Journal articles on the topic 'Islet/β-cell replacement'
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1
Da Silva Xavier, Gabriela. "The Cells of the Islets of Langerhans." Journal of Clinical Medicine 7, no. 3 (March 12, 2018): 54. http://dx.doi.org/10.3390/jcm7030054.
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Islets of Langerhans are islands of endocrine cells scattered throughout the pancreas. A number of new studies have pointed to the potential for conversion of non-β islet cells in to insulin-producing β-cells to replenish β-cell mass as a means to treat diabetes. Understanding normal islet cell mass and function is important to help advance such treatment modalities: what should be the target islet/β-cell mass, does islet architecture matter to energy homeostasis, and what may happen if we lose a particular population of islet cells in favour of β-cells? These are all questions to which we will need answers for islet replacement therapy by transdifferentiation of non-β islet cells to be a reality in humans. We know a fair amount about the biology of β-cells but not quite as much about the other islet cell types. Until recently, we have not had a good grasp of islet mass and distribution in the human pancreas. In this review, we will look at current data on islet cells, focussing more on non-β cells, and on human pancreatic islet mass and distribution.
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Quizon, Michelle J., and Andrés J. García. "Engineering β Cell Replacement Therapies for Type 1 Diabetes: Biomaterial Advances and Considerations for Macroscale Constructs." Annual Review of Pathology: Mechanisms of Disease 17, no. 1 (January 24, 2022): 485–513. http://dx.doi.org/10.1146/annurev-pathol-042320-094846.
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While significant progress has been made in treatments for type 1 diabetes (T1D) based on exogenous insulin, transplantation of insulin-producing cells (islets or stem cell–derived β cells) remains a promising curative strategy. The current paradigm for T1D cell therapy is clinical islet transplantation (CIT)—the infusion of islets into the liver—although this therapeutic modality comes with its own limitations that deteriorate islet health. Biomaterials can be leveraged to actively address the limitations of CIT, including undesired host inflammatory and immune responses, lack of vascularization, hypoxia, and the absence of native islet extracellular matrix cues. Moreover, in efforts toward a clinically translatable T1D cell therapy, much research now focuses on developing biomaterial platforms at the macroscale, at which implanted platforms can be easily retrieved and monitored. In this review, we discuss how biomaterials have recently been harnessed for macroscale T1D β cell replacement therapies.
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Stephens, Clarissa Hernandez, Rachel A. Morrison, Madeline McLaughlin, Kara Orr, Sarah A. Tersey, J. Catharine Scott-Moncrieff, Raghavendra G. Mirmira, Robert V. Considine, and Sherry Voytik-Harbin. "Oligomeric collagen as an encapsulation material for islet/β-cell replacement: effect of islet source, dose, implant site, and administration format." American Journal of Physiology-Endocrinology and Metabolism 319, no. 2 (August 1, 2020): E388—E400. http://dx.doi.org/10.1152/ajpendo.00066.2020.
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Replacement of islets/β-cells that provide long-lasting glucose-sensing and insulin-releasing functions has the potential to restore extended glycemic control in individuals with type 1 diabetes. Unfortunately, persistent challenges preclude such therapies from widespread clinical use, including cumbersome administration via portal vein infusion, significant loss of functional islet mass upon administration, limited functional longevity, and requirement for systemic immunosuppression. Previously, fibril-forming type I collagen (oligomer) was shown to support subcutaneous injection and in situ encapsulation of syngeneic islets within diabetic mice, with rapid (<24 h) reversal of hyperglycemia and maintenance of euglycemia for beyond 90 days. Here, we further evaluated this macroencapsulation strategy, defining effects of islet source (allogeneic and xenogeneic) and dose (500 and 800 islets), injection microenvironment (subcutaneous and intraperitoneal), and macrocapsule format (injectable and preformed implantable) on islet functional longevity and recipient immune response. We found that xenogeneic rat islets functioned similarly to or better than allogeneic mouse islets, with only modest improvements in longevity noted with dosage. Additionally, subcutaneous injection led to more consistent encapsulation outcomes along with improved islet health and longevity, compared with intraperitoneal administration, whereas no significant differences were observed between subcutaneous injectable and preformed implantable formats. Collectively, these results document the benefits of incorporating natural collagen for islet/β-cell replacement therapies.
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Burns, Christopher J., Shanta J. Persaud, and Peter M. Jones. "Stem cell therapy for diabetes: do we need to make beta cells?" Journal of Endocrinology 183, no. 3 (December 2004): 437–43. http://dx.doi.org/10.1677/joe.1.05981.
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Type 1 diabetes can now be ameliorated by islet transplantation, although this treatment is restricted by the insufficient supply of islet tissue. The need for an essentially limitless supply of a substitute for primary human islets of Langerhans has led to research into the suitability of stem/progenitor cells to generate insulin-producing cells to use in replacement therapies for diabetes. Although there has been much research in this area, an efficient and reproducible protocol for the differentiation of stem cells into functional insulin-secreting β-cells that are suitable for transplantation has yet to be reported. In this commentary we examine the minimum requirements for replacement β-cells and outline some of the potential sources of these cells. We also argue that the generation of the ‘perfect’ beta-cell may not necessarily lead to the most suitable tissue for transplantation.
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Brusko, Todd M., Holger A. Russ, and Cherie L. Stabler. "Strategies for durable β cell replacement in type 1 diabetes." Science 373, no. 6554 (July 29, 2021): 516–22. http://dx.doi.org/10.1126/science.abh1657.
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Technological advancements in blood glucose monitoring and therapeutic insulin administration have improved the quality of life for people with type 1 diabetes. However, these efforts fall short of replicating the exquisite metabolic control provided by native islets. We examine the integrated advancements in islet cell replacement and immunomodulatory therapies that are coalescing to enable the restoration of endogenous glucose regulation. We highlight advances in stem cell biology and graft site design, which offer innovative sources of cellular material and improved engraftment. We also cover cutting-edge approaches for preventing allograft rejection and recurrent autoimmunity. These insights reflect a growing understanding of type 1 diabetes etiology, β cell biology, and biomaterial design, together highlighting therapeutic opportunities to durably replace the β cells destroyed in type 1 diabetes.
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Carlotti, Françoise, Arnaud Zaldumbide, Johanne H. Ellenbroek, H. Siebe Spijker, Rob C. Hoeben, and Eelco J. de Koning. "β-Cell Generation: Can Rodent Studies Be Translated to Humans?" Journal of Transplantation 2011 (2011): 1–15. http://dx.doi.org/10.1155/2011/892453.
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β-cell replacement by allogeneic islet transplantation is a promising approach for patients with type 1 diabetes, but the shortage of organ donors requires new sources ofβcells. Islet regenerationin vivoand generation ofβ-cellsex vivofollowed by transplantation represent attractive therapeutic alternatives to restore theβ-cell mass. In this paper, we discuss different postnatal cell types that have been envisaged as potential sources for futureβ-cell replacement therapy. The ultimate goal being translation to the clinic, a particular attention is given to the discrepancies between findings from studies performed in rodents (bothex vivoon primary cells andin vivoon animal models), when compared with clinical data and studies performed on human cells.
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Ermakova, P. S., E. I. Cherkasova, N. A. Lenshina, A. N. Konev, M. A. Batenkin, S. A. Chesnokov, D. M. Kuchin, E. V. Zagainova, V. E. Zagainov, and A. V. Kashina. "Modern pancreatic islet encapsulation technologies for the treatment of type 1 diabetes." Russian Journal of Transplantology and Artificial Organs 23, no. 4 (October 22, 2021): 95–109. http://dx.doi.org/10.15825/1995-1191-2021-4-95-109.
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The review includes the results of analytical research on the problem of application of pancreatic islet encapsulation technologies for compensation of type 1 diabetes. We present a review of modern encapsulation technologies, approaches to encapsulation strategies, insulin replacement technologies: auto-, allo- and xenotransplantation; prospects for cell therapy for insulin-dependent conditions; modern approaches to β-cell encapsulation, possibilities of optimization of encapsulation biomaterials to increase survival of transplanted cells and reduce adverse consequences for the recipient. The main problems that need to be solved for effective transplantation of encapsulated islets of Langerhans are identified and the main strategies for translating the islet encapsulation technology into medical reality are outlined.
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Berney, Thierry, Olle Korsgren, Andrew Posselt, and Antonello Pileggi. "Islet Transplantation &β-Cell Replacement Therapies for Diabetes." Journal of Transplantation 2011 (2011): 1–2. http://dx.doi.org/10.1155/2011/157840.
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Shinzato, Misaki, Chika Miyagi-Shiohira, Kazuho Kuwae, Kai Nishime, Yoshihito Tamaki, Tasuku Yonaha, Mayuko Sakai-Yonaha, et al. "AP39, a Mitochondrial-Targeted H2S Donor, Improves Porcine Islet Survival in Culture." Journal of Clinical Medicine 11, no. 18 (September 14, 2022): 5385. http://dx.doi.org/10.3390/jcm11185385.
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The rapid deterioration of transplanted islets in culture is a well-established phenomenon. We recently reported that pancreas preservation with AP39 reduces reactive oxygen species (ROS) production and improves islet graft function. In this study, we investigated whether the addition of AP39 to the culture medium could reduce isolated islet deterioration and improve islet function. Isolated islets from porcine pancreata were cultured with 400 nM AP39 or without AP39 at 37 °C. After culturing for 6–72 h, the islet equivalents of porcine islets in the AP39(+) group were significantly higher than those in the AP39(−) group. The islets in the AP39(+) group exhibited significantly decreased levels of ROS production compared to the islets in the AP39(−) group. The islets in the AP39(+) group exhibited significantly increased mitochondrial membrane potential compared to the islets in the AP39(−) group. A marginal number (1500 IEs) of cultured islets from each group was then transplanted into streptozotocin-induced diabetic mice. Culturing isolated islets with AP39 improved islet transplantation outcomes in streptozotocin-induced diabetic mice. The addition of AP39 in culture medium reduces islet deterioration and furthers the advancements in β-cell replacement therapy.
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Niu, Guoguang, John P. McQuilling, Yu Zhou, Emmanuel C. Opara, Giuseppe Orlando, and Shay Soker. "In VitroProliferation of Porcine Pancreatic Islet Cells forβ-Cell Therapy Applications." Journal of Diabetes Research 2016 (2016): 1–8. http://dx.doi.org/10.1155/2016/5807876.
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β-Cell replacement through transplantation is the only curative treatment to establish a long-term stable euglycemia in diabetic patients. Owing to the shortage of donor tissue, attempts are being made to develop alternative sources of insulin-secreting cells. Stem cells differentiation and reprograming as well as isolating pancreatic progenitors from different sources are some examples; however, no approach has yet yielded a clinically relevant solution. Dissociated islet cells that are cultured in cell numbers byin vitroproliferation provide a promising platform for redifferentiation towardsβ-cells phenotype. In this study, we cultured islet-derived cellsin vitroand examined the expression ofβ-cell genes during the proliferation. Islets were isolated from porcine pancreases and enzymatically digested to dissociate the component cells. The cells proliferated well in tissue culture plates and were subcultured for no more than 5 passages. Only 10% of insulin expression, as measured by PCR, was preserved in each passage. High glucose media enhanced insulin expression by about 4–18 fold, suggesting a glucose-dependent effect in the proliferated islet-derived cells. The islet-derived cells also expressed other pancreatic genes such as Pdx1, NeuroD, glucagon, and somatostatin. Taken together, these results indicate that pancreatic islet-derived cells, proliferatedin vitro, retained the expression capacity for key pancreatic genes, thus suggesting that the cells may be redifferentiated into insulin-secretingβ-like cells.
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Espona-Noguera, Albert, Jesús Ciriza, Alberto Cañibano-Hernández, Gorka Orive, Rosa María Hernández, Laura Saenz del Burgo, and Jose Pedraz. "Review of Advanced Hydrogel-Based Cell Encapsulation Systems for Insulin Delivery in Type 1 Diabetes Mellitus." Pharmaceutics 11, no. 11 (November 12, 2019): 597. http://dx.doi.org/10.3390/pharmaceutics11110597.
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: Type 1 Diabetes Mellitus (T1DM) is characterized by the autoimmune destruction of β-cells in the pancreatic islets. In this regard, islet transplantation aims for the replacement of the damaged β-cells through minimally invasive surgical procedures, thereby being the most suitable strategy to cure T1DM. Unfortunately, this procedure still has limitations for its widespread clinical application, including the need for long-term immunosuppression, the lack of pancreas donors and the loss of a large percentage of islets after transplantation. To overcome the aforementioned issues, islets can be encapsulated within hydrogel-like biomaterials to diminish the loss of islets, to protect the islets resulting in a reduction or elimination of immunosuppression and to enable the use of other insulin-producing cell sources. This review aims to provide an update on the different hydrogel-based encapsulation strategies of insulin-producing cells, highlighting the advantages and drawbacks for a successful clinical application.
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Brown, Melissa L., Danielle Andrzejewski, Amy Burnside, and Alan L. Schneyer. "Activin Enhances α- to β-Cell Transdifferentiation as a Source For β-Cells In Male FSTL3 Knockout Mice." Endocrinology 157, no. 3 (January 4, 2016): 1043–54. http://dx.doi.org/10.1210/en.2015-1793.
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Abstract Diabetes results from inadequate β-cell number and/or function to control serum glucose concentrations so that replacement of lost β-cells could become a viable therapy for diabetes. In addition to embryonic stem cell sources for new β-cells, evidence for transdifferentiation/reprogramming of non-β-cells to functional β-cells is accumulating. In addition, de-differentiation of β-cells observed in diabetes and their subsequent conversion to α-cells raises the possibility that adult islet cell fate is malleable and controlled by local hormonal and/or environmental cues. We previously demonstrated that inactivation of the activin antagonist, follistatin-like 3 (FSTL3) resulted in β-cell expansion and improved glucose homeostasis in the absence of β-cell proliferation. We recently reported that activin directly suppressed expression of critical α-cell genes while increasing expression of β-cell genes, supporting the hypothesis that activin is one of the local hormones controlling islet cell fate and that increased activin signaling accelerates α- to β-cell transdifferentiation. We tested this hypothesis using Gluc-Cre/yellow fluorescent protein (YFP) α-cell lineage tracing technology combined with FSTL3 knockout (KO) mice to label α-cells with YFP. Flow cytometry was used to quantify unlabeled and labeled α- and β-cells. We found that Ins+/YFP+ cells were significantly increased in FSTL3 KO mice compared with wild type littermates. Labeled Ins+/YFP+ cells increased significantly with age in FSTL3 KO mice but not wild type littermates. Sorting results were substantiated by counting fluorescently labeled cells in pancreatic sections. Activin treatment of isolated islets significantly increased the number of YFP+/Ins+ cells. These results suggest that α- to β-cell transdifferentiation is influenced by activin signaling and may contribute substantially to β-cell mass.
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Cole, Lori, Miranda Anderson, Parker B. Antin, and Sean W. Limesand. "One process for pancreatic β-cell coalescence into islets involves an epithelial–mesenchymal transition." Journal of Endocrinology 203, no. 1 (July 16, 2009): 19–31. http://dx.doi.org/10.1677/joe-09-0072.
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Islet replacement is a promising therapy for treating diabetes mellitus, but the supply of donor tissue for transplantation is limited. To overcome this limitation, endocrine tissue can be expanded, but this requires an understanding of normal developmental processes that regulate islet formation. In this study, we compare pancreas development in sheep and human, and provide evidence that an epithelial–mesenchymal transition (EMT) is involved in β-cell differentiation and islet formation. Transcription factors know to regulate pancreas formation, pancreatic duodenal homeobox factor 1, neurogenin 3, NKX2-2, and NKX6-1, which were expressed in the appropriate spatial and temporal pattern to coordinate pancreatic bud outgrowth and direct endocrine cell specification in sheep. Immunofluorescence staining of the developing pancreas was used to co-localize insulin and epithelial proteins (cytokeratin, E-cadherin, and β-catenin) or insulin and a mesenchymal protein (vimentin). In sheep, individual β-cells become insulin-positive in the progenitor epithelium, then lose epithelial characteristics, and migrate out of the epithelial layer to form islets. As β-cells exit the epithelial progenitor cell layer, they acquire mesenchymal characteristics, shown by their acquisition of vimentin. In situ hybridization expression analysis of the SNAIL family members of transcriptional repressors (SNAIL1, -2, and -3; listed as SNAI1, -2, -3 in the HUGO Database) showed that each of the SNAIL genes was expressed in the ductal epithelium during development, and SNAIL-1 and -2 were co-expressed with insulin. Our findings provide strong evidence that the movement of β-cells from the pancreatic ductal epithelium involves an EMT.
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Bellofatto, Kevin, Beat Moeckli, Charles-Henri Wassmer, Margaux Laurent, Graziano Oldani, Axel Andres, Thierry Berney, Ekaterine Berishvili, Christian Toso, and Andrea Peloso. "Bioengineered Islet Cell Transplantation." Current Transplantation Reports 8, no. 2 (March 13, 2021): 57–66. http://dx.doi.org/10.1007/s40472-021-00318-1.
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Abstract Purpose of Review β cell replacement via whole pancreas or islet transplantation has greatly evolved for the cure of type 1 diabetes. Both these strategies are however still affected by several limitations. Pancreas bioengineering holds the potential to overcome these hurdles aiming to repair and regenerate β cell compartment. In this review, we detail the state-of-the-art and recent progress in the bioengineering field applied to diabetes research. Recent Findings The primary target of pancreatic bioengineering is to manufacture a construct supporting insulin activity in vivo. Scaffold-base technique, 3D bioprinting, macro-devices, insulin-secreting organoids, and pancreas-on-chip represent the most promising technologies for pancreatic bioengineering. Summary There are several factors affecting the clinical application of these technologies, and studies reported so far are encouraging but need to be optimized. Nevertheless pancreas bioengineering is evolving very quickly and its combination with stem cell research developments can only accelerate this trend.
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Pathak, Varun, Nupur Madhur Pathak, Christina L. O’Neill, Jasenka Guduric-Fuchs, and Reinhold J. Medina. "Therapies for Type 1 Diabetes: Current Scenario and Future Perspectives." Clinical Medicine Insights: Endocrinology and Diabetes 12 (January 2019): 117955141984452. http://dx.doi.org/10.1177/1179551419844521.
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Type 1 diabetes (T1D) is caused by autoimmune destruction of insulin-producing β cells located in the endocrine pancreas in areas known as islets of Langerhans. The current standard-of-care for T1D is exogenous insulin replacement therapy. Recent developments in this field include the hybrid closed-loop system for regulated insulin delivery and long-acting insulins. Clinical studies on prediction and prevention of diabetes-associated complications have demonstrated the importance of early treatment and glucose control for reducing the risk of developing diabetic complications. Transplantation of primary islets offers an effective approach for treating patients with T1D. However, this strategy is hampered by challenges such as the limited availability of islets, extensive death of islet cells, and poor vascular engraftment of islets post-transplantation. Accordingly, there are considerable efforts currently underway for enhancing islet transplantation efficiency by harnessing the beneficial actions of stem cells. This review will provide an overview of currently available therapeutic options for T1D, and discuss the growing evidence that supports the use of stem cell approaches to enhance therapeutic outcomes.
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Noguchi, Hirofumi, Koichi Oishi, Michiko Ueda, Hiroshi Yukawa, Shuji Hayashi, Naoya Kobayashi, Marlon F. Levy, and Shinichi Matusmoto. "Establishment of Mouse Pancreatic Stem Cell Line." Cell Transplantation 18, no. 5-6 (May 2009): 563–72. http://dx.doi.org/10.1177/096368970901805-612.
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β-Cell replacement therapy via islet transplantation is a promising possibility for the optimal treatment of type 1 diabetes. However, such an approach is severely limited by the shortage of donor organs. Pancreatic stem/progenitor cells could become a useful target for β-cell replacement therapy in diabetic patients because the cells are abundantly available in the pancreas of these patients and in donor organs. In this study, we established a mouse pancreatic stem cell line without genetic manipulation. The duct-rich population after islet isolation was inoculated into 96-well plates in limiting dilution. From over 200 clones, 15 clones were able to be cultured for over 3 months. The HN#13 cells, which had the highest expression of insulin mRNA after induction, expressed PDX-1 transcription factor, glucagon-like peptide-1 (GLP-1) receptor, and cytokeratin-19 (duct-like cells). These cells continue to divide actively beyond the population doubling level (PDL) of 300. Exendin-4 treatment and transduction of PDX-1 and NeuroD proteins by protein transduction technology in HN#13 cells induced insulin and pancreas-related gene expression. This cell line could be useful for analyzing pancreatic stem cell differentiation. Moreover, the isolation technique might be useful for identification and isolation of human pancreatic stem/progenitor cells.
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Tse, Hubert M., Veronika Kozlovskaya, Eugenia Kharlampieva, and Chad S. Hunter. "Minireview: Directed Differentiation and Encapsulation of Islet β-Cells—Recent Advances and Future Considerations." Molecular Endocrinology 29, no. 10 (October 1, 2015): 1388–99. http://dx.doi.org/10.1210/me.2015-1085.
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Abstract Diabetes mellitus has rapidly become a 21st century epidemic with the promise to create vast economic and health burdens, if left unchecked. The 2 major forms of diabetes arise from unique causes, with outcomes being an absolute (type 1) or relative (type 2) loss of functional pancreatic islet β-cell mass. Currently, patients rely on exogenous insulin and/or other pharmacologies that restore glucose homeostasis. Although these therapies have prolonged countless lives over the decades, the striking increases in both type 1 and type 2 diabetic diagnoses worldwide suggest a need for improved treatments. To this end, islet biologists are developing cell-based therapies by which a patient's lost insulin-producing β-cell mass is replenished. Pancreatic or islet transplantation from cadaveric donors into diabetic patients has been successful, yet the functional islet demand far surpasses supply. Thus, the field has been striving toward transplantation of renewable in vitro-derived β-cells that can restore euglycemia. Challenges have been numerous, but progress over the past decade has generated much excitement. In this review we will summarize recent findings that have placed us closer than ever to β-cell replacement therapies. With the promise of cell-based diabetes therapies on the horizon, we will also provide an overview of cellular encapsulation technologies that will deliver critical protection of newly implanted cells.
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Norris, Andrew W., Katie Larson Ode, Lina Merjaneh, Srinath Sanda, Yaling Yi, Xingshen Sun, John F. Engelhardt, and Rebecca L. Hull. "Survival in a bad neighborhood: pancreatic islets in cystic fibrosis." Journal of Endocrinology 241, no. 1 (April 2019): R35—R50. http://dx.doi.org/10.1530/joe-18-0468.
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In cystic fibrosis (CF), ductal plugging and acinar loss result in rapid decline of exocrine pancreatic function. This destructive process results in remodeled islets, with only a modest reduction in insulin-producing β cells. However, β-cell function is profoundly impaired, with decreased insulin release and abnormal glucose tolerance being present even in infants with CF. Ultimately, roughly half the CF subjects develop diabetes (termed CF-related diabetes (CFRD)). Importantly, CFRD increases CF morbidity and mortality via worsening catabolism and pulmonary disease. Current accepted treatment options for CFRD are aimed at insulin replacement, thereby improving glycemia as well as preventing nutritional losses and lung decline. CFRD is a unique form of diabetes with a distinct pathophysiology that is as yet incompletely understood. Recent studies highlight emerging areas of interest. First, islet inflammation and lymphocyte infiltration are common even in young children with CF and may contribute to β-cell failure. Second, controversy exists in the literature regarding the presence/importance of β-cell intrinsic functions of CFTR and its direct role in modulating insulin release. Third, loss of the CF transmembrane conductance regulator (CFTR) from pancreatic ductal epithelium, the predominant site of its synthesis, results in paracrine effects that impair insulin release. Finally, the degree of β-cell loss in CFRD does not appear sufficient to explain the deficit in insulin release. Thus, it may be possible to enhance the function of the remaining β-cells using strategies such as targeting islet inflammation or ductal CFTR deficiency to effectively treat or even prevent CFRD.
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Petry, Florian, and Denise Salzig. "Large-Scale Production of Size-Adjusted β-Cell Spheroids in a Fully Controlled Stirred-Tank Reactor." Processes 10, no. 5 (April 27, 2022): 861. http://dx.doi.org/10.3390/pr10050861.
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For β-cell replacement therapies, one challenge is the manufacturing of enough β-cells (Edmonton protocol for islet transplantation requires 0.5–1 × 106 islet equivalents). To maintain their functionality, β-cells should be manufactured as 3D constructs, known as spheroids. In this study, we investigated whether β-cell spheroid manufacturing can be addressed by a stirred-tank bioreactor (STR) process. STRs are fully controlled bioreactor systems, which allow the establishment of robust, larger-scale manufacturing processes. Using the INS-1 β-cell line as a model for process development, we investigated the dynamic agglomeration of β-cells to determine minimal seeding densities, spheroid strength, and the influence of turbulent shear stress. We established a correlation to exploit shear forces within the turbulent flow regime, in order to generate spheroids of a defined size, and to predict the spheroid size in an STR by using the determined spheroid strength. Finally, we transferred the dynamic agglomeration process from shaking flasks to a fully controlled and monitored STR, and tested the influence of three different stirrer types on spheroid formation. We achieved the shear stress-guided production of up to 22 × 106 ± 2 × 106 viable and functional β-cell spheroids per liter of culture medium, which is sufficient for β-cell therapy applications.
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Milanesi, Anna, Jang-Won Lee, Qijin Xu, Laura Perin, and John S. Yu. "Differentiation of nestin-positive cells derived from bone marrow into pancreatic endocrine and ductal cells in vitro." Journal of Endocrinology 209, no. 2 (February 17, 2011): 193–201. http://dx.doi.org/10.1530/joe-10-0344.
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Promising results of pancreatic islet transplantation to treat type 1 diabetes mellitus, combined with severe shortage of donor pancreata, have spurred efforts to generate pancreatic islet-like cells and insulin-producing β-cells from various progenitor populations. In this study, we show for the first time that multipotent nestin-positive stem cells selected from rat bone marrow can be differentiated into pancreatic ductal and insulin-producing β-cells in vitro. We report an effective multistep protocol in a serum-free system, which could efficiently induce β-cell differentiation from multipotent nestin-positive bone marrow stem cells. To enhance the induction and differentiation toward pancreatic lineage we used trichostatin A, an important regulator of chromatin remodeling, and 5-aza 2′ deoxycytidine, an inhibitor of DNA methylase. All-trans retinoic acid was then utilized to promote pancreatic differentiation. We sequentially induced important transcription factor genes, such as Pdx1, Ngn3, and Pax6, following the in vivo development timeline of the pancreas in rats. Furthermore, in the final stage with the presence of nicotinamide, the induced cells expressed islet and ductal specific markers. The differentiated cells not only expressed insulin and glucose transporter 2, but also displayed a glucose-responsive secretion of the hormone. Our results delineate a new model system to study islet neogenesis and possible pharmaceutical targets. Nestin-positive bone marrow stem cells may be therapeutically relevant for β-cell replacement in type 1 diabetes.
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Bonner-Weir, Susan, and Gordon C. Weir. "Strategies for β-cell replacement in diabetes: obtaining and protecting islet tissue." Current Opinion in Endocrinology & Diabetes 8, no. 4 (August 2001): 213–18. http://dx.doi.org/10.1097/00060793-200108000-00008.
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Burrack, Adam L., Kevin Osum, Kristen Pauken, and Brian Fife. "Exploiting T cell co-inhibition to delay autoimmune disease recurrence." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 70.20. http://dx.doi.org/10.4049/jimmunol.196.supp.70.20.
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Abstract Type 1 diabetes (T1D) results from T cell-mediated destruction of insulin-producing pancreatic β cells. Individuals with long-term disease are at risk of developing life-threatening complications. β cell replacement is a therapy for T1D but is limited by recurrent autoreactive T cell targeted β cell death. Thus, β cells better equipped to inhibit local T cell responses may survive longer in autoimmune recipients. Programmed-death 1 (PD-1) signaling through its ligand PD-L1 inhibits T cells, and may serve as a prominent defense in T1D. Using flow cytometric analysis, in the absence of T cells in NOD.RAG−/− mice we do not detect β cell PD-L1 expression. However, with T cells, we observed an increased proportion of β cells expressing PD-L1 in female non-obese diabetic (NOD) mice which had not developed diabetes. In addition, the majority of remaining live β cells at diabetes onset in NOD mice continue to express high levels of PD-L1. These three situations suggest that islet β cells may increase PD-L1 expression as a last line of defense to limit infiltrating T cell mediated destruction. To manipulate β cell PD-L1 expression prior to transplantation, we screened a panel of diabetes-related cytokines and found that IFN-γ enhances β cell PD-L1 expression. Unfortunately, islet transplant survival was not prolonged, which we hypothesized was due to enhanced MHC class I expression, facilitating CD8+ T cell-mediated killing. We therefore de-coupled PD-L1 from enhanced MHC I expression. Using this approach, enforced β cell PD-L1 expression delays disease recurrence. These data support our hypothesis that β cells expressing T cell co-inhibitory molecules, like PD-L1, can locally inhibit autoreactive T cells which may prevent transplant destruction.
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Zhang, Yichen, Yutian Lei, Mohsen Honarpisheh, Elisabeth Kemter, Eckhard Wolf, and Jochen Seissler. "Butyrate and Class I Histone Deacetylase Inhibitors Promote Differentiation of Neonatal Porcine Islet Cells into Beta Cells." Cells 10, no. 11 (November 19, 2021): 3249. http://dx.doi.org/10.3390/cells10113249.
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Neonatal porcine islets-like clusters (NPICCs) are a promising source for cell therapy of type 1 diabetes. Freshly isolated NPICCs are composed of progenitor cells and endocrine cells, which undergo a maturation process lasting several weeks until the normal beta cell function has developed. Here, we investigated the effects of short-chain fatty acids on the maturation of islet cells isolated from two to three day-old piglets. NPICCs were cultivated with acetate, butyrate and propionate (0–2000 µM) for one to eight days. Incubation with butyrate resulted in a significant upregulation of insulin gene expression and an increased beta cell number, whereas acetate or propionate had only marginal effects. Treatment with specific inhibitors of G-protein-coupled receptor GPR41 (β-hydroxybutyrate) and/or GPR43 (GPLG0974) did not abolish butyrate induced insulin expression. However, incubation of NPICCs with class I histone deacetylase inhibitors (HDACi) mocetinostat and MS275, but not selective class II HDACi (TMP269, MC1568) mimicked the butyrate effect on beta cell differentiation. Our study revealed that butyrate treatment has the capacity to increase the number of beta cells, which may be predominantly mediated through its HDAC inhibitory activity. Butyrate and specific class I HDAC inhibitors may represent beneficial supplements to promote differentiation of neonatal porcine islet cells towards beta cells for cell replacement therapies.
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Sahu, Subhshri, David Tosh, and Anandwardhan A. Hardikar. "New sources of β-cells for treating diabetes." Journal of Endocrinology 202, no. 1 (May 5, 2009): 13–16. http://dx.doi.org/10.1677/joe-09-0097.
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The treatment of diabetes by islet transplantation is presently hampered by the shortage of organ donors. The generation of insulin-producing cells is therefore a major objective in the long-term goal of curing diabetes. Alternative sources of pancreatic β-cells include existing pancreatic cells, embryonic stem cells, and cells from other tissues such as liver. This commentary considers evidence for two new sources of β-cells: intrahepatic biliary epithelial cells and gall bladder epithelium. These observations raise the possibility that a patient's own cells may be used as a source of insulin-producing cells for cell replacement in diabetes.
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Rathod, Sanjay. "Novel Insights into the Immunotherapy-Based Treatment Strategy for Autoimmune Type 1 Diabetes." Diabetology 3, no. 1 (February 7, 2022): 79–96. http://dx.doi.org/10.3390/diabetology3010007.
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Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing pancreatic β-cells by their own immune system, resulting in lifelong insulin deficiency. Continuous exogenous insulin replacement therapy is the current standard of care for T1D. Transplantation of primary pancreatic islets or the entire pancreas is a viable remedy for managing patients with autoimmune T1D. However, this strategy is not feasible due to several obstacles, including a scarcity of donors, islet cells, and poor vascular engraftment of islets post-transplantation, as well as the need for prolonged immune suppression. Innovative approaches must be developed to counteract pancreatic β-cell destruction and salvage endogenic insulin production, thereby regulating blood glucose levels. This review includes an overview of autoimmune T1D, immune cells involved in T1D pathophysiology, and immunotherapy-based strategies to treat and prevent autoimmune T1D. Recent immunotherapy progress toward targeting pancreatic islet-specific immune pathways tangled tolerance has fueled the advancement of therapies that may allow for the prevention or reversal of this autoimmune T1D while avoiding other adverse reactions associated with the previous attempt, which was mostly immunosuppressive. As a result, significant efforts are currently underway to improve the efficacy of immunotherapy-based approaches by leveraging the beneficial actions of immune cells, specifically effector CD4+, CD8+, and regulatory T cells. This review will provide an overview of currently available immune-based therapeutic options for T1D and will examine the growing evidence that supports the use of immune cell-based approaches to improve therapeutic outcomes in the prevention or reversal of autoimmune T1D.
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Yang, Kisuk, Miseon Lee, Peter Anthony Jones, Sophie S. Liu, Angela Zhou, Jun Xu, Vedagopuram Sreekanth, et al. "A 3D culture platform enables development of zinc-binding prodrugs for targeted proliferation of β cells." Science Advances 6, no. 47 (November 2020): eabc3207. http://dx.doi.org/10.1126/sciadv.abc3207.
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Advances in treating β cell loss include islet replacement therapies or increasing cell proliferation rate in type 1 and type 2 diabetes, respectively. We propose developing multiple proliferation-inducing prodrugs that target high concentration of zinc ions in β cells. Unfortunately, typical two-dimensional (2D) cell cultures do not mimic in vivo conditions, displaying a markedly lowered zinc content, while 3D culture systems are laborious and expensive. Therefore, we developed the Disque Platform (DP)—a high-fidelity culture system where stem cell–derived β cells are reaggregated into thin, 3D discs within 2D 96-well plates. We validated the DP against standard 2D and 3D cultures and interrogated our zinc-activated prodrugs, which release their cargo upon zinc chelation—so preferentially in β cells. Through developing a reliable screening platform that bridges the advantages of 2D and 3D culture systems, we identified an effective hit that exhibits 2.4-fold increase in β cell proliferation compared to harmine.
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Pylaev, T. E., I. V. Smyshlyaeva, and E. B. Popyhova. "Regeneration of β-cells of the islet apparatus of the pancreas. Literature review." Diabetes mellitus 25, no. 4 (August 29, 2022): 395–404. http://dx.doi.org/10.14341/dm12872.
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Diabetes of both type 1 and type 2 is characterized by a progressive loss of β-cell mass, which contributes to the disruption of glucose homeostasis. The optimal antidiabetic therapy would be simple replacement of lost cells, but at present, many researchers have shown that the pancreas (PZ) of adults has a limited regenerative potential. In this regard, significant efforts of researchers are directed to methods of inducing the proliferation of β-cells, stimulating the formation of β-cells from alternative endogenous sources and/or the generation of β-cells from pluripotent stem cells. Factors that regulate β-cell regeneration under physiological or pathological conditions, such as mediators, transcription factors, signaling pathways and potential pharmaceuticals, are also being intensively studied. In this review, we consider recent scientific studies carried out in the field of studying the development and regeneration of insulin-producing cells obtained from exogenous and endogenous sources and their use in the treatment of diabetes. The literature search while writing this review was carried out using the databases of the RSIC, CyberLeninka, Scopus, Web of Science, MedLine, PubMed for the period from 2005 to 2021. using the following keywords: diabetes mellitus, pancreas, regeneration, β-cells, stem cells, diabetes therapy.
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Docherty, Kevin. "Pancreatic stellate cells can form new β-like cells." Biochemical Journal 421, no. 2 (June 26, 2009): e1-e4. http://dx.doi.org/10.1042/bj20090779.
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Regenerative medicine, including cell-replacement strategies, may have an important role in the treatment of Type 1 and Type 2 diabetes, both of which are associated with decreased islet cell mass. To date, significant progress has been made in deriving insulin-secreting β-like cells from human ES (embryonic stem) cells. However, the cells are not fully differentiated, and there is a long way to go before they could be used as a replenishable supply of insulin-secreting β-cells for transplantation. For this reason, adult pancreatic stem cells are seen as an alternative source that could be expanded and differentiated ex vivo, or induced to form new islets in situ. In this issue of the Biochemical Journal, Mato et al. used drug selection to purify a population of stellate cells from explant cultures of pancreas from lactating rats. The selected cells express some stem-cell markers and can be grown for over 2 years as a fibroblast-like monolayer. When plated on extracellular matrix, along with a cocktail of growth factors that included insulin, transferrin, selenium and the GLP-1 (glucagon-like peptide-1) analogue exendin-4, the cells differentiated into cells that expressed many of the phenotypic markers characteristic of a β-cell, and exhibited an insulin-secretory response, albeit weak, to glucose. The ability to purify this cell population opens up the possibility of unravelling the mechanisms that control self-renewal and differentiation of pancreatic cells that share some of the properties of stem cells.
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Jamison, Braxton L., James E. DiLisio, K. Scott Beard, Tobias Neef, Brenda Bradley, Jessica Goodman, Ronald G. Gill, Stephen D. Miller, Rocky L. Baker, and Kathryn Haskins. "Tolerogenic Delivery of a Hybrid Insulin Peptide Markedly Prolongs Islet Graft Survival in the NOD Mouse." Diabetes 71, no. 3 (January 18, 2022): 483–96. http://dx.doi.org/10.2337/db20-1170.
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The induction of antigen (Ag)-specific tolerance and replacement of islet β-cells are major ongoing goals for the treatment of type 1 diabetes (T1D). Our group previously showed that a hybrid insulin peptide (2.5HIP) is a critical autoantigen for diabetogenic CD4+ T cells in the NOD mouse model. In this study, we investigated whether induction of Ag-specific tolerance using 2.5HIP-coupled tolerogenic nanoparticles (NPs) could protect diabetic NOD mice from disease recurrence upon syngeneic islet transplantation. Islet graft survival was significantly prolonged in mice treated with 2.5HIP NPs, but not NPs containing the insulin B chain peptide 9-23. Protection in 2.5HIP NP-treated mice was attributed both to the simultaneous induction of anergy in 2.5HIP-specific effector T cells and the expansion of Foxp3+ regulatory T cells specific for the same Ag. Notably, our results indicate that effector function of graft-infiltrating CD4+ and CD8+ T cells specific for other β-cell epitopes was significantly impaired, suggesting a novel mechanism of therapeutically induced linked suppression. This work establishes that tolerance induction with an HIP can delay recurrent autoimmunity in NOD mice, which could inform the development of an Ag-specific therapy for T1D.
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Chen, Cheng, Pengfei Rong, Min Yang, Xiaoqian Ma, Zhichao Feng, and Wei Wang. "The Role of Interleukin-1β in Destruction of Transplanted Islets." Cell Transplantation 29 (January 1, 2020): 096368972093441. http://dx.doi.org/10.1177/0963689720934413.
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Islet transplantation is a promising β-cell replacement therapy for type 1 diabetes, which can reduce glucose lability and hypoglycemic episodes compared with standard insulin therapy. Despite the tremendous progress made in this field, challenges remain in terms of long-term successful transplant outcomes. The insulin independence rate remains low after islet transplantation from one donor pancreas. It has been reported that the islet-related inflammatory response is the main cause of early islet damage and graft loss after transplantation. The production of interleukin-1β (IL-1β) has considered to be one of the primary harmful inflammatory events during pancreatic procurement, islet isolation, and islet transplantation. Evidence suggests that the innate immune response is upregulated through the activity of Toll-like receptors and The NACHT Domain-Leucine-Rich Repeat and PYD-containing Protein 3 inflammasome, which are the starting points for a series of signaling events that drive excessive IL-1β production in islet transplantation. In this review, we show recent contributions to the advancement of knowledge of IL-1β in islet transplantation and discuss several strategies targeting IL-1β for improving islet engraftment.
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Rodrigues Oliveira, Sonia M., António Rebocho, Ehsan Ahmadpour, Veeranoot Nissapatorn, and Maria de Lourdes Pereira. "Type 1 Diabetes Mellitus: A Review on Advances and Challenges in Creating Insulin Producing Devices." Micromachines 14, no. 1 (January 6, 2023): 151. http://dx.doi.org/10.3390/mi14010151.
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Type 1 diabetes mellitus (T1DM) is the most common autoimmune chronic disease in young patients. It is caused by the destruction of pancreatic endocrine β-cells that produce insulin in specific areas of the pancreas, known as islets of Langerhans. As a result, the body becomes insulin deficient and hyperglycemic. Complications associated with diabetes are life-threatening and the current standard of care for T1DM consists still of insulin injections. Lifesaving, exogenous insulin replacement is a chronic and costly burden of care for diabetic patients. Alternative therapeutic options have been the focus in these fields. Advances in molecular biology technologies and in microfabrication have enabled promising new therapeutic options. For example, islet transplantation has emerged as an effective treatment to restore the normal regulation of blood glucose in patients with T1DM. However, this technique has been hampered by obstacles, such as limited islet availability, extensive islet apoptosis, and poor islet vascular engraftment. Many of these unsolved issues need to be addressed before a potential cure for T1DM can be a possibility. New technologies like organ-on-a-chip platforms (OoC), multiplexed assessment tools and emergent stem cell approaches promise to enhance therapeutic outcomes. This review will introduce the disorder of type 1 diabetes mellitus, an overview of advances and challenges in the areas of microfluidic devices, monitoring tools, and prominent use of stem cells, and how they can be linked together to create a viable model for the T1DM treatment. Microfluidic devices like OoC platforms can establish a crucial platform for pathophysiological and pharmacological studies as they recreate the pancreatic environment. Stem cell use opens the possibility to hypothetically generate a limitless number of functional pancreatic cells. Additionally, the integration of stem cells into OoC models may allow personalized or patient-specific therapies.
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Dayan, Colin M., Rachel E. J. Besser, Richard A. Oram, William Hagopian, Manu Vatish, Owen Bendor-Samuel, Matthew D. Snape, and John A. Todd. "Preventing type 1 diabetes in childhood." Science 373, no. 6554 (July 29, 2021): 506–10. http://dx.doi.org/10.1126/science.abi4742.
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Type 1 diabetes (T1D) is an autoimmune disease in which the insulin-producing β cells of the pancreas are destroyed by T lymphocytes. Recent studies have demonstrated that monitoring for pancreatic islet autoantibodies, combined with genetic risk assessment, can identify most children who will develop T1D when they still have sufficient β cell function to control glucose concentrations without the need for insulin. In addition, there has been recent success in secondary prevention using immunotherapy to delay the progression of preclinical disease, and primary prevention approaches to inhibiting the initiating autoimmune process have entered large-scale clinical trials. By changing the focus of T1D management from late diagnosis and insulin replacement to early diagnosis and β cell preservation, we can anticipate a future without the need for daily insulin injections for children with T1D.
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Gu, Liangbiao, Dandan Wang, Xiaona Cui, Tianjiao Wei, Kun Yang, Jin Yang, Rui Wei, and Tianpei Hong. "Combination of GLP-1 Receptor Activation and Glucagon Blockage Promotes Pancreatic β-Cell Regeneration In Situ in Type 1 Diabetic Mice." Journal of Diabetes Research 2021 (November 25, 2021): 1–7. http://dx.doi.org/10.1155/2021/7765623.
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Pancreatic β-cell neogenesis in vivo holds great promise for cell replacement therapy in diabetic patients, and discovering the relevant clinical therapeutic strategies would push it forward to clinical application. Liraglutide, a widely used antidiabetic glucagon-like peptide-1 (GLP-1) analog, has displayed diverse β-cell-protective effects in type 2 diabetic animals. Glucagon receptor (GCGR) monoclonal antibody (mAb), a preclinical agent that blocks glucagon pathway, can promote recovery of functional β-cell mass in type 1 diabetic mice. Here, we conducted a 4-week treatment of the two drugs alone or in combination in type 1 diabetic mice. Although liraglutide neither lowered the blood glucose level nor increased the plasma insulin level, the immunostaining showed that liraglutide expanded β-cell mass through self-replication, differentiation from precursor cells, and transdifferentiation from pancreatic α cells to β cells. The pancreatic β-cell mass increased more significantly after GCGR mAb treatment, while the combination group did not further increase the pancreatic β-cell area. However, compared with the GCGR mAb group, the combined treatment reduced the plasma glucagon level and increased the proportion of β cells/α cells. Our study evaluated the effect of liraglutide, GCGR mAb monotherapy, or combined strategy in glucose control and islet β-cell regeneration and provided useful clues for the future clinical application in type 1 diabetes.
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Sutherland, David E. R., Angelika Gruessner, and Bernhard J. Hering. "β-Cell replacement therapy (pancreas and islet transplantation) for treatment of diabetes mellitus: an integrated approach." Endocrinology and Metabolism Clinics of North America 33, no. 1 (March 2004): 135–48. http://dx.doi.org/10.1016/s0889-8529(03)00099-9.
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Wei, A. H., W. J. Wang, X. P. Mu, H. M. Li, and W. Q. Yan. "Enhanced Differentiation of Human Adipose Tissue-derived Stromal Cells into Insulin-producing Cells with Glucagon-like Peptide-1." Experimental and Clinical Endocrinology & Diabetes 120, no. 01 (September 13, 2011): 28–34. http://dx.doi.org/10.1055/s-0031-1280807.
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AbstractType 1 diabetes mellitus (T1DM) is mainly caused by reduction of the endogenous insulin secretion due to autoimmune destruction of pancreatic β cells, and a promising therapeutic approach for T1DM is pancreas and islet cell replacement. The major obstacle is the limited source of insulin-producing cells. Here, we report an efficient approach to induce human adipose-derived stromal cells (hADSCs) to differentiate into insulin-producing cells, with glucagon-like peptide-1 (GLP-1). hADSCs were successfully isolated from the adipose tissue, with adipogenic and osteogenic differentiation potency. Islet-like cell clusters formed in the culture, which was enhanced with the treatment of GLP-1. Reverse transcription polymerase chain reaction analysis showed the expression of the pancreas-related genes in the differentiated cells, such as pdx-1, ngn3, insulin, glucagon, somatostatin, glucokinase n and glut2. Immunocytochemical analysis showed that the induced cells co-expressed insulin, C-peptide and PDX-1. The GLP-1 receptor was present in the differentiated cells. In addition, flow cytometry analysis and ELISA showed that, in the presence of GLP-1, the percentage of insulin-producing cells was increased from 5.9% to 28.0% and the release of insulin increased from 9.53±0.7 pmol/106 cells to 15.86±1.3 pmol/106 cells. Insulin was released in response to glucose stimulation in a manner comparable to that of adult human islets. These results indicated that hADSCs isolated from adipose tissues can be induced to differentiate into insulin-producing cells, which is further enhanced with the treatment of GLP-1. These findings confirm that the differentiation of hADSCs to insulin-producing cells is indeed possible and indicate that the differentiated insulin-producing cells can be used as a potential source for transplantation into patients with T1DM.
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Wisel, Steven A., Hillary J. Braun, and Peter G. Stock. "Current outcomes in islet versus solid organ pancreas transplant for β-cell replacement in type 1 diabetes." Current Opinion in Organ Transplantation 21, no. 4 (August 2016): 399–404. http://dx.doi.org/10.1097/mot.0000000000000332.
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Nicholson, J. Michael, Edith J. Arany, and David J. Hill. "Changes in islet microvasculature following streptozotocin-induced β-cell loss and subsequent replacement in the neonatal rat." Experimental Biology and Medicine 235, no. 2 (February 2010): 189–98. http://dx.doi.org/10.1258/ebm.2009.009316.
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Cito, Monia, Silvia Pellegrini, Lorenzo Piemonti, and Valeria Sordi. "The potential and challenges of alternative sources of β cells for the cure of type 1 diabetes." Endocrine Connections 7, no. 3 (March 2018): R114—R125. http://dx.doi.org/10.1530/ec-18-0012.
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The experience in the field of islet transplantation shows that it is possible to replace β cells in a patient with type 1 diabetes (T1D), but this cell therapy is limited by the scarcity of organ donors and by the danger associated to the immunosuppressive drugs. Stem cell therapy is becoming a concrete opportunity to treat various diseases. In particular, for a disease like T1D, caused by the loss of a single specific cell type that does not need to be transplanted back in its originating site to perform its function, a stem cell-based cell replacement therapy seems to be the ideal cure. New and infinite sources of β cells are strongly required. In this review, we make an overview of the most promising and advanced β cell production strategies. Particular hope is placed in pluripotent stem cells (PSC), both embryonic (ESC) and induced pluripotent stem cells (iPSC). The first phase 1/2 clinical trials with ESC-derived pancreatic progenitor cells are ongoing in the United States and Canada, but a successful strategy for the use of PSC in patients with diabetes has still to overcome several important hurdles. Another promising strategy of generation of new β cells is the transdifferentiation of adult cells, both intra-pancreatic, such as alpha, exocrine and ductal cells or extra-pancreatic, in particular liver cells. Finally, new advances in gene editing technologies have given impetus to research on the production of human organs in chimeric animals and on in situ reprogramming of adult cells through in vivo target gene activation.
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Dew, Kristen, Martin J. Hessner, Shuang Jia, Tarun Pant, Mark F. Roethle, Ru-Jeng Teng, and Pinar Sargin. "OR14-6 Probiotic Supplementation with Lactiplantibacillus Plantarum 299v Modulates β-Cell Endoplasmic Reticulum Stress and Prevents Type 1 Diabetes in Biobreeding Rats." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A615—A616. http://dx.doi.org/10.1210/jendso/bvac150.1276.
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Abstract Type 1 diabetes (T1D) is a complex disease characterized by the loss of pancreatic beta-cells and lifelong dependence on insulin replacement therapy. As the worldwide incidence of T1D has increased and the prevalence of high-risk HLA haplotypes has declined among new diagnoses, a greater focus has been placed on environmental factors contributing to T1D pathogenesis. Lactiplantibacillus plantarum 299v (Lp299v) supplement is reported to increase plasma and stool levels of anti-inflammatory short-chain fatty acids (SCFAs) and promote IL-10 signaling in colonic derived macrophages and T-cells. Therefore, we investigated the effect of Lp299v supplement on T1D pathogenesis in diabetes-prone BioBreeding DRlyp/lyp rats. Rats were weaned at 21 days of age (D21) onto a normal cereal diet (ND) or a gluten-free hydrolyzed casein diet (HCD), with or without daily Lp299v supplementation. All rats provided ND developed diabetes by D83 and supplementing ND with Lp299v did not significantly delay progression. Rats provided HCD showed a significant delay in diabetes onset over ND, while progression was even more delayed in the HCD+Lp299v group, with 25% of animals remaining diabetes-free to D130 (study end). Relative to the other groups, HCD+Lp299v rats exhibited significant increases in the plasma levels of the SCFAs propionate and butyrate (beneficial metabolites produced by intestinal bacteria). In addition, stool microbiota showed increased abundances of SCFA-producing taxa at D40. Gene expression analysis of pancreatic islets was conducted at D40, prior to insulitis. Lp299v supplementation favorably modulated islet expression levels of pathways related to endoplasmic reticulum (ER) stress, and the major arms of the unfolded protein response (UPR), especially in combination with the HCD. Notably, ER stress has been implicated in the formation of islet neoantigens that may underlie the initial loss of immune tolerance in T1D. Lp299v supplement differentially modulated the UPR to favor the expression of the transcription factor Atf6, increase expression of transcripts related to cell survival/proliferation, and the ER-associated protein degradation (ERAD) pathway of the UPR. This contrasted with HCD alone, which promoted a transcriptional program related to autophagy. To colocalize and confirm activities detected in the transcriptional analyses to β-cells, pancreata of D40 rats were subjected to dual immunofluorescence staining for insulin and UPR-related proteins. Consistent with elevated ERAD activity, significantly greater EIF4G1 and OS9 expression were observed in HCD+Lp299v islets. Phospho-PERK staining was significantly higher in islets of the HCD-alone group, consistent with the elevated expression of autophagy transcripts. Analysis of plasma proinsulin: C-peptide ratios revealed that Lp299v alone could improve islet function, as significant decreases were measured in all groups relative to ND. While ongoing studies aim to define the bacterial metabolites underlying the favorable outcomes, these studies suggest that Lp299v supplementation improves proteostasis capacity in β-cells and slows T1D progression in DRlyp/lyp rats. Presentation: Sunday, June 12, 2022 12:15 p.m. - 12:30 p.m.
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Williams, Michael D., Mugdha V. Joglekar, Sarang N. Satoor, Wilson Wong, Effie Keramidaris, Amanda Rixon, Philip O’Connell, Wayne J. Hawthorne, Geraldine M. Mitchell, and Anandwardhan A. Hardikar. "Epigenetic and Transcriptome Profiling Identifies a Population of Visceral Adipose-Derived Progenitor Cells with the Potential to Differentiate into an Endocrine Pancreatic Lineage." Cell Transplantation 28, no. 1 (October 30, 2018): 89–104. http://dx.doi.org/10.1177/0963689718808472.
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Type 1 diabetes (T1D) is characterized by the loss of insulin-producing β-cells in the pancreas. T1D can be treated using cadaveric islet transplantation, but this therapy is severely limited by a lack of pancreas donors. To develop an alternative cell source for transplantation therapy, we carried out the epigenetic characterization in nine different adult mouse tissues and identified visceral adipose-derived progenitors as a candidate cell population. Chromatin conformation, assessed using chromatin immunoprecipitation (ChIP) sequencing and validated by ChIP-polymerase chain reaction (PCR) at key endocrine pancreatic gene promoters, revealed similarities between visceral fat and endocrine pancreas. Multiple techniques involving quantitative PCR, in-situ PCR, confocal microscopy, and flow cytometry confirmed the presence of measurable (2–1000-fold over detectable limits) pancreatic gene transcripts and mesenchymal progenitor cell markers (CD73, CD90 and CD105; >98%) in visceral adipose tissue-derived mesenchymal cells (AMCs). The differentiation potential of AMCs was explored in transgenic reporter mice expressing green fluorescent protein (GFP) under the regulation of the Pdx1 (pancreatic and duodenal homeobox-1) gene promoter. GFP expression was measured as an index of Pdx1 promoter activity to optimize culture conditions for endocrine pancreatic differentiation. Differentiated AMCs demonstrated their capacity to induce pancreatic endocrine genes as evidenced by increased GFP expression and validated using TaqMan real-time PCR (at least 2–200-fold relative to undifferentiated AMCs). Human AMCs differentiated using optimized protocols continued to produce insulin following transplantation in NOD/SCID mice. Our studies provide a systematic analysis of potential islet progenitor populations using genome-wide profiling studies and characterize visceral adipose-derived cells for replacement therapy in diabetes.
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Ma, Lian, Hongwu Wang, Hongyan He, Limin Lin, Weizhong Li, Tianhua Huang, Guixia Ma, and Aihong Wang. "Human Umbilical Cord Wharton's Jelly-Derived Mesenchymal Stem Cells Differentiate Into Insulin-Producing Cells." Blood 114, no. 22 (November 20, 2009): 4578. http://dx.doi.org/10.1182/blood.v114.22.4578.4578.
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Abstract Abstract 4578 Introduction Islet transplantation is an effective way of reversing type 1 diabetes. However, islet transplantation has been hampered by problems, such as immune rejection, and the scarcity of donor islets. Human Umbilical Cord Wharton's Jelly-derived Mesenchymal Stem Cells (huMSCs), which can be differentiated into insulin-producing cells could provide a source of cells for transplant. Methods Vitro Research We isolated and cultured huMSCs, and induced huMSCs differentiated into insulin-producing cells in the condition of islet cells grows. The morphology of huMSCs after induction were monitored by under inversion phase contrast microscope?GImmunocytochemical methods were used to detect the insulin and glucagon protein, and reverse transcription-polymerase chain reaction (RT-PCR) method was used to detect Human insulin gene and PDX-1 gene. Dithizon-stained was used to detect zinc hydronium and radio-immunity was used to detect insulin level of culture supernatant.Vivo Research huMSCs were transplanted into the body of diabetic rats through vena caudalis, and then we observed the change of blood glucose?Abody weight ?Aserum insulin levels and survival ratio in STZ-induced diabetic rats. We detected human insulin by immunohistochemistry and RT-PCR. HE stain was used to detect the morphological changes of rat's pancreatic island. Results Vitro Research The morphology of huMSCs under medicine induction gradually changed from fibroblast to round and some of then had the tend of forming clusters.?GThe result of immunocytochemical showed that the expression of human insulin and glucagon was positive after treatment with medicine?GhuMSCs induced by medicine can express insulin and PDX-1 gene by RT-PCR?GDithizon stain show that the cytoplasm of huMSCs after induction were stained in Brownish red color?Gthe results of radio-immunity manifested that the insulin quantity secreted by medicine induction were significant differences compared with control group(t??6.183,P<0.05). Vivo Research When transplanted into Streptozotocin(STZ)-treated diabetics rats, huMSCs can decreased blood glucose, increased body weight and survival ratio in diabetic rats?GAfter being transplanted for one month, we discovered that it can be planted into rat's pancreas and liver by Hoechst33258?Gimmunohistochemistry and RT-PCR show that the pancreas of rat can express human insulin?Gthe morphology of rats' pancreatic island was repaired obviously if compared with diabetic rats before the transplantation through HE-stain. Conclusion huMSCs can be differentiated into insulin-producing cells in vitro or in vivo. Therefore, huMSCs have the potential to become an excellent candidate in β cell replacement therapy of diabetes. Disclosures: No relevant conflicts of interest to declare.
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Goncharov, A. G., V. V. Shupletsova, N. M. Todosenko, E. A. Goncharova, and L. S. Litvinova. "Production of growth factors, pro – and anti-inflammatory cytokines by postnatal MMSCs from various tissue sources during in vitro co-cultivation with immunoisolated pancreatic β-cells." Russian Journal of Immunology 24, no. 4 (October 15, 2021): 477–82. http://dx.doi.org/10.46235/1028-7221-1058-pog.
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The article presents the results of evaluating growth factors, pro – and anti-inflammatory cytokine production by multipotent mesenchymal stem cell cultures under the conditions of co-cultivation with immuno-isolated beta-cells of the pancreas. β-cell transplantation is a minimally invasive therapeutic approach (compared to transplantation of entire pancreas), and it provides better metabolic control with respect to insulin administration. However, when transplanting β-cells, there is always a risk of immune rejection of the grafted cells. It is generally recognized that encapsulation is an effective means of immunological protection against the recipient’s immune system during transplantation. Regulation of the autoimmune response to transplanted cells is crucial for the treatment of type I diabetes mellitus. In recent years, along with replacement of islet cells, much attention has been paid to the use of multipotent mesenchymal stem cells with immunomodulatory and/or immunosuppressive properties, aimed for the correction of diabetes mellitus. Either in vitro and in vivo, they impact not only T-lymphocytes, but also B-lymphocytes, dendritic and NK-cells. Mesenchymal stem cells are able to inhibit proliferation of immune cells and reduce their secretion of inflammatory cytokines, acting as auxiliary cells to improve the survival of islets in the early post-transplant phase. Combined transplantation of multipotent mesenchymal stem cells and pancreatic β-cells is a promising approach to the treatment of type I diabetes mellitus. Deeper study of the mechanisms that cause their cytoprotective effect upon the transplant may be helpful for implementation of this therapeutic approach and improve its efficiency. In our study, a 1% solution of low-viscosity sodium alginate with addition of saline solution (0.9% sodium chloride) was used to create immuno-insulating scaffolds, and a 2.2% BaCl2 solution was added for polymerization. Decreased production of proinflammatory cytokines (TNFα, IL-12, IL-5) and growth factor (GM-CSF) was registered in co-cultures of β-cells with mesenchymal stem cells of bone marrow origin, and those obtained from subcutaneous adipose tissue. Anti-inflammatory activity was more pronounced in adipose stem cells and their immunomodulatory effects were shown via changes of their cytokine-producing activity. Hence, the multipotent mesenchymal stem cells obtained from adipose tissue and bone marrow have shown to exert cytoprotective effect upon pancreatic beta-cells by shifting the cytokine-producing activity towards an antiinflammatory profile.
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Barrio, Raquel. "MANAGEMENT OF ENDOCRINE DISEASE: Cystic fibrosis-related diabetes: novel pathogenic insights opening new therapeutic avenues." European Journal of Endocrinology 172, no. 4 (April 2015): R131—R141. http://dx.doi.org/10.1530/eje-14-0644.
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Cystic fibrosis (CF) is a recessive genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR).CFTRis primarily present in epithelial cells of the airways, intestine and in cells with exocrine and endocrine functions. Mutations in the gene encoding the channel protein complex (CFTR) cause alterations in the ionic composition of secretions from the lung, gastrointestinal tract, liver, and also the pancreas. CF-related diabetes (CFRD), the most common complication of CF, has a major detrimental impact on pulmonary function, nutrition and survival. Glucose derangements in CF seem to start from early infancy and, even when the pathophysiology is multifactorial, insulin insufficiency is clearly a major component. Consistently, recent evidence has confirmed that CFTR is an important regulator of insulin secretion by islet β-cells. In addition, several other mechanisms were also recognized from cellular and animals models also contributing to either β-cell mass reduction or β-cell malfunction. Understanding such mechanisms is crucial for the development of the so-called ‘transformational’ therapies in CF, including the preservation of insulin secretion. Innovative therapeutic approaches aim to modify specific CFTR mutant proteins or positively modulate their function. CFTR modulators have recently shownin vitrocapacity to enhance insulin secretion and thereby potential clinical utility in CFDR, including synergistic effects between corrector and potentiator drugs. The introduction of incretins and the optimization of exocrine pancreatic replacement complete the number of therapeutic options of CFRD besides early diagnosis and implementation of insulin therapy. This review focuses on the recently identified pathogenic mechanisms leading to CFRD relevant for the development of novel pharmacological avenues in CFRD therapy.
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Nordheim, Espen, Jørn Petter Lindahl, Rasmus Kirkeskov Carlsen, Anders Åsberg, Kåre Inge Birkeland, Rune Horneland, Birgitte Boye, Hanne Scholz, and Trond Geir Jenssen. "Patient selection for islet or solid organ pancreas transplantation: experiences from a multidisciplinary outpatient-clinic approach." Endocrine Connections 10, no. 2 (February 2021): 230–39. http://dx.doi.org/10.1530/ec-20-0519.
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Objective β-cell replacement therapy (βCRT), including pancreas transplantation alone (PTA) and islet transplantation (ITX), is a treatment option for selected type 1 diabetes patients. All potential candidates for βCRT in Norway are referred to one national transplant centre for evaluation before any pre-transplant workup is started. This evaluation was performed by a transplant nephrologist alone prior to 2015 and by a multidisciplinary team (MDT) from 2015. We have reviewed the allocation of patients to treatment modality and the 1-year clinical outcome for the patients after transplantation. Research design and methods Medical charts of all patients evaluated for βCRT between 2010 and 2020 in Norway were retrospectively analysed and the outcome of patients receiving βCRT were studied. Results One hundred and forty-four patients were assessed for βCRT eligibility between 2010 and 2020. After MDT evaluation was introduced for βCRT eligibility in 2015, the percentage of referred patients accepted for the transplant waiting list fell from 84% to 40% (P < 0.005). One year after transplantation, 73% of the PTA and none of the ITX patients were independent of exogenous insulin, 8% of the PTA and 90% of the ITX patients had partial graft function while 19% of the PTA and 10% of the ITX patients suffered from graft loss. Conclusion The acceptance rate for βCRT was significantly reduced during a 10-year observation period and 81% of the PTA and 90% of the ITX patients had partial or normal graft function 1 year post-transplant.
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Amin, Md Lutful, Kylie Deng, Hien A. Tran, Reena Singh, Jelena Rnjak-Kovacina, and Peter Thorn. "Glucose-Dependent Insulin Secretion from β Cell Spheroids Is Enhanced by Embedding into Softer Alginate Hydrogels Functionalised with RGD Peptide." Bioengineering 9, no. 12 (November 23, 2022): 722. http://dx.doi.org/10.3390/bioengineering9120722.
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Type 1 diabetes results from the loss of pancreatic β cells, reduced insulin secretion and dysregulated blood glucose levels. Replacement of these lost β cells with stem cell-derived β cells, and protecting these cells within macro-device implants is a promising approach to restore glucose homeostasis. However, to achieve this goal of restoration of glucose balance requires work to optimise β cell function within implants. We know that native β cell function is enhanced by cell–cell and cell–extracellular matrix interactions within the islets of Langerhans. Reproducing these interactions in 2D, such as culture on matrix proteins, does enhance insulin secretion. However, the impact of matrix proteins on the 3D organoids that would be in implants has not been widely studied. Here, we use native β cells that are dispersed from islets and reaggregated into small spheroids. We show these β cell spheroids have enhanced glucose-dependent insulin secretion when embedded into softer alginate hydrogels conjugated with RGD peptide (a common motif in extracellular matrix proteins). Embedding into alginate–RGD causes activation of integrin responses and repositioning of liprin, a protein that controls insulin secretion. We conclude that insulin secretion from β cell spheroids can be enhanced through manipulation of the surrounding environment.
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Tan, Gemma, Andrew G. Elefanty, and Edouard G. Stanley. "β-cell regeneration and differentiation: how close are we to the ‘holy grail’?" Journal of Molecular Endocrinology 53, no. 3 (December 2014): R119—R129. http://dx.doi.org/10.1530/jme-14-0188.
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Diabetes can be managed by careful monitoring of blood glucose and timely delivery of exogenous insulin. However, even with fastidious compliance, people with diabetes can suffer from numerous complications including atherosclerosis, retinopathy, neuropathy, and kidney disease. This is because delivery of exogenous insulin coupled with glucose monitoring cannot provide the fine level of glucose control normally provided by endogenous β-cells in the context of intact islets. Moreover, a subset of people with diabetes lack awareness of hypoglycemic events; a status that can have grave consequences. Therefore, much effort has been focused on replacing lost or dysfunctional β-cells with cells derived from other sources. The advent of stem cell biology and cellular reprogramming strategies have provided impetus to this work and raised hopes that a β-cell replacement therapy is on the horizon. In this review, we look at two components that will be required for successful β-cell replacement therapy: a reliable and safe source of β-cells and a mechanism by which such cells can be delivered and protected from host immune destruction. Particular attention is paid to insulin-producing cells derived from pluripotent stem cells because this platform addresses the issue of scale, one of the more significant hurdles associated with potential cell-based therapies. We also review methods for encapsulating transplanted cells, a technique that allows grafts to evade immune attack and survive for a long term in the absence of ongoing immunosuppression. In surveying the literature, we conclude that there are still several substantial hurdles that need to be cleared before a stem cell-based β-cell replacement therapy for diabetes becomes a reality.
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Csobonyeiova, Maria, Stefan Polak, and Lubos Danisovic. "Generation of Pancreatic β-cells From iPSCs and their Potential for Type 1 Diabetes Mellitus Replacement Therapy and Modelling." Experimental and Clinical Endocrinology & Diabetes 128, no. 05 (August 16, 2018): 339–46. http://dx.doi.org/10.1055/a-0661-5873.
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AbstractDiabetes type 1 (T1D) is a common autoimmune disease characterized by permanent destruction of the insulin-secreting β-cells in pancreatic islets, resulting in a deficiency of the glucose-lowering hormone insulin and persisting high blood glucose levels. Insulin has to be replaced by regular subcutaneous injections, and blood glucose level must be monitored due to the risk of hyperglycemia. Recently, transplantation of new pancreatic β-cells into T1D patients has come to be considered one of the most potentially effective treatments for this disease. Therefore, much effort has focused on understanding the regulation of β-cells. Induced pluripotent stem cells (iPSCs) represent a valuable source for T1D modelling and cell replacement therapy because of their ability to differentiate into all cell types in vitro. Recent advances in stem cell-based therapy and gene-editing tools have enabled the generation of functionally adult pancreatic β-cells derived from iPSCs. Although animal and human pancreatic development and β-cell physiology have significant differences, animal models represent an important tool in evaluating the therapeutic potential of iPSC-derived β-cells on type 1 diabetes treatment. This review outlines the recent progress in iPSC-derived β-cell differentiation methods, disease modelling, and future perspectives.
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O’Driscoll, Lorraine, Patrick Gammell, Eadaoin McKiernan, Eoin Ryan, Per Bendix Jeppesen, Sweta Rani, and Martin Clynes. "Phenotypic and global gene expression profile changes between low passage and high passage MIN-6 cells." Journal of Endocrinology 191, no. 3 (December 2006): 665–76. http://dx.doi.org/10.1677/joe.1.06894.
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The long-term potential to routinely use replacement β cells/islets as cell therapy for type 1 diabetes relies on our ability to culture such cells/islets, in vitro, while maintaining their functional status. Previous β cell studies, by ourselves and other researchers, have indicated that the glucose-stimulated insulin secretion (GSIS) phenotype is relatively unstable, in long-term culture. This study aimed to investigate phenotypic and gene expression changes associated with this loss of GSIS, using the MIN-6 cell line as model. Phenotypic differences between MIN-6(L, low passage) and MIN-6(H, high passage) were determined by ELISA (assessing GSIS and cellular (pro)insulin content), proliferation assays, phase contrast light microscopy and analysis of alkaline phosphatase expression. Differential mRNA expression was investigated using microarray, bioinformatics and real-time PCR technologies. Long-term culture was found to be associated with many phenotypic changes, including changes in growth rate and cellular morphology, as well as loss of GSIS. Microarray analyses indicate expression of many mRNAs, including many involved in regulated secretion, adhesion and proliferation, to be significantly affected by passaging/ long-term culture. Loss/reduced levels, in high passage cells, of certain transcripts associated with the mature β cell, together with increased levels of neuron/glia-associated mRNAs, suggest that, with time in culture, MIN-6 cells may revert to an early (possibly multi-potential), poorly differentiated, ‘precursor-like’ cell type. This observation is supported by increased expression of the stem cell marker, alkaline phosphatase.
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Krol, Silke, Walter Baronti, and Piero Marchetti. "Nanoencapsulated human pancreatic islets for β-cell replacement in Type 1 diabetes." Nanomedicine 15, no. 18 (August 2020): 1735–38. http://dx.doi.org/10.2217/nnm-2020-0166.
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Stock, Aaron A., Vita Manzoli, Teresa De Toni, Maria M. Abreu, Yeh-Chuin Poh, Lillian Ye, Adam Roose, et al. "Conformal Coating of Stem Cell-Derived Islets for β Cell Replacement in Type 1 Diabetes." Stem Cell Reports 14, no. 1 (January 2020): 91–104. http://dx.doi.org/10.1016/j.stemcr.2019.11.004.
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