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Review
. 2021 Apr 1:12:635662.
doi: 10.3389/fendo.2021.635662. eCollection 2021.

Modeling Type 1 Diabetes Using Pluripotent Stem Cell Technology

Kriti Joshi  1   2   3 , Fergus Cameron  3   4   5 , Swasti Tiwari  2 , Stuart I Mannering  6 , Andrew G Elefanty  3   5   7 , Edouard G Stanley  3   5   7
Affiliations
Review

Modeling Type 1 Diabetes Using Pluripotent Stem Cell Technology

Kriti Joshi et al. Front Endocrinol (Lausanne). .

Abstract

Induced pluripotent stem cell (iPSC) technology is increasingly being used to create in vitro models of monogenic human disorders. This is possible because, by and large, the phenotypic consequences of such genetic variants are often confined to a specific and known cell type, and the genetic variants themselves can be clearly identified and controlled for using a standardized genetic background. In contrast, complex conditions such as autoimmune Type 1 diabetes (T1D) have a polygenic inheritance and are subject to diverse environmental influences. Moreover, the potential cell types thought to contribute to disease progression are many and varied. Furthermore, as HLA matching is critical for cell-cell interactions in disease pathogenesis, any model that seeks to test the involvement of particular cell types must take this restriction into account. As such, creation of an in vitro model of T1D will require a system that is cognizant of genetic background and enables the interaction of cells representing multiple lineages to be examined in the context of the relevant environmental disease triggers. In addition, as many of the lineages critical to the development of T1D cannot be easily generated from iPSCs, such models will likely require combinations of cell types derived from in vitro and in vivo sources. In this review we imagine what an ideal in vitro model of T1D might look like and discuss how the required elements could be feasibly assembled using existing technologies. We also examine recent advances towards this goal and discuss potential uses of this technology in contributing to our understanding of the mechanisms underlying this autoimmune condition.

Keywords: T cell receptor; T cells; antigen presenting cells; induced pluripotent stem cells; macrophages; type 1 diabetes.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Overview of the pathogenesis of T1D. This process envisages an initial insult that creates beta cell stress or death. The former potentially leading to the production of neoantigens and the latter resulting in the release of beta cell proteins. This damage results in the attraction of immune cells, with emigrant antigen presenting cells picking up and processing the proteins and conveying them to the pancreatic lymph nodes. Here, autoreactive or neoantigen specific T cells are recruited and these then migrate back to the pancreas, potentially promoting further inflammation, stress and cell death. This positive feedback loop ultimately results in the loss of beta cells.
Figure 2
Figure 2
Utility of an idealized model of T1D. The schematic suggests various inputs to the model, how the effects of these inputs could be assayed, as well as long term potential outputs. Note that this representation of the model does not specifically include a host of non-immune and non-endocrine cells which may also impact on the disease pathogenesis. Additionally, although a limited number of assays are shown, analyses specific to particular cell types are likely to increase the breadth and depth of data that could collected from such a system.
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References

    1. Mannering SI, Pathiraja V, Kay TW. The case for an autoimmune aetiology of type 1 diabetes. Clin Exp Immunol (2016) 1831(1):8–15. 10.1111/cei.12699 - DOI - PMC - PubMed
    1. Federation ID. International Diabetes Federation. IDF Diabetes Atlas, 9th edn.: Brussels, Belgium: International Diabetes Federation. (2019) 2019.
    1. Staeva TP, Chatenoud L, Insel R, Atkinson MA. Recent lessons learned from prevention and recent-onset type 1 diabetes immunotherapy trials. Diabetes (2013) 621(5):9–17. 10.2337/db12-0562 - DOI - PMC - PubMed
    1. Reed JC, Herold KC. Thinking bedside at the bench: the NOD mouse model of T1DM. Nat Rev Endocrinol (2015) 115(5):308–14. 10.1038/nrendo.2014.236 - DOI - PMC - PubMed
    1. Roep BO, Atkinson M, von Herrath M. Satisfaction (not) guaranteed: re-evaluating the use of animal models of type 1 diabetes. Nat Rev Immunol (2004) 412(12):989–97. 10.1038/nri1502 - DOI - PubMed

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