In search of a surrogate: engineering human beta cell lines for therapy

Newby, Brittney N.; Terada, Naohiro; Mathews, Clayton E.

doi:10.1016/j.tem.2014.05.006

Cited by 11 publications

(9 citation statements)

References 16 publications

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“…The creation of reliable human insulin‐releasing beta‐cell line could allow the generation of an unlimited number of cells for the study of human beta‐cell physiology, immunogenicity, drug targets and functional mechanisms underlying cellular proliferation, defence and death (Figure ). In addition, such an approach could potentially provide a sustainable supply of cells for antidiabetic insulin cell therapy …”

Section: Human Beta‐cell Line Development and Potential For Therapeutmentioning

confidence: 99%

“…Accordingly, the generation of stable human beta‐cell lines would enormously aid the progression of human‐derived tissue testing, thereby facilitating drug development and a better understanding of human beta‐cell function . Additionally, there is potential for human insulin‐releasing beta‐cell lines, possessing specific attributes, to be implanted into diabetic patients as a means of replacing lost beta‐cells in type‐1 diabetes . Such cells would provide a sustainable alternative to current antidiabetic cell therapy models such as islet transplantation.…”

Section: Introduction and Historical Perspectivementioning

confidence: 99%

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Cellular models for beta‐cell function and diabetes gene therapy

2018

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Diabetes is characterized by the destruction and/or relative dysfunction of insulin-secreting beta-cells in the pancreatic islets of Langerhans. Consequently, considerable effort has been made to understand the physiological processes governing insulin production and secretion in these cells and to elucidate the mechanisms involved in their deterioration in the pathogenesis of diabetes. To date, considerable research has exploited clonal beta-cell lines derived from rodent insulinomas. Such cell lines have proven to be a great asset in diabetes research, in vitro drug testing, and studies of beta-cell physiology and provide a sustainable, and in many cases, more practical alternative to the use of animals or primary tissue. However, selection of the most appropriate rodent beta cell line is often challenging and no single cell line entirely recapitulates the properties of human beta-cells. The generation of stable human beta-cell lines would provide a much more suitable model for studies of human beta-cell physiology and pathology and could potentially be used as a readily available source of implantable insulin-releasing tissue for cell-based therapies of diabetes. In this review, we discuss the history, development, functional characteristics and use of available clonal rodent beta-cell lines, as well as reflecting on recent advances in the generation of human-derived beta-cell lines, their use in research studies and their potential for cell therapy of diabetes.

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Section: Human Beta‐cell Line Development and Potential For Therapeutmentioning

confidence: 99%

Section: Introduction and Historical Perspectivementioning

confidence: 99%

Cellular models for beta‐cell function and diabetes gene therapy

2018

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“…Several alternative sources of beta cells are currently being explored, including human embryonic stem cells (hESCs) [1], proliferating beta cell lines [2], induced pluripotent stem cells [3,4] and xenogeneic islets [5,6]. hESC-derived beta cells are well on the way to clinical translation with recent publications on improved safety and scaling of a protocol being made by Kroon and colleagues [1,7,8].…”

Section: Introductionmentioning

confidence: 99%

Immunogenicity of human embryonic stem cell-derived beta cells

et al. 2016

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Aims/hypothesis To overcome the donor shortage in the treatment of advanced type 1 diabetes by islet transplantation, human embryonic stem cells (hESCs) show great potential as an unlimited alternative source of beta cells. hESCs may have immune privileged properties and it is important to determine whether these properties are preserved in hESC-derived cells. Methods We comprehensively investigated interactions of both innate and adaptive auto-and allo-immunity with hESC-derived pancreatic progenitor cells and hESC-derived endocrine cells, retrieved after in-vivo differentiation in capsules in the subcutis of mice. Results We found that hESC-derived pancreatic endodermal cells expressed relatively low levels of HLA endorsing protection from specific immune responses. HLA was upregulated when exposed to IFNγ, making these endocrine progenitor cells vulnerable to cytotoxic T cells and alloreactive antibodies. In vivo-differentiated endocrine cells were protected from complement, but expressed more HLA and were targets for alloreactive antibody-dependent cellular cytotoxicity and alloreactive cytotoxic T cells. After HLA compatibility was provided by transduction with HLA-A2, preproinsulin-specific T cells killed insulin-producing cells. Conclusions/interpretation hESC-derived pancreatic progenitors are hypoimmunogenic, while in vivo-differentiated endocrine cells represent mature targets for adaptive immune responses. Our data support the need for immune intervention in transplantation of hESC-derived pancreatic progenitors. Cell-impermeable macro-encapsulation may suffice.

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“…In addition, several relatively common drugs were reported to impair β cell function [3,4]. In the past several years, β cell replacement therapy has gained attention as a possibility for addressing β cell loss; unlike whole pancreas transplantation, it has become feasible to explore both pancreatic islet transplantation of islets isolated from organ donors, and cell grafting of singular β cells from sources such as stem cells, transformed cells or human β cell lines [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Differences between studying an islet β cell and studying whole pancreatic islets: immunological implications

2017

JCEI

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The main role of the pancreatic islet β cell is to release the appropriate amount of insulin upon glucose stimulation. For this reason, islet transplantation has been advancing in the past few years as a therapeutic alternative for patients with diabetes, alongside the exciting field of manipulating β cell differentiation for the sake of β cell transplantation. However, do isolated β cells function the same as β cells within an intact islet? Within islets, β cells are surrounded by other cell types, including endocrine cells, endothelial cells and immune cells, a proximity which appears to be relevant for proper glucose homeostasis. Although insulin and glucose are the main regulators in this scenario, other factors, such as angiogenesis, local anti-inflammatory components and the activity profile of resident macrophages, have a profound effect on the function and fate of β cells. A paracrine interaction between β cells and α cell holds a dramatic effect on β cell function, which is additionally dependent on blood flow through the islet. Another important intercellular communication exists between β cells and endothelial cells, in this case a bidirectional interface. Moreover, β cell survival and proliferation is dependent on the potency of ECM proteins. Further parameters distinguish functionally between the isolated β cell and the intact islet, including the deposition of Zinc by β cells, synchronicity by electrical and calcium routes, the physical innervation of islets and more. In this review, we explore major parameters that relate to differences between the function of the isolated β cell and that of the β cell within an intact islet. These and some yet to be investigated aspects of β cell function should be included in the list of considerations when examining therapeutic targets for β cell–related pathologies and for the prospect of effective β cell replacement therapy

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In search of a surrogate: engineering human beta cell lines for therapy

Cited by 11 publications

References 16 publications

Cellular models for beta‐cell function and diabetes gene therapy

Cellular models for beta‐cell function and diabetes gene therapy

Immunogenicity of human embryonic stem cell-derived beta cells

Differences between studying an islet β cell and studying whole pancreatic islets: immunological implications

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