Journal articles: 'Β-cell replacement'

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Castro-Gutierrez, Roberto, Aaron W. Michels, and Holger A. Russ. "β Cell replacement." Current Opinion in Endocrinology & Diabetes and Obesity 25, no. 4 (August 2018): 251–57. http://dx.doi.org/10.1097/med.0000000000000418.

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Schuetz, Christian, Takayuki Anazawa, Sarah E. Cross, Leticia Labriola, Raphael P. H. Meier, Robert R. Redfield, Hanne Scholz, Peter G. Stock, and Nathan W. Zammit. "β Cell Replacement Therapy." Transplantation 102, no. 2 (February 2018): 215–29. http://dx.doi.org/10.1097/tp.0000000000001937.

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Dirice, Ercument. "β-cell Heterogeneity: The Key to β-cell Replacement Therapy." Pancreas - Open Journal 2, no. 1 (November 8, 2018): e10-e11. http://dx.doi.org/10.17140/poj-2-e009.

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Fellous, Tariq G., Naomi J. Guppy, Mairi Brittan, and Malcolm R. Alison. "Cellular pathways to β-cell replacement." Diabetes/Metabolism Research and Reviews 23, no. 2 (2007): 87–99. http://dx.doi.org/10.1002/dmrr.692.

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Muschter, N., A. Richter, H. Ahrens, G. Gosheger, M. Fehr, J. Bullerdiek, and G. Hauschild. "Cartilage replacement in dogs." Veterinary and Comparative Orthopaedics and Traumatology 22, no. 03 (2009): 216–21. http://dx.doi.org/10.3415/vcot08-02-0021.

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SummaryThe objective of this study was to examine the behaviour of canine chondrocytes following colonisation of a β-tricalcium phosphate (β-TCP, Cerasorb®, Curasan) matrix. In total, five of these cylinders were inoculated with 1.5 ml of cell suspension and subsequently incubated for about one week. In the second part of the experiment, another five Cerasorb® cylinders were each studded with two cartilage chips of variable size and then incubated for about one week. The series of experiments were analyzed using cell staining and imaging techniques that included scanning electron microscopy. Cell migration onto the matrix was proven for both colonization methods. It was observed that colonising the cylinders by pipetting cell suspension on them produced far better results, with respect to both growth rate and spreading of the cells, than did colonisation by studding with cartilage chips. A homogenous, surface-covering colonisation with predominantly living cells was demonstrated by scanning electron microscopy in the chondrocyte morphology. In comparison to cell-culture controls, there was a clearly better colonisation, with cells attached to both the material's primary grains and its micropores. The ceramic studied is well accepted by canine chondrocytes, and appears to be fundamentally well-suited as a matrix for bio-artificial bone-cartilage replacement. Additional qualitative analyses and a series of experiments aiming to accelerate cell proliferation are planned for subsequent studies.

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Salinno, Cota, Bastidas-Ponce, Tarquis-Medina, Lickert, and Bakhti. "β-Cell Maturation and Identity in Health and Disease." International Journal of Molecular Sciences 20, no. 21 (October 30, 2019): 5417. http://dx.doi.org/10.3390/ijms20215417.

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The exponential increase of patients with diabetes mellitus urges for novel therapeutic strategies to reduce the socioeconomic burden of this disease. The loss or dysfunction of insulin-producing β-cells, in patients with type 1 and type 2 diabetes respectively, put these cells at the center of the disease initiation and progression. Therefore, major efforts have been taken to restore the β-cell mass by cell-replacement or regeneration approaches. Implementing novel therapies requires deciphering the developmental mechanisms that generate β-cells and determine the acquisition of their physiological phenotype. In this review, we summarize the current understanding of the mechanisms that coordinate the postnatal maturation of β-cells and define their functional identity. Furthermore, we discuss different routes by which β-cells lose their features and functionality in type 1 and 2 diabetic conditions. We then focus on potential mechanisms to restore the functionality of those β-cell populations that have lost their functional phenotype. Finally, we discuss the recent progress and remaining challenges facing the generation of functional mature β-cells from stem cells for cell-replacement therapy for diabetes treatment.

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Calafiore, Riccardo, Pia Montanucci, and Giuseppe Basta. "Stem cells for pancreatic β-cell replacement in diabetes mellitus." Current Opinion in Organ Transplantation 19, no. 2 (April 2014): 162–68. http://dx.doi.org/10.1097/mot.0000000000000055.

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OBERHOLZER, JOSÉ, CHRISTIAN TOSO, FRÉDÉRIC RIS, PASCAL BUCHER, FRÉDÉRIC TRIPONEZ, ALP DEMIRAG, JINNING LOU, and PHILIPPE MOREL. "β Cell Replacement for the Treatment of Diabetes." Annals of the New York Academy of Sciences 944, no. 1 (January 25, 2006): 373–87. http://dx.doi.org/10.1111/j.1749-6632.2001.tb03849.x.

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Choi, Soo Bong, Jin Sun Jang, and Sunmin Park. "Estrogen and Exercise May Enhance β-Cell Function and Mass via Insulin Receptor Substrate 2 Induction in Ovariectomized Diabetic Rats." Endocrinology 146, no. 11 (November 1, 2005): 4786–94. http://dx.doi.org/10.1210/en.2004-1653.

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The prevalence and progression of type 2 diabetes have increased remarkably in postmenopausal women. Although estrogen replacement and exercise have been studied for their effect in modulating insulin sensitivity in the case of insufficient estrogen states, their effects on β-cell function and mass have not been studied. Ovariectomized (OVX) female rats with 90% pancreatectomy were given a 30% fat diet for 8 wk with a corresponding administration of 17β-estradiol (30 μg/kg body weight) and/or regular exercise. Amelioration of insulin resistance by estrogen replacement or exercise was closely related to body weight reduction. Insulin secretion in first and second phases was lower in OVX during hyperglycemic clamp, which was improved by estrogen replacement and exercise but not by weight reduction induced by restricted diets. Both estrogen replacement and exercise overcame reduced pancreatic β-cell mass in OVX rats via increased proliferation and decreased apoptosis of β-cells, but they did not exhibit an additive effect. However, restricted diets did not stimulate β-cell proliferation. Increased β-cell proliferation was associated with the induction of insulin receptor substrate-2 and pancreatic homeodomain protein-1 via the activation of the cAMP response element binding protein. Estrogen replacement and exercise shared a common pathway, which led to the improvement of β-cell function and mass, via cAMP response element binding protein activation, explaining the lack of an additive effect with combined treatments. In conclusion, decreased β-cell mass leading to impaired insulin secretion triggers glucose dysregulation in estrogen insufficiency, regardless of body fat. Regular moderate exercise eliminates the risk factors of contracting diabetes in the postmenopausal state.

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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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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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Chang, Ryan, Gaetano Faleo, Holger A. Russ, Audrey V. Parent, Susanna K. Elledge, Daniel A. Bernards, Jessica L. Allen, et al. "Nanoporous Immunoprotective Device for Stem-Cell-Derived β-Cell Replacement Therapy." ACS Nano 11, no. 8 (August 7, 2017): 7747–57. http://dx.doi.org/10.1021/acsnano.7b01239.

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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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Bakhti, Mostafa, and Heiko Lickert. "New insights into β-cell failure, regeneration and replacement." Nature Reviews Endocrinology 18, no. 2 (December 10, 2021): 79–80. http://dx.doi.org/10.1038/s41574-021-00611-0.

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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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Pfeifer, Anja, Monica Courtney, Nouha Ben-Othman, Keith Al-Hasani, Elisabet Gjernes, Andhira Vieira, Noémie Druelle, et al. "Induction of multiple cycles of pancreatic β-cell replacement." Cell Cycle 12, no. 20 (October 15, 2013): 3243–44. http://dx.doi.org/10.4161/cc.26357.

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Pellegrini, Silvia, Giovanni B. Pipitone, Alessandro Cospito, Fabio Manenti, Gaia Poggi, Marta T. Lombardo, Rita Nano, et al. "Generation of β Cells from iPSC of a MODY8 Patient with a Novel Mutation in the Carboxyl Ester Lipase (CEL) Gene." Journal of Clinical Endocrinology & Metabolism 106, no. 5 (January 8, 2021): e2322-e2333. http://dx.doi.org/10.1210/clinem/dgaa986.

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Abstract Context Maturity-onset diabetes of the young (MODY) 8 is a rare form of monogenic diabetes characterized by a mutation in CEL (carboxyl ester lipase) gene, which leads to exocrine pancreas dysfunction, followed by β cell failure. Induced pluripotent stem cells can differentiate into functional β cells. Thus, β cells from MODY8 patients can be generated in vitro and used for disease modelling and cell replacement therapy. Methods A genetic study was performed in a patient suspected of monogenic diabetes. Results A novel heterozygous pathogenic variant in CEL (c.1818delC) was identified in the proband, allowing diagnosis of MODY8. Three MODY8-iPSC (induced pluripotent stem cell) clones were reprogrammed from skin fibroblasts of the patient, and their pluripotency and genomic stability confirmed. All 3 MODY8-iPSC differentiated into β cells following developmental stages. MODY8-iPSC–derived β cells were able to secrete insulin upon glucose dynamic perifusion. The CEL gene was not expressed in iPSCs nor during any steps of endocrine differentiation. Conclusion iPSC lines from a MODY8 patient with a novel pathogenic variant in the CEL gene were generated; they are capable of differentiation into endocrine cells, and β cell function is preserved in mutated cells. These results set the basis for in vitro modelling of the disease and potentially for autologous β cell replacement.

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Ball, Stephen G., and Thomas M. Barber. "Molecular development of the pancreatic β cell: implications for cell replacement therapy." Trends in Endocrinology & Metabolism 14, no. 8 (October 2003): 349–55. http://dx.doi.org/10.1016/s1043-2760(03)00105-x.

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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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Seidenstuecker, Michael, Svenja Lange, Steffen Esslinger, Sergio H. Latorre, Rumen Krastev, Rainer Gadow, Hermann O. Mayr, and Anke Bernstein. "Inversely 3D-Printed β-TCP Scaffolds for Bone Replacement." Materials 12, no. 20 (October 18, 2019): 3417. http://dx.doi.org/10.3390/ma12203417.

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The aim of this study was to predefine the pore structure of β-tricalcium phosphate (β-TCP) scaffolds with different macro pore sizes (500, 750, and 1000 µm), to characterize β-TCP scaffolds, and to investigate the growth behavior of cells within these scaffolds. The lead structures for directional bone growth (sacrificial structures) were produced from polylactide (PLA) using the fused deposition modeling techniques. The molds were then filled with β-TCP slurry and sintered at 1250 °C, whereby the lead structures (voids) were burnt out. The scaffolds were mechanically characterized (native and after incubation in simulated body fluid (SBF) for 28 d). In addition, biocompatibility was investigated by live/dead, cell proliferation and lactate dehydrogenase assays. The scaffolds with a strand spacing of 500 µm showed the highest compressive strength, both untreated (3.4 ± 0.2 MPa) and treated with simulated body fluid (2.8 ± 0.2 MPa). The simulated body fluid reduced the stability of the samples to 82% (500), 62% (750) and 56% (1000). The strand spacing and the powder properties of the samples were decisive factors for stability. The fact that β-TCP is a biocompatible material is confirmed by the experiments. No lactate dehydrogenase activity of the cells was measured, which means that no cytotoxicity of the material could be detected. In addition, the proliferation rate of all three sizes increased steadily over the test days until saturation. The cells were largely adhered to or within the scaffolds and did not migrate through the scaffolds to the bottom of the cell culture plate. The cells showed increased growth, not only on the outer surface (e.g., 500: 36 ± 33 vital cells/mm² after three days, 180 ± 33 cells/mm² after seven days, and 308 ± 69 cells/mm² after 10 days), but also on the inner surface of the samples (e.g., 750: 49 ± 17 vital cells/mm² after three days, 200 ± 84 cells/mm² after seven days, and 218 ± 99 living cells/mm² after 10 days). This means that the inverse 3D printing method is very suitable for the presetting of the pore structure and for the ingrowth of the cells. The experiments on which this work is based have shown that the fused deposition modeling process with subsequent slip casting and sintering is well suited for the production of scaffolds for bone replacement.

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Huang, Yan, Jian Wan, Yibing Guo, Shajun Zhu, Yao Wang, Lei Wang, Qingsong Guo, Yuhua Lu, and Zhiwei Wang. "Transcriptome Analysis of Induced Pluripotent Stem Cell (iPSC)-derived Pancreatic β-like Cell Differentiation." Cell Transplantation 26, no. 8 (August 2017): 1380–91. http://dx.doi.org/10.1177/0963689717720281.

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Diabetes affects millions of people worldwide, and β-cell replacement is one of the promising new strategies for treatment. Induced pluripotent stem cells (iPSCs) can differentiate into any cell type, including pancreatic β cells, providing a potential treatment for diabetes. However, the molecular mechanisms underlying the differentiation of iPSC-derived β cells have not yet been fully elucidated. Here, we generated pancreatic β-like cells from mouse iPSCs using a 3-step protocol and performed deep RNA sequencing to get a transcriptional landscape of iPSC-derived pancreatic β-like cells during the selective differentiation period. We then focused on the differentially expressed genes (DEGs) during the time course of the differentiation period, and these genes underwent Gene Ontology annotation and Kyoto Encyclopedia of Genes and Genomes pathway analysis. In addition, gene-act networks were constructed for these DEGs, and the expression of pivotal genes detected by quantitative real-time polymerase chain reaction was well correlated with RNA sequence (RNA-seq). Overall, our study provides valuable information regarding the transcriptome changes in β cells derived from iPSCs during differentiation, elucidates the biological process and pathways underlying β-cell differentiation, and promotes the identification and functional analysis of potential genes that could be used for improving functional β-cell generation from iPSCs.

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Raducanu, Aurelia, and Heiko Lickert. "Understanding Pancreas Development for β-Cell Repair and Replacement Therapies." Current Diabetes Reports 12, no. 5 (July 11, 2012): 481–89. http://dx.doi.org/10.1007/s11892-012-0301-8.

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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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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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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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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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Maxwell, Kristina G., Punn Augsornworawat, Leonardo Velazco-Cruz, Michelle H. Kim, Rie Asada, Nathaniel J. Hogrebe, Shuntaro Morikawa, Fumihiko Urano, and Jeffrey R. Millman. "Gene-edited human stem cell–derived β cells from a patient with monogenic diabetes reverse preexisting diabetes in mice." Science Translational Medicine 12, no. 540 (April 22, 2020): eaax9106. http://dx.doi.org/10.1126/scitranslmed.aax9106.

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Differentiation of insulin-producing pancreatic β cells from induced pluripotent stem cells (iPSCs) derived from patients with diabetes promises to provide autologous cells for diabetes cell replacement therapy. However, current approaches produce patient iPSC-derived β (SC-β) cells with poor function in vitro and in vivo. Here, we used CRISPR-Cas9 to correct a diabetes-causing pathogenic variant in Wolfram syndrome 1 (WFS1) in iPSCs derived from a patient with Wolfram syndrome (WS). After differentiation to β cells with our recent six-stage differentiation strategy, corrected WS SC-β cells performed robust dynamic insulin secretion in vitro in response to glucose and reversed preexisting streptozocin-induced diabetes after transplantation into mice. Single-cell transcriptomics showed that corrected SC-β cells displayed increased insulin and decreased expression of genes associated with endoplasmic reticulum stress. CRISPR-Cas9 correction of a diabetes-inducing gene variant thus allows for robust differentiation of autologous SC-β cells that can reverse severe diabetes in an animal model.

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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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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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Pellegrini, Silvia, Valentina Zamarian, Elisa Landi, Alessandro Cospito, Marta Tiffany Lombardo, Fabio Manenti, Antonio Citro, Marco Schiavo Lena, Lorenzo Piemonti, and Valeria Sordi. "Treating iPSC-Derived β Cells with an Anti-CD30 Antibody–Drug Conjugate Eliminates the Risk of Teratoma Development upon Transplantation." International Journal of Molecular Sciences 23, no. 17 (August 26, 2022): 9699. http://dx.doi.org/10.3390/ijms23179699.

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Insulin-producing cells derived from induced pluripotent stem cells (iPSCs) are promising candidates for β cell replacement in type 1 diabetes. However, the risk of teratoma formation due to residual undifferentiated iPSCs contaminating the differentiated cells is still a critical concern for clinical application. Here, we hypothesized that pretreatment of iPSC-derived insulin-producing cells with an anti-CD30 antibody–drug conjugate could prevent in vivo teratoma formation by selectively killing residual undifferentiated cells. CD30 is expressed in all human iPSCs clones tested by flow cytometry (n = 7) but not in iPSC-derived β cells (iβs). Concordantly, anti-CD30 treatment in vitro for 24 h induced a dose-dependent cell death (up to 90%) in human iPSCs while it did not kill iβs nor had an impact on iβ identity and function, including capacity to secrete insulin in response to stimuli. In a model of teratoma assay associated with iβ transplantation, the pretreatment of cells with anti-CD30 for 24 h before the implantation into NOD-SCID mice completely eliminated teratoma development (0/10 vs. 8/8, p < 0.01). These findings suggest that short-term in vitro treatment with clinical-grade anti-CD30, targeting residual undifferentiated cells, eliminates the tumorigenicity of iPSC-derived β cells, potentially providing enhanced safety for iPSC-based β cell replacement therapy in clinical scenarios.

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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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Benthuysen, Jacqueline R., Andrea C. Carrano, and Maike Sander. "Advances in β cell replacement and regeneration strategies for treating diabetes." Journal of Clinical Investigation 126, no. 10 (October 3, 2016): 3651–60. http://dx.doi.org/10.1172/jci87439.

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Levine, Fred. "Gene therapy for diabetes: strategies for β-cell modification and replacement." Diabetes / Metabolism Reviews 13, no. 4 (December 1997): 209–46. http://dx.doi.org/10.1002/(sici)1099-0895(199712)13:4<209::aid-dmr198>3.0.co;2-n.

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Sambathkumar, Rangarajan, Adriana Migliorini, and Maria Cristina Nostro. "Pluripotent Stem Cell-Derived Pancreatic Progenitors and β-Like Cells for Type 1 Diabetes Treatment." Physiology 33, no. 6 (November 1, 2018): 394–402. http://dx.doi.org/10.1152/physiol.00026.2018.

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In this review, we focus on the processes guiding human pancreas development and provide an update on methods to efficiently generate pancreatic progenitors (PPs) and β-like cells in vitro from human pluripotent stem cells (hPSCs). Furthermore, we assess the strengths and weaknesses of using PPs and β-like cell for cell replacement therapy for the treatment of Type 1 diabetes with respect to cell manufacturing, engrafting, functionality, and safety. Finally, we discuss the identification and use of specific cell surface markers to generate safer populations of PPs for clinical translation and to study the development of PPs in vivo and in vitro.

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Assefa, Zerihun, Sarah Akbib, Astrid Lavens, Geert Stangé, Zhidong Ling, Karine H. Hellemans, and Daniel Pipeleers. "Direct effect of glucocorticoids on glucose-activated adult rat β-cells increases their cell number and their functional mass for transplantation." American Journal of Physiology-Endocrinology and Metabolism 311, no. 4 (October 1, 2016): E698—E705. http://dx.doi.org/10.1152/ajpendo.00070.2016.

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Compounds that increase β-cell number can serve as β-cell replacement therapies in diabetes. In vitro studies have identified several agents that can activate DNA synthesis in primary β-cells but only in small percentages of cells and without demonstration of increases in cell number. We used whole well multiparameter imaging to first screen a library of 1,280 compounds for their ability to recruit adult rat β-cells into DNA synthesis and then assessed influences of stimulatory agents on the number of living cells. The four compounds with highest β-cell recruitment were glucocorticoid (GC) receptor ligands. The GC effect occurred in glucose-activated β-cells and was associated with increased glucose utilization and oxidation. Hydrocortisone and methylprednisolone almost doubled the number of β-cells in 2 wk. The expanded cell population provided an increased functional β-cell mass for transplantation in diabetic animals. These effects are age dependent; they did not occur in neonatal rat β-cells, where GC exposure suppressed basal replication and was cytotoxic. We concluded that GCs can induce the replication of adult rat β-cells through a direct action, with intercellular differences in responsiveness that have been related to differences in glucose activation and in age. These influences can explain variability in GC-induced activation of DNA synthesis in rat and human β-cells. Our study also demonstrated that β-cells can be expanded in vitro to increase the size of metabolically adequate grafts.

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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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Chhoun, Jennifer M., Kristin J. Voltzke, and Meri T. Firpo. "From cell culture to a cure: pancreatic β-cell replacement strategies for diabetes mellitus." Regenerative Medicine 7, no. 5 (September 2012): 685–95. http://dx.doi.org/10.2217/rme.12.39.

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Corritore, Elisa, Yong-Syu Lee, Etienne M. Sokal, and Philippe A. Lysy. "β-cell replacement sources for type 1 diabetes: a focus on pancreatic ductal cells." Therapeutic Advances in Endocrinology and Metabolism 7, no. 4 (July 31, 2016): 182–99. http://dx.doi.org/10.1177/2042018816652059.

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Rapoport, Daniel H., Sandra Danner, and Charli Kruse. "Glandular stem cells are a promising source for much more than β-cell replacement." Annals of Anatomy - Anatomischer Anzeiger 191, no. 1 (January 2009): 62–69. http://dx.doi.org/10.1016/j.aanat.2008.06.004.

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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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Kitamura, Tadahiro, Yukari Ido Kitamura, Masaki Kobayashi, Osamu Kikuchi, Tsutomu Sasaki, Ronald A. DePinho, and Domenico Accili. "Regulation of Pancreatic Juxtaductal Endocrine Cell Formation by FoxO1." Molecular and Cellular Biology 29, no. 16 (June 8, 2009): 4417–30. http://dx.doi.org/10.1128/mcb.01622-08.

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ABSTRACT An understanding of the mechanisms that govern pancreatic endocrine cell ontogeny may offer strategies for their somatic replacement in diabetic patients. During embryogenesis, transcription factor FoxO1 is expressed in pancreatic progenitor cells. Subsequently, it becomes restricted to β cells and to a rare population of insulin-negative juxtaductal cells (FoxO1+ Ins−). It is unclear whether FoxO1+ Ins− cells give rise to endocrine cells. To address this question, we first evaluated FoxO1's role in pancreas development using gain- and loss-of-function alleles in mice. Premature FoxO1 activation in pancreatic progenitors promoted α-cell formation but curtailed exocrine development. Conversely, FoxO1 ablation in pancreatic progenitor cells, but not in committed endocrine progenitors or terminally differentiated β cells, selectively increased juxtaductal β cells. As these data indicate an involvement of FoxO1 in pancreatic lineage determination, FoxO1+ Ins− cells were clonally isolated and assayed for their capacity to undergo endocrine differentiation. Upon FoxO1 activation, FoxO1+ Ins− cultures converted into glucagon-producing cells. We conclude that FoxO1+ Ins− juxtaductal cells represent a hitherto-unrecognized pancreatic cell population with in vitro capability of endocrine differentiation.

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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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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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Saleh, Mohamed, George K. Gittes, and Krishna Prasadan. "Alpha-to-beta cell trans-differentiation for treatment of diabetes." Biochemical Society Transactions 49, no. 6 (December 9, 2021): 2539–48. http://dx.doi.org/10.1042/bst20210244.

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Diabetes mellitus is a significant cause of morbidity and mortality in the United States and worldwide. According to the CDC, in 2017, ∼34.2 million of the American population had diabetes. Also, in 2017, diabetes was the seventh leading cause of death and has become the number one biomedical financial burden in the United States. Insulin replacement therapy and medications that increase insulin secretion and improve insulin sensitivity are the main therapies used to treat diabetes. Unfortunately, there is currently no radical cure for the different types of diabetes. Loss of β cell mass is the end result that leads to both type 1 and type 2 diabetes. In the past decade, there has been an increased effort to develop therapeutic strategies to replace the lost β cell mass and restore insulin secretion. α cells have recently become an attractive target for replacing the lost β cell mass, which could eventually be a potential strategy to cure diabetes. This review highlights the advantages of using α cells as a source for generating new β cells, the various investigative approaches to convert α cells into insulin-producing cells, and the future prospects and problems of this promising diabetes therapeutic strategy.

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Orlando, Giuseppe, Pierre Gianello, Marcus Salvatori, Robert J. Stratta, Shay Soker, Camillo Ricordi, and Juan Domínguez-Bendala. "Cell Replacement Strategies Aimed at Reconstitution of the β-Cell Compartment in Type 1 Diabetes." Diabetes 63, no. 5 (April 22, 2014): 1433–44. http://dx.doi.org/10.2337/db13-1742.

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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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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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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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Rickels, Michael R., Peter G. Stock, Eelco J. P. de Koning, Lorenzo Piemonti, Johann Pratschke, Rodolfo Alejandro, Melena D. Bellin, et al. "Defining Outcomes for β-cell Replacement Therapy in the Treatment of Diabetes." Transplantation 102, no. 9 (September 2018): 1479–86. http://dx.doi.org/10.1097/tp.0000000000002158.

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Raducanu, Aurelia, and Heiko Lickert. "Erratum to: Understanding Pancreas Development for β-Cell Repair and Replacement Therapies." Current Diabetes Reports 12, no. 5 (July 31, 2012): 633. http://dx.doi.org/10.1007/s11892-012-0312-5.

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Journal articles on the topic 'Β-cell replacement'

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