Adenoviruses Expressing PDX-1, BETA2/NeuroD and MafA Induces the Transdifferentiation of Porcine Neonatal Pancreas Cell Clusters and Adult Pig Pancreatic Cells into Beta-Cells

You, Young-Hye; Ham, Dong-Sik; Park, Heon‐Seok; Rhee, Marie; Kim, Jiwon; Yoon, Kun‐Ho

doi:10.4093/dmj.2011.35.2.119

Cited by 15 publications

(13 citation statements)

References 20 publications

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“…Previous studies have demonstrated that differentiated insulinproducing cells from non-β-cells are useful sources to overcome the shortage of human islets for transplantation [16,[24][25][26][27]. In this study, we demonstrated that mouse small intestinal cells could be induced to differentiate into insulin-producing To improve the efficiency of transduction, we found a specific arterial delivery system for the induction of genes combined with PMB into the small intestine.…”

Section: Discussionmentioning

confidence: 81%

Generation of Insulin Expressing Cells in Mouse Small Intestine by Pdx1, MafA, and BETA2/NeuroD

Hyun¹,

Kim²,

Yoon³

2018

Diabetes

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Background:To develop surrogate insulin-producing cells for diabetes therapy, adult stem cells have been identified in various tissues and studied for their conversion into β-cells. Pancreatic progenitor cells are derived from the endodermal epithelium and formed in a manner similar to gut progenitor cells. Here, we generated insulin-producing cells from the intestinal epithelial cells that induced many of the specific pancreatic transcription factors using adenoviral vectors carrying three genes: PMB (pancreatic and duodenal homeobox 1 [Pdx1], V-maf musculoaponeurotic fibrosarcoma oncogene homolog A [MafA], and BETA2/NeuroD). Methods: By direct injection into the intestine through the cranial mesenteric artery, adenoviruses (Ad) were successfully delivered to the entire intestine. After virus injection, we could confirm that the small intestine of the mouse was appropriately infected with the Ad-Pdx1 and triple Ad-PMB. Results: Four weeks after the injection, insulin mRNA was expressed in the small intestine, and the insulin gene expression was induced in Ad-Pdx1 and Ad-PMB compared to control Ad-green fluorescent protein. In addition, the conversion of intestinal cells into insulin-expressing cells was detected in parts of the crypts and villi located in the small intestine. Conclusion: These data indicated that PMB facilitate the differentiation of mouse intestinal cells into insulin-expressing cells. In conclusion, the small intestine is an accessible and abundant source of surrogate insulin-producing cells.

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Section: Discussionmentioning

confidence: 81%

Generation of Insulin Expressing Cells in Mouse Small Intestine by Pdx1, MafA, and BETA2/NeuroD

Hyun¹,

Kim²,

Yoon³

2018

Diabetes

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“…It is important that transcription factors are turned on and off at appropriate times for determining cell fate. PDX1 alone has little activity or it induces other pancreatic cells; however, it becomes a potent factor when it interacts with NEUROD1 [37,38]. Another important transcription factor for β-cell-specific differentiation is MAFA [39][40][41][42].…”

Section: Discussionmentioning

confidence: 99%

Improvement of therapeutic capacity of insulin-producing cells trans-differentiated from human liver cells using engineered cell sheet

Lee

Seo

et al. 2020

Preprint

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Background: Although pancreatic islet transplantation therapy is ideal for diabetes patients, several hurdles have prevented it from becoming a standard treatment, including donor shortage and low engraftment efficacy. In this study, we prepared insulin-producing cells trans-differentiated from adult human liver cells as a new islet source. Also, cell sheets formation could improve differentiation efficiency and graft survival.Methods: Liver cells were expanded in vitro and trans-differentiated to IPCs using adenovirus vectors carrying human genes for PDX1, NEUROD1 and MAFA. IPCs were seeded on temperature-responsive culture dishes to form cell sheets. Differentiation efficiency were confirmed by ß cell-specific gene expression, insulin production, and immunohistochemistry. IPCs suspension was injected by portal vein (PV), and IPCs sheet was transplanted on the liver surface of the diabetic nude mouse. The therapeutic effect of IPC sheet was evaluated by comparing blood glucose control, weight gain, histological evaluation and hepatotoxicity with IPCs injection group. Also, cell biodistribution was assessed by in vivo/ex vivo fluorescence image tagging.Results: Insulin gene expression and protein production were significantly increased on IPC sheets compared with those in IPCs cultured on conventional culture dishes. Transplanted IPC sheets displayed significantly higher engraftment efficiency and fewer transplanted cells in other organs than injected IPCs, and also lower liver toxicity, improved blood glucose levels, and weight gain. One and two weeks following IPC sheet transplantation, immunohistochemical analyses of liver tissue revealed positive staining for PDX1 and insulin.Conclusions: In conclusion, cell sheet formation enhanced the differentiation function and maturation of IPCs in vitro. Additionally, parameters for clinical application such as distribution, therapeutic efficacy, and toxicity were favorable. The cell sheet technique may be used with IPCs derived from various cell sources in clinical applications.

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“…This concept has been tested both in vitro and in vivo. The adenovirus-mediated overexpression of Pdx1, NeuroD and MafA was shown to induce insulin gene expression in porcine neonatal pancreas non-endocrine cells but not in adult pig pancreatic cells [72]. Pdx1 transduction into human pancreatic ductal cells induced insulin gene expression [73].…”

Section: Pdx1 Neurod and Mafamentioning

confidence: 96%

β‐Cell differentiation and regeneration in type 1 diabetes

Ding

Gysemans

Mathieu

2013

Diabetes Obesity Metabolism

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Pancreatic insulin-producing β-cells have traditionally been viewed as a quiescent cell population. However, several recent lines of evidence indicated that like most tissues the β-cell mass is dynamically regulated with ongoing β-cell regeneration throughout life to replenish lost or damaged β-cells. In type 1 diabetes (T1D), this fine-tuned balance between β-cell death and β-cell renewal in the endocrine pancreas is lost and the deficit in β-cell mass is largely caused by autoimmune-mediated apoptosis. Currently, the concept that a cure for T1D will require both re-establishment of immunological tolerance along with replacement or regeneration of a functional β-cell mass in T1D patients is generally accepted. In this study our current understanding of the events directing β-cell replication, β-cell reprogramming from different cell types and β-cell regeneration is reviewed, in view of the results of various immunomodulatory strategies aiming at blocking autoimmune responses against pancreatic β-cells and at improving β-cell mass and function in subjects with T1D. Keywords: β-cells, regeneration, reprogramming, replication, type 1 diabetes Date submitted 21 March 2013; date of final acceptance 24 April 2013 IntroductionDiabetes mellitus is an epidemic around the globe that affects nearly 6% of the world's adult population with almost 80% of the totality in undeveloped territories. The World Health Organization estimates that the number of diabetics will increase from 366 million in 2011 to 552 million by 2030 (http://www.idf.org/media-events/pressreleases/2011/diabetes-atlas-5th-edition). Of all diagnosed cases of diabetes, type 1 diabetes (T1D) that results from a selective destruction of the pancreatic insulin-producing β-cells by CD4+ and CD8+ T cells recognizing many islet auto-antigens, accounts for 5-10% [1]. Although its onset is usually during infancy and puberty, it can occur at any age, even during late adulthood. By the time of diagnosis, about 70-80% of the β-cell mass is lost or damaged largely because of β-cell apoptosis. As a result, exogenous insulin supplementation is needed to promote tight glucose control and diminish the majority of chronic diabetic complications. However, insulin is not a cure for this chronic disease. Currently, it is generally accepted that a cure for overt T1D will require shutting off autoimmunity along with replenishment or stimulating regeneration of a functional β-cell mass in T1D subjects in order to improve blood glucose without treatment-derived adverse effects. However, at present it is unknown whether the existing immunotherapies that are able to restore normal glucose homeostasis in the preclinical and clinical setting of T1D act via β-cell regeneration (by β-cell replication, β-cell neogenesis from progenitors or by β-cell reprogramming/transdifferentiation from acinar-or α-cells)Correspondence to: Conny Gysemans, PhD, Laboratory of Clinical and Experimental Endocrinology (CEE), Campus Gasthuisberg O&N1, Katholieke Universiteit Leuven (KU LEUVEN), Herestraat 4...

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Adenoviruses Expressing PDX-1, BETA2/NeuroD and MafA Induces the Transdifferentiation of Porcine Neonatal Pancreas Cell Clusters and Adult Pig Pancreatic Cells into Beta-Cells

Cited by 15 publications

References 20 publications

Generation of Insulin Expressing Cells in Mouse Small Intestine by Pdx1, MafA, and BETA2/NeuroD

Generation of Insulin Expressing Cells in Mouse Small Intestine by Pdx1, MafA, and BETA2/NeuroD

Improvement of therapeutic capacity of insulin-producing cells trans-differentiated from human liver cells using engineered cell sheet

β‐Cell differentiation and regeneration in type 1 diabetes

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