Use of Induced Pluripotent Stem Cells to Build Isogenic Systems and Investigate Type 1 Diabetes

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 is...

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Autores principales:	Lucas H. Armitage, Scott E. Stimpson, Katherine E. Santostefano, Lina Sui, Similoluwa Ogundare, Brittney N. Newby, Roberto Castro-Gutierrez, Mollie K. Huber, Jared P. Taylor, Prerana Sharma, Ilian A. Radichev, Daniel J. Perry, Natalie C. Fredette, Alexei Y. Savinov, Mark A. Wallet, Naohiro Terada, Todd M. Brusko, Holger A. Russ, Jing Chen, Dieter Egli, Clayton E. Mathews
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	type 1 diabetes mellitus isogenic human beta cells immunity autoimmunity Diseases of the endocrine glands. Clinical endocrinology RC648-665
Acceso en línea:	https://doaj.org/article/4cc69f69404e4a1aa049c8589a0add98
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spelling	oai:doaj.org-article:4cc69f69404e4a1aa049c8589a0add982021-11-09T06:46:09ZUse of Induced Pluripotent Stem Cells to Build Isogenic Systems and Investigate Type 1 Diabetes1664-239210.3389/fendo.2021.737276https://doaj.org/article/4cc69f69404e4a1aa049c8589a0add982021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fendo.2021.737276/fullhttps://doaj.org/toc/1664-2392Type 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.Lucas H. ArmitageLucas H. ArmitageScott E. StimpsonScott E. StimpsonKatherine E. SantostefanoKatherine E. SantostefanoKatherine E. SantostefanoLina SuiSimiloluwa OgundareSimiloluwa OgundareBrittney N. NewbyBrittney N. NewbyRoberto Castro-GutierrezMollie K. HuberMollie K. HuberJared P. TaylorPrerana SharmaIlian A. RadichevDaniel J. PerryDaniel J. PerryNatalie C. FredetteNatalie C. FredetteAlexei Y. SavinovMark A. WalletMark A. WalletMark A. WalletNaohiro TeradaNaohiro TeradaTodd M. BruskoTodd M. BruskoHolger A. RussJing ChenJing ChenDieter EgliClayton E. MathewsClayton E. MathewsClayton E. MathewsFrontiers Media S.A.articletype 1 diabetes mellitusisogenichumanbeta cellsimmunityautoimmunityDiseases of the endocrine glands. Clinical endocrinologyRC648-665ENFrontiers in Endocrinology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	type 1 diabetes mellitus isogenic human beta cells immunity autoimmunity Diseases of the endocrine glands. Clinical endocrinology RC648-665
spellingShingle	type 1 diabetes mellitus isogenic human beta cells immunity autoimmunity Diseases of the endocrine glands. Clinical endocrinology RC648-665 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 Use of Induced Pluripotent Stem Cells to Build Isogenic Systems and Investigate Type 1 Diabetes
description	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.
format	article
author	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
author_facet	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
author_sort	Lucas H. Armitage
title	Use of Induced Pluripotent Stem Cells to Build Isogenic Systems and Investigate Type 1 Diabetes
title_short	Use of Induced Pluripotent Stem Cells to Build Isogenic Systems and Investigate Type 1 Diabetes
title_full	Use of Induced Pluripotent Stem Cells to Build Isogenic Systems and Investigate Type 1 Diabetes
title_fullStr	Use of Induced Pluripotent Stem Cells to Build Isogenic Systems and Investigate Type 1 Diabetes
title_full_unstemmed	Use of Induced Pluripotent Stem Cells to Build Isogenic Systems and Investigate Type 1 Diabetes
title_sort	use of induced pluripotent stem cells to build isogenic systems and investigate type 1 diabetes
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/4cc69f69404e4a1aa049c8589a0add98
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Use of Induced Pluripotent Stem Cells to Build Isogenic Systems and Investigate Type 1 Diabetes

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