Modeling Type 1 Diabetes Using Pluripotent Stem Cell Technology

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.

Modeling human T1D-associated autoimmune processes

“…The iiChip and other MPS also have the capability to use iPSCs from donors with or without T1D to generate endothelial/endocrine tissues along with immune cells. Importantly, iPSC-derived systems provide the most flexibility in producing isogenic systems with a variety of cell types (β-cells, endothelial cells, mesenchymal cells, monocytes, macrophages, DCs) from the same iPSC line [ 87 ] ( Figure 1 C). What makes iPSCs particularly attractive is the fact that they can be produced from any living donor with a desired genotype/endotype (preserving the genetics of the disease) without requiring invasive procedures or treatments, and they can be genetically engineered to dissect the role of specific genes.…”

“…TECs), it has not yet been possible to differentiate them in vitro such that they sufficiently resemble the native cell phenotypically and functionally. Current in vitro studies using multiple iPSC-derived cell types are focusing on the interaction between iPSC-derived β-cells and primary T cells [ 93 ], although iPSC-derived myeloid cells have also been used [ 87 ]. The use of MPS and iPSCs to produce complex isogenic systems and its challenges will be the subject of a dedicated review in the series.…”

“…For in vitro models to be physiologically relevant, multiple cell types will have to be generated, combined together in the right proportions and maintained under appropriate conditions for the duration of the experiment. For example, modeling infiltrated islets in T1D will require islet organoids containing not only β-cells but other endocrine cells, macrophages, endothelial cells, fibroblasts, T and B lymphocytes, and possibly other populations such as neural cells [ 87 ]. For in vivo models, on the other hand, improved humanized recipient mice will provide the stromal infrastructure and many of the signals required for human immune cells to develop, and in this case, most efforts should be focused on producing iPSC-derived HSCs with comparable differentiation potential as bona fide HSCs.…”

Stem Cell-Derived β Cells: A Versatile Research Platform to Interrogate the Genetic Basis of β Cell Dysfunction

“…The use of isogenic hESC platforms and patient-derived iPSCs to survey the genetics of T1D at multiple cellular levels has been suggested in the literature [ 250 , 251 , 252 ]. Studies with patient-derived stem cells to model T1D include examples such as: the use of iPSC-derived SC-β to evaluate their response to cytokines [ 253 , 254 ], generation of iPSC-derived APCs to model their interaction with T cells [ 255 ] or complex autologous platforms with iPSC-derived SC-β and immune cells from the same patients [ 256 ].…”

Human Pluripotent Stem Cells Go Diabetic: A Glimpse on Monogenic Variants

“…Co-culture studies of iPSCs derived from T1D patients together with immune cells are one such way to model the mechanisms of T1D in vitro (165). Yet, it has to be kept in mind that this kind of model requires additional prerequisites such as environmental factors and complex composition of different immune cell types as recently reviewed by Joshi et al (166). Modeling T2D in vitro is far more complex as many more different pathogenic mechanisms can cause or even interact to promote T2D development, including multiple genetic and environmental factors.…”