AUTHOR=Armitage Lucas H. , Stimpson Scott E. , Santostefano Katherine E. , Sui Lina , Ogundare Similoluwa , Newby Brittney N. , Castro-Gutierrez Roberto , Huber Mollie K. , Taylor Jared P. , Sharma Prerana , Radichev Ilian A. , Perry Daniel J. , Fredette Natalie C. , Savinov Alexei Y. , Wallet Mark A. , Terada Naohiro , Brusko Todd M. , Russ Holger A. , Chen Jing , Egli Dieter , Mathews Clayton E. TITLE=Use of Induced Pluripotent Stem Cells to Build Isogenic Systems and Investigate Type 1 Diabetes JOURNAL=Frontiers in Endocrinology VOLUME=12 YEAR=2021 URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2021.737276 DOI=10.3389/fendo.2021.737276 ISSN=1664-2392 ABSTRACT=

Type 1 diabetes (T1D) is a disease that arises due to complex immunogenetic mechanisms. Key cell-cell interactions involved in the pathogenesis of T1D are activation of autoreactive T cells by dendritic cells (DC), migration of T cells across endothelial cells (EC) lining capillary walls into the islets of Langerhans, interaction of T cells with macrophages in the islets, and killing of β-cells by autoreactive CD8+ T cells. Overall, pathogenic cell-cell interactions are likely regulated by the individual’s collection of genetic T1D-risk variants. To accurately model the role of genetics, it is essential to build systems to interrogate single candidate genes in isolation during the interactions of cells that are essential for disease development. However, obtaining single-donor matched cells relevant to T1D is a challenge. Sourcing these genetic variants from human induced pluripotent stem cells (iPSC) avoids this limitation. Herein, we have differentiated iPSC from one donor into DC, macrophages, EC, and β-cells. Additionally, we also engineered T cell avatars from the same donor to provide an in vitro platform to study genetic influences on these critical cellular interactions. This proof of concept demonstrates the ability to derive an isogenic system from a single donor to study these relevant cell-cell interactions. Our system constitutes an interdisciplinary approach with a controlled environment that provides a proof-of-concept for future studies to determine the role of disease alleles (e.g. IFIH1, PTPN22, SH2B3, TYK2) in regulating cell-cell interactions and cell-specific contributions to the pathogenesis of T1D.