Genetically Engineered Human Islets Protected From CD8-mediated Autoimmune Destruction In Vivo

Zaldumbide, Arnaud; Alkemade, Gonnie M.; Carlotti, Françoise; Nikolić, Tatjana; Abreu, Joana R. F.; Engelse, Marten A.; Skowera, Anja; Koning, Eelco J.P. de; Peakman, Mark; Roep, Bart O.; Hoeben, Rob C.; Wiertz, Emmanuel J. H. J.

doi:10.1038/mt.2013.105

Cited by 26 publications

(14 citation statements)

References 49 publications

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“…Pancreatic islets can be dispersed to single cell suspensions for efficient viral transduction; these cells spontaneously re-aggregate into ‘pseudo-islet’ clusters (Hopcroft et al, 1985; Zaldumbide et al, 2013). Using this approach we detected marker gene production (GFP, Figure 5F) in 70–80% of islet cells after dispersion, lentiviral transduction and re-aggregation.…”

Section: Resultsmentioning

confidence: 99%

Age-Dependent Pancreatic Gene Regulation Reveals Mechanisms Governing Human β Cell Function

et al. 2016

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SUMMARY Intensive efforts are focused on identifying regulators of human pancreatic islet cell growth and maturation to accelerate development of therapies for diabetes. After birth, islet cell growth and function are dynamically regulated; however establishing these age-dependent changes in humans has been challenging. Here we describe a multimodal strategy for isolating pancreatic endocrine and exocrine cells from children and adults to identify age-dependent gene expression and chromatin changes on a genomic scale. These profiles revealed distinct proliferative and functional states of islet α-cells or β-cells, and histone modifications underlying age-dependent gene expression changes. Expression of SIX2 and SIX3, transcription factors without prior known functions in the pancreas and linked to fasting hyperglycemia risk, increased with age specifically in human islet β-cells. SIX2 and SIX3 were sufficient to enhance insulin content or secretion in immature β-cells. Our work provides a unique resource to study human-specific regulators of islet cell maturation and function.

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Section: Resultsmentioning

confidence: 99%

Age-Dependent Pancreatic Gene Regulation Reveals Mechanisms Governing Human β Cell Function

et al. 2016

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“…In this context, human islets frequently have been transplanted under the kidney capsule of mice [213] but also into the liver, pancreas, lung, spleen [214] , muscle [215] , bone marrow [216] , and the eye of mice [36] . Even more manifold than the transplantation sites used were the topics investigated in these studies, which include almost all aspects of human islet biology, including T1D [36] , [217] , T2D [218] , [219] and islet transplantation [220] . Also, determinants of human beta cell mass, in particular beta cell proliferation [40] , [221] and apoptosis [222] , as well as modulators of beta cell function have been investigated intensely.…”

Section: Technologies To Study Human Beta Cell Mass and Functionmentioning

confidence: 99%

Human beta cell mass and function in diabetes: Recent advances in knowledge and technologies to understand disease pathogenesis

Chen

Cohrs

Stertmann

et al. 2017

Molecular Metabolism

419

308

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BackgroundPlasma insulin levels are predominantly the product of the morphological mass of insulin producing beta cells in the pancreatic islets of Langerhans and the functional status of each of these beta cells. Thus, deficiency in either beta cell mass or function, or both, can lead to insufficient levels of insulin, resulting in hyperglycemia and diabetes. Nonetheless, the precise contribution of beta cell mass and function to the pathogenesis of diabetes as well as the underlying mechanisms are still unclear. In the past, this was largely due to the restricted number of technologies suitable for studying the scarcely accessible human beta cells. However, in recent years, a number of new platforms have been established to expand the available techniques and to facilitate deeper insight into the role of human beta cell mass and function as cause for diabetes and as potential treatment targets.Scope of ReviewThis review discusses the current knowledge about contribution of human beta cell mass and function to different stages of type 1 and type 2 diabetes pathogenesis. Furthermore, it highlights standard and newly developed technological platforms for the study of human beta cell biology, which can be used to increase our understanding of beta cell mass and function in human glucose homeostasis.Major ConclusionsIn contrast to early disease models, recent studies suggest that in type 1 and type 2 diabetes impairment of beta cell function is an early feature of disease pathogenesis while a substantial decrease in beta cell mass occurs more closely to clinical manifestation. This suggests that, in addition to beta cell mass replacement for late stage therapies, the development of novel strategies for protection and recovery of beta cell function could be most promising for successful diabetes treatment and prevention. The use of today's developing and wide range of technologies and platforms for the study of human beta cells will allow for a more detailed investigation of the underlying mechanisms and will facilitate development of treatment approaches to specifically target human beta cell mass and function.

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“…Human islets were isolated from brain-dead organ donors, as described previously [19]. Briefly, islets were isolated in Good Manufacturing Practice (GMP) facilities at the Leiden University Medical Centre.…”

Section: Proteome Analysis Of Human Isletsmentioning

confidence: 99%

Human islets and dendritic cells generate post-translationally modified islet autoantigens

McLaughlin

Haan

Zaldumbide³

et al. 2016

Clinical and Experimental Immunology

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SummaryThe initiation of type 1 diabetes (T1D) requires a break in peripheral tolerance. New insights into neoepitope formation indicate that posttranslational modification of islet autoantigens, for example via deamidation, may be an important component of disease initiation or exacerbation. Indeed, deamidation of islet autoantigens increases their binding affinity to the T1D highest-risk human leucocyte antigen (HLA) haplotypes HLA-DR3/DQ2 and -DR4/DQ8, increasing the chance that T cells reactive to deamidated autoantigens can be activated upon T cell receptor ligation. Here we investigated human pancreatic islets and inflammatory and tolerogenic human dendritic cells (DC and tolDC) as potential sources of deamidated islet autoantigens and examined whether deamidation is altered in an inflammatory environment. Islets, DC and tolDC contained tissue transglutaminase, the key enzyme responsible for peptide deamidation, and enzyme activity increased following an inflammatory insult. Islets treated with inflammatory cytokines were found to contain deamidated insulin C-peptide. DC, heterozygous for the T1D highest-risk DQ2/8, pulsed with native islet autoantigens could present naturally processed deamidated neoepitopes. HLA-DQ2 or -DQ8 homozygous DC did not present deamidated islet peptides. This study identifies both human islets and DC as sources of deamidated islet autoantigens and implicates inflammatory activation of tissue transglutaminase as a potential mechanism for islet and DC deamidation.

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Genetically Engineered Human Islets Protected From CD8-mediated Autoimmune Destruction In Vivo

Cited by 26 publications

References 49 publications

Age-Dependent Pancreatic Gene Regulation Reveals Mechanisms Governing Human β Cell Function

Age-Dependent Pancreatic Gene Regulation Reveals Mechanisms Governing Human β Cell Function

Human beta cell mass and function in diabetes: Recent advances in knowledge and technologies to understand disease pathogenesis

Human islets and dendritic cells generate post-translationally modified islet autoantigens

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