Abstract
Diabetes mellitus is a multifactorial disease affecting increasing numbers of patients worldwide. Progression to insulin-dependent diabetes mellitus is characterized by the loss or dysfunction of pancreatic β-cells, but the pathomechanisms underlying β-cell failure in type 1 diabetes mellitus and type 2 diabetes mellitus are still poorly defined. Regeneration of β-cell mass from residual islet cells or replacement by β-like cells derived from stem cells holds great promise to stop or reverse disease progression. However, the development of new treatment options is hampered by our limited understanding of human pancreas organogenesis due to the restricted access to primary tissues. Therefore, the challenge is to translate results obtained from preclinical model systems to humans, which requires comparative modelling of β-cell biology in health and disease. Here, we discuss diverse modelling systems across different species that provide spatial and temporal resolution of cellular and molecular mechanisms to understand the evolutionary conserved genotype–phenotype relationship and translate them to humans. In addition, we summarize the latest knowledge on organoids, stem cell differentiation platforms, primary micro-islets and pseudo-islets, bioengineering and microfluidic systems for studying human pancreas development and homeostasis ex vivo. These new modelling systems and platforms have opened novel avenues for exploring the developmental trajectory, physiology, biology and pathology of the human pancreas.
Key points
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The evolutionary differences in pancreas development, function and failure undermine the translation of successful preclinical studies from animal models to humans.
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Establishing novel therapeutic approaches for treatment of diabetes mellitus requires comprehensive understanding of human endocrine pancreas formation and function.
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The proper development of endocrine cells relies on the tight coupling of morphogenetic events with cell differentiation programmes.
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3D organoids and stem cell differentiation systems provide unique platforms for modelling human endocrine cell morphogenesis and differentiation.
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Large animals, such as minipigs, offer novel systems for modelling diabetes mellitus closely to the disease development and progression in humans.
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Establishing organizations that provide human primary pancreatic samples that are healthy or have diabetes mellitus have increased our understanding of pathomechanism of diabetes mellitus.
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Acknowledgements
The authors apologize to those whose work has not been cited due to limited space. The authors would like to thank Ciro Salinno for helpful comments on the manuscript. The authors acknowledge the support of the Helmholtz Association (Helmholtz-Gemeinschaft), German Research Foundation (Deutsche Forschungsgemeinschaft) and German Center for Diabetes Research (Deutsches Zentrum für Diabetes Forschung, DZD e.V.).
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Juvenile Diabetes Research Foundation (JDRF) network program: www.JDRFnPOD.org
Integrated islet distribution program (IIDP): https://iidp.coh.org
Human islet research network (HIRN): https://hirnetwork.org
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Bakhti, M., Böttcher, A. & Lickert, H. Modelling the endocrine pancreas in health and disease. Nat Rev Endocrinol 15, 155–171 (2019). https://doi.org/10.1038/s41574-018-0132-z
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DOI: https://doi.org/10.1038/s41574-018-0132-z
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