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PTPN2 deficiency amplifies interferon signaling and impairs functional maturation of human stem cell-derived islets [ATAC-Seq]

ABSTRACT: Background: Protein tyrosine phosphatases (PTPs) play key roles in b-cell function and diabetes development. PTPN2 is a candidate gene for type 1 diabetes (T1D) that negatively regulates the JAK/STAT signaling. However, the impact of PTPN2 deficiency on the differentiation and functionality of human stem cell-derived somatic metabolic cells remains unclear. Methods: PTPN2 expression in b cells from T1D organ donors and during the differentiation of human stem cell-derived islets (SC-islets) was evaluated in single-cell RNA-Sequencing data. Moreover, we differentiated CRISPR-Cas12a genome-edited PTPN2-deficient H1 human embryonic stem cells (H1-hESCs) into SC-islets, and sc RNA-Seq was performed. The maturation and functionality PTPN2 deficient SC-islets were assessed by implantation under the kidney capsule of NOD-SCID mice. Results: scRNA-Seq analysis showed that PTPN2 expression was increased in b cells from recently diagnosed T1D and decreased in long-standing T1D organ donors, compared with controls. Conversely, we found that PTPN2 expression was decreased at early stages of SC-islet differentiation and reconstituted at later stages, suggesting a developmental dynamic. CRISPR/Cas12-mediated gene editing was used to generate PTPN2-knockout human embryonic stem cells. PTPN2 deficiency exacerbated interferon-induced inflammatory signaling in stem cells and differentiated somatic metabolic cells. Interestingly, PTPN2 deficiency increased hedgehog signaling and reduced SC-islet differentiation efficiency in vitro. In addition, PTPN2-knockout SC-islets exhibited reduced glycemic control after implantation in vivo, mediated by reduced cell endocrine identity and enhanced interferon signaling. Conclusions: Our study postulates a key role of PTPN2 in preserving b-cell function during inflammatory and metabolic stress in SC-islets.

ORGANISM(S): Homo sapiens

PROVIDER: GSE303368 | GEO | 2026/03/18

REPOSITORIES: GEO

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Project description:Background: Thioredoxin-interacting protein (TXNIP) regulates endoplasmic reticulum (ER) and oxidative stress, impairing glucose homeostasis in diabetes. However, it is unclear if TXNIP deficiency can improve differentiation or functionality of human stem cell-derived somatic metabolic cells. Methods: Using CRISPR-Cas12a genome editing, we generated TXNIP-deficient (TXNIP-/-) H1 human embryonic stem cells (H1-hESCs). These cells were differentiated into hepatocyte-like cells (HLCs) and stem-cell-derived insulin-producing islets (SC-islets). TXNIP-/- and TXNIP+/+ SC-islet maturation and functionality was assessed by implantation under the kidney capsule of NOD-SCID mice. Results: TXNIP deficiency significantly increased H1-hESC proliferation without affecting pluripotency, viability, or differentiation potential into HLCs and SC-islets. Bulk RNA-sequencing of thapsigargin-treated TXNIP-/- and TXNIP+/+ hESCs revealed differential expression of stress-responsive genes, with enriched apoptosis-related pathways in TXNIP+/+ cells but minimal transcriptional changes specific to TXNIP deficiency. In HLCs, TXNIP deletion reduced albumin secretion and insulin signalling, as indicated by decreased AKT phosphorylation, while showing no differences in glycolytic activity or lipid metabolism markers. Under thapsigargin-induced ER stress, TXNIP-/- HLCs exhibited transiently reduced eIF2α phosphorylation and lower BiP expression, suggesting compromised adaptive responses to prolonged stress. SC-islets derived from TXNIP-/- hESCs showed comparable viability, endocrine cell composition, and cytokine responses to TXNIP+/+ islets. Upon IFNα and IFNγ treatment, STAT1 phosphorylation was increased in TXNIP-/- SC-islets, indicating that IFN signalling remains active despite TXNIP deficiency. TXNIP-/- or TXNIP+/+ islets SC-islets implanted into NOD-SCID mice produced human C-peptide and responded to glucose stimulation. However, TXNIP-/- SC-islets showed no enhancement in glycaemic control or glucose-stimulated insulin secretion compared to controls. Conclusions: Our study demonstrates that TXNIP deficiency does not improve the differentiation of HLCs and SC-islets. We report the generation and characterization of TXNIP-/- and TXNIP+/+ H1-hESCs, HLCs and SC-islets as robust models for future studies of TXNIP’s role in metabolic cell biology.

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PTPN2 deficiency amplifies interferon signaling and impairs functional maturation of human stem cell-derived islets [ATAC-Seq]

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