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Background <p>Endothelial cell (EC) senescence driven by oxidative stress is a pivotal contributor to vasculopathy in systemic sclerosis (SSc), leading to impaired angiogenesis and loss of vascular integrity. Three-dimensional (3D) cultured human umbilical cord-derived mesenchymal stromal cells (MSCs) represent a promising therapeutic strategy for SSc due to their enhanced anti-fibrotic and immunomodulatory properties. However, their potential to mitigate EC senescence remains unclear. This study aims to investigate whether 3D-MSCs confer superior therapeutic effects over conventional MSCs by ameliorating EC senescence and to elucidate the underlying mechanism.</p> Methods <p>The anti-senescent effects of 3D-MSCs and two-dimensional (2D)-MSCs were compared in vitro using a hydrogen peroxide (H₂O₂)-induced EC senescence model and in vivo using a bleomycin-induced SSc mouse model. RNA sequencing identified vasohibin-2 (VASH2) as a key factor, which was further validated using siRNA knockdown. The specific inhibitor EpoY was used to assess the role of VASH2 in microtubule detyrosination in senescent ECs.</p> Results <p>3D-MSCs prevented H₂O₂-induced EC senescence and restored angiogenic capacity in vitro. Administration of 3D-MSCs ameliorated skin fibrosis and vasculopathy in SSc mouse models by mitigating EC senescence, thereby improving vascular density and restoring endothelial barrier integrity. Mechanistically, 3D-MSCs secreted VASH2, which then interacted with the small vasohibin-binding protein (SVBP) to restore microtubule detyrosination in senescent ECs under oxidative stress. Inhibition of the VASH/SVBP complex by EpoY impaired the anti-senescent benefits of 3D-MSCs.</p> Conclusions <p>Our study demonstrates that 3D-MSCs alleviate oxidative stress-induced EC senescence and associated vasculopathy primarily via VASH2 secretion, which restores α-tubulin detyrosination to promote microtubule stability. These findings reveal a novel mechanism against EC senescence and underscore the therapeutic potential of 3D-MSCs in vasculopathy.</p>

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3D-Mesenchymal stromal cells derived VASH2 alleviates oxidative stress-induced endothelial senescence by mediating α-tubulin detyrosination in systemic sclerosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月11日

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  • Yue Zhang,
  • Yirui Shi,
  • Sha Liu,
  • Yunxia Yan,
  • Zhikang Wang,
  • Dapeng Yang,
  • Xin Wen,
  • Ying Zhu,
  • Xiulan Zheng,
  • Yuxuan Chen,
  • Shanshan Liu,
  • Lingyun Sun

摘要

Background

Endothelial cell (EC) senescence driven by oxidative stress is a pivotal contributor to vasculopathy in systemic sclerosis (SSc), leading to impaired angiogenesis and loss of vascular integrity. Three-dimensional (3D) cultured human umbilical cord-derived mesenchymal stromal cells (MSCs) represent a promising therapeutic strategy for SSc due to their enhanced anti-fibrotic and immunomodulatory properties. However, their potential to mitigate EC senescence remains unclear. This study aims to investigate whether 3D-MSCs confer superior therapeutic effects over conventional MSCs by ameliorating EC senescence and to elucidate the underlying mechanism.

Methods

The anti-senescent effects of 3D-MSCs and two-dimensional (2D)-MSCs were compared in vitro using a hydrogen peroxide (H₂O₂)-induced EC senescence model and in vivo using a bleomycin-induced SSc mouse model. RNA sequencing identified vasohibin-2 (VASH2) as a key factor, which was further validated using siRNA knockdown. The specific inhibitor EpoY was used to assess the role of VASH2 in microtubule detyrosination in senescent ECs.

Results

3D-MSCs prevented H₂O₂-induced EC senescence and restored angiogenic capacity in vitro. Administration of 3D-MSCs ameliorated skin fibrosis and vasculopathy in SSc mouse models by mitigating EC senescence, thereby improving vascular density and restoring endothelial barrier integrity. Mechanistically, 3D-MSCs secreted VASH2, which then interacted with the small vasohibin-binding protein (SVBP) to restore microtubule detyrosination in senescent ECs under oxidative stress. Inhibition of the VASH/SVBP complex by EpoY impaired the anti-senescent benefits of 3D-MSCs.

Conclusions

Our study demonstrates that 3D-MSCs alleviate oxidative stress-induced EC senescence and associated vasculopathy primarily via VASH2 secretion, which restores α-tubulin detyrosination to promote microtubule stability. These findings reveal a novel mechanism against EC senescence and underscore the therapeutic potential of 3D-MSCs in vasculopathy.