" for T1D is pancreas transplantation or islet-cell transplantation; however, this is hampered by the limited number of donors and the requirement for life-long immunosuppression. As a result, the need for alternative therapies is vital. One of the strategies employed to correct T1D is the use of gene transfer to generate the production of an "artificial" β-cell that is capable of secreting insulin in response to fluctuating glucose concentrations that normally occurs in people without T1D. The treatment of many diseases using cell and gene therapy is generating significant attention in the T1D research community; however, for a cell therapy to enter clinical trials, success and safety must first be shown in an appropriate animal model. Animal models have been used in diabetes research for over a century, have improved our understanding of the pathophysiology of diabetes, and have led to the discovery of useful drugs for the treatment of the disease. Currently, the nonobese diabetic mouse is the animal model of choice for the study of T1D as it most closely reflects disease development in humans. The aim of this review is to evaluate the success of cell and gene therapy to reverse T1D in animal models for future clinical application.

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“…Mindez nem váltott ki gyulladásos vagy egyéb reakciót, a májenzimek szintje nem emelkedett [15,16]. Hasonló experimentális eredményeket közöltek Elsner és mtsai, valamint Gerace és mtsai is [17,18].…”

Section: Langerhans-sziget-neogenezis In Vivo Körülmények Közöttunclassified

Őssejtterápia, β-sejt- és Langerhans-sziget-neogenezis: a jövő lehetséges terápiái 1-es típusú diabetesben?

Gerö

2016

Orvosi Hetilap

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Tökéletes normoglykaemia az 1-es típusú diabeteses betegekben csak sikeres pancreas-vagy Langerhans-szigettranszplantációval érhető el. A teljes pancreas sebészi beültetése invazív, a beteget jelentősen terhelő beavatkozás. A Langerhans-szigetek átültetése nem jelent nagyobb terhelést, de a szigetgraft túlélése korlátozott. Mindkét beavatkozás közös hátránya a nagyfokú donorhiány. A nehézségek egy része áthidalható lenne olyan "mesterséges β-sejtek" alkalmazásával, amelyek ultrastruktúrája azonos a természetes ß-sejtekével, és glükózdependens módon termelnek és választanak el inzulint. Jelenleg három ilyen módszer is rendelkezésünkre áll: β-sejt-képzés az exokrin pancreas ductalis sejtjeiből, β-sejt-képzés őssejtekből, valamint a transzkripciós faktorok virális bevitelével előidézett Langerhanssziget-neogenezis. A szerző e három módszerrel szerzett tapasztalatokat, experimentális eredményeket foglalja össze. Orv. Hetil, 2016, 157(19), 740-745.Kulcsszavak: 1-es típusú diabetes, mesterséges β-sejt, pluripotens őssejt, β-sejt-és szigetneogenezis Stem-cell therapy, β-cell-and islet cell-neogenesis: possible treatments of type 1 diabetes in the future?In type 1 diabetic patients perfect normoglycaemia can only be achieved by successful transplantation of the pancreas or Langerhans' islets. Surgical transplantation of the whole pancreas is an invasive operation exerting great burden on the patients. Transplantation of the islets of Langerhans does not burden the patients but the survival of the islet grafts is limited. Both interventions are hampered by the lack of donor organs. However, much of these difficulties could be overcome by the use of "artificial β-cells" which ought to have an ultrastructure identical with that of natural β-cells and produce and secrete insulin in a glucose dependent manner. At present three such methods are at our disposal: transformation of the ductal cells of the exocrine pancreas into β-cells, development of β-cells from stem-cells, and neogenesis of Langerhans' islets induced by viral delivery of transcription factors. The author summarises the experience and experimental results obtained with the use of the three methods. Rövidítések ActA = ActivinA; Btc = betacellulin; GLP-1 = glükagonszerű peptid-1; HNF = hepaticus nukleáris faktor; Ngn3 = neurogenin-3; NOD-egér = (non-obese diabetic mous) nem elhízott diabeteses egér; PD-L1 = programmed-death ligand1; SC-β = (stem-cell-derived β-cell) őssejt eredetű β-sejt; SPK = (simultaneous pancreas-kidney [transplantation]) szimultán pancreasvese [átültetés] Az 1-es típusú diabetes kialakulásának oka a β-sejtek ellen irányuló autoimmun folyamat, amely e sejtek pusztulásához és így az endogén inzulintermelés teljes és végle-ges megszűnéséhez vezet. E betegeknek tehát az életben maradáshoz inzulinterápiára van szükségük. Amíg azonban az endogén inzulinelválasztás szinte másodpercnyi pontossággal követi a vércukorszint változásait (és ezzel

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

Cited by 4 publications

References 0 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

Diabetes reversal via gene transfer: building on successes in animal models

Őssejtterápia, β-sejt- és Langerhans-sziget-neogenezis: a jövő lehetséges terápiái 1-es típusú diabetesben?

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