Frontiers in Endocrinology (Nov 2021)
Use of Induced Pluripotent Stem Cells to Build Isogenic Systems and Investigate Type 1 Diabetes
- Lucas H. Armitage,
- Lucas H. Armitage,
- Scott E. Stimpson,
- Scott E. Stimpson,
- Katherine E. Santostefano,
- Katherine E. Santostefano,
- Katherine E. Santostefano,
- Lina Sui,
- Similoluwa Ogundare,
- Similoluwa Ogundare,
- Brittney N. Newby,
- Brittney N. Newby,
- Roberto Castro-Gutierrez,
- Mollie K. Huber,
- Mollie K. Huber,
- Jared P. Taylor,
- Prerana Sharma,
- Ilian A. Radichev,
- Daniel J. Perry,
- Daniel J. Perry,
- Natalie C. Fredette,
- Natalie C. Fredette,
- Alexei Y. Savinov,
- Mark A. Wallet,
- Mark A. Wallet,
- Mark A. Wallet,
- Naohiro Terada,
- Naohiro Terada,
- Todd M. Brusko,
- Todd M. Brusko,
- Holger A. Russ,
- Jing Chen,
- Jing Chen,
- Dieter Egli,
- Clayton E. Mathews,
- Clayton E. Mathews,
- Clayton E. Mathews
Affiliations
- Lucas H. Armitage
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, United States
- Lucas H. Armitage
- University of Florida Diabetes Institute, University of Florida, Gainesville, FL, United States
- Scott E. Stimpson
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, United States
- Scott E. Stimpson
- University of Florida Diabetes Institute, University of Florida, Gainesville, FL, United States
- Katherine E. Santostefano
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, United States
- Katherine E. Santostefano
- Center for Cellular Reprogramming, College of Medicine, University of Florida, Gainesville, FL, United States
- Katherine E. Santostefano
- Century Therapeutics, iPSC Biology, Philadelphia, PA, United States
- Lina Sui
- Department of Pediatrics, Naomi Berrie Diabetes Center, Columbia Stem Cell Initiative, Columbia University, New York, NY, United States
- Similoluwa Ogundare
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, United States
- Similoluwa Ogundare
- University of Florida Diabetes Institute, University of Florida, Gainesville, FL, United States
- Brittney N. Newby
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, United States
- Brittney N. Newby
- University of Florida Diabetes Institute, University of Florida, Gainesville, FL, United States
- Roberto Castro-Gutierrez
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, United States
- Mollie K. Huber
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, United States
- Mollie K. Huber
- University of Florida Diabetes Institute, University of Florida, Gainesville, FL, United States
- Jared P. Taylor
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, United States
- Prerana Sharma
- Children’s Health Research Center, Sanford Research, Sioux Falls, SD, United States
- Ilian A. Radichev
- Children’s Health Research Center, Sanford Research, Sioux Falls, SD, United States
- Daniel J. Perry
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, United States
- Daniel J. Perry
- University of Florida Diabetes Institute, University of Florida, Gainesville, FL, United States
- Natalie C. Fredette
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, United States
- Natalie C. Fredette
- Center for Cellular Reprogramming, College of Medicine, University of Florida, Gainesville, FL, United States
- Alexei Y. Savinov
- Children’s Health Research Center, Sanford Research, Sioux Falls, SD, United States
- Mark A. Wallet
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, United States
- Mark A. Wallet
- University of Florida Diabetes Institute, University of Florida, Gainesville, FL, United States
- Mark A. Wallet
- Century Therapeutics, Immunology, Philadelphia, PA, United States
- Naohiro Terada
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, United States
- Naohiro Terada
- Center for Cellular Reprogramming, College of Medicine, University of Florida, Gainesville, FL, United States
- Todd M. Brusko
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, United States
- Todd M. Brusko
- University of Florida Diabetes Institute, University of Florida, Gainesville, FL, United States
- Holger A. Russ
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, United States
- Jing Chen
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, United States
- Jing Chen
- University of Florida Diabetes Institute, University of Florida, Gainesville, FL, United States
- Dieter Egli
- Department of Pediatrics, Naomi Berrie Diabetes Center, Columbia Stem Cell Initiative, Columbia University, New York, NY, United States
- Clayton E. Mathews
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, United States
- Clayton E. Mathews
- University of Florida Diabetes Institute, University of Florida, Gainesville, FL, United States
- Clayton E. Mathews
- Center for Cellular Reprogramming, College of Medicine, University of Florida, Gainesville, FL, United States
- DOI
- https://doi.org/10.3389/fendo.2021.737276
- Journal volume & issue
-
Vol. 12
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.
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