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

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PTPN2 deficiency amplifies inflammatory signalling and impairs functional maturation of human stem cell-derived islets

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月7日

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  • Valerie Vandenbempt,
  • Javier Negueruela,
  • Francisco Ribeiro-Costa,
  • Mariana Nunes,
  • Leonardo Traini,
  • Sema Elif Eski,
  • Wadsen St-Pierre-Wijckmans,
  • Stéphane Demine,
  • Nicolas Baeyens,
  • Hazem Ibrahim,
  • Luciano G. Martelotto,
  • Sumeet Pal Singh,
  • Alessandra K. Cardozo,
  • Mayank Bansal,
  • Esteban N. Gurzov

摘要

Background

Protein tyrosine phosphatases (PTPs) play key roles in β-cell function and diabetes development. PTPN2 is a candidate gene for type 1 diabetes (T1D) that negatively regulates JAK/STAT signalling. 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 β cells from T1D organ donors and during the differentiation of human stem cell-derived islets (SC-islets) was evaluated using single-cell RNA-Sequencing (scRNA-Seq) datasets. We differentiated CRISPR-Cas12a genome-edited PTPN2-deficient H1 human embryonic stem cells (H1-hESCs) into SC-islets, and scRNA-Seq was performed. The maturation and functionality of 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 β 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 the early stages of SC-islet differentiation and reconstituted at the later stages, suggesting a developmental dynamic. PTPN2 deficiency exacerbated interferon-induced inflammatory signalling in stem cells and differentiated somatic metabolic cells. Interestingly, PTPN2 deficiency increased hedgehog signalling and reduced SC-islet differentiation efficiency in vitro. In addition, PTPN2-knockout SC-islets exhibited reduced glycaemic control after implantation in vivo, mediated by reduced endocrine cell identity and enhanced interferon signalling.

Conclusions

Our study postulates a key role of PTPN2 in preserving β-cell function during inflammatory and metabolic stress in SC-islets.