Stem-Cell-Derived β-Like Cells with a Functional PTPN2 Knockout Display Increased Immunogenicity

Type 1 diabetes is a polygenic disease that results in an autoimmune response directed against insulin-producing beta cells. is a known high-risk type 1 diabetes associated gene expressed in both immune- and pancreatic beta cells, but how genes affect the development of autoimmune diabetes is largel...

Full description

Saved in:

Bibliographic Details
Published in:	Cells (Basel, Switzerland) Vol. 11; no. 23; p. 3845
Main Authors:	Triolo, Taylor M, Matuschek, J Quinn, Castro-Gutierrez, Roberto, Shilleh, Ali H, Williams, Shane P M, Hansen, Maria S, McDaniel, Kristen, Barra, Jessie M, Michels, Aaron, Russ, Holger A
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 30-11-2022 MDPI
Subjects:	Apoptosis Autoimmune diseases autoimmunity Beta cells Cell culture Cell Differentiation Cloning CRISPR CRISPR/Cas9 knockout Diabetes Diabetes mellitus (insulin dependent) Diabetes Mellitus, Type 1 - genetics Disease Genes Genetic aspects genetic risk Genomes Glucose Health aspects Histocompatibility antigen HLA Humans Immunogenicity Inflammation Insulin Insulin-Secreting Cells Lymphocytes T Pluripotency Pluripotent Stem Cells Preproinsulin Protein Tyrosine Phosphatase, Non-Receptor Type 2 - genetics PTPN2 PTPN2 protein Risk factors Signal transduction Sodium Stem cells stem-cell-derived pancreatic beta cells T-Lymphocytes Transcriptomics Type 1 diabetes United States United States > US stem-cell-derived pancreatic beta cells type 1 diabetes autoimmunity autoreactive TCR transductants direct differentiation genetic risk CRISPR/Cas9 knockout co-culture PTPN2
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Type 1 diabetes is a polygenic disease that results in an autoimmune response directed against insulin-producing beta cells. is a known high-risk type 1 diabetes associated gene expressed in both immune- and pancreatic beta cells, but how genes affect the development of autoimmune diabetes is largely unknown. We employed CRISPR/Cas9 technology to generate a functional knockout of in human pluripotent stem cells (hPSC) followed by differentiating stem-cell-derived beta-like cells (sBC) and detailed phenotypical analyses. The differentiation efficiency of knockout (PTPN2 KO) sBC is comparable to wild-type (WT) control sBC. Global transcriptomics and protein assays revealed the increased expression of HLA Class I molecules in PTPN2 KO sBC at a steady state and upon exposure to proinflammatory culture conditions, indicating a potential for the increased immune recognition of human beta cells upon differential expression. sBC co-culture with autoreactive preproinsulin-reactive T cell transductants confirmed increased immune stimulations by PTPN2 KO sBC compared to WT sBC. Taken together, our results suggest that the dysregulation of expression in human beta cell may prime autoimmune T cell reactivity and thereby contribute to the development of type 1 diabetes.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2073-4409 2073-4409
DOI:	10.3390/cells11233845