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Background <p>Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) remains a critical respiratory condition with limited effective treatments.</p> Methods <p>This study investigated whether mesenchymal stem cells (MSCs) preconditioned with supernatant from hypoxia-cultured telocytes (TCs) could enhance therapeutic efficacy in ALI through regulatory T cell (Treg) modulation.</p> Results <p>MSCs preconditioned with 5% hypoxic TC supernatant demonstrated superior efficacy in ameliorating LPS-induced lung injury compared to conventional MSCs or TC monotherapy, as evidenced by preserved alveolar architecture, reduced inflammatory infiltration, and decreased pro-inflammatory cytokines. Mechanistically, these preconditioned MSCs significantly enhanced Treg recruitment to injured lung tissues and improved their immunosuppressive function through the CXCL5/6-CXCR1 axis, an effect that was substantially attenuated upon siRNA-mediated disruption of this pathway, and was further corroborated in a humanized ALI mouse model where preconditioned-MSC treatment improved survival, reduced lung injury severity, and enhanced Treg recruitment and function in a CXCL5/6 signaling-dependent manner.</p> Conclusions <p>These findings reveal a novel mechanism by which hypoxic TC supernatant enhances MSC therapeutic efficacy in ALI through the CXCL5/6-CXCR1 axis, providing a promising strategy for optimizing cellular therapy in inflammatory pulmonary disorders.</p>

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Hypoxic TCs-preconditioned MSCs ameliorate acute lung injury via enhanced Treg recruitment and function through CXCL5/6-CXCR1 axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月26日

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  • Luoyue Yin,
  • Xu Zhang,
  • Yile Zhou,
  • Huihui Ju,
  • Youwei Zhu,
  • Rongrong Gao,
  • Pinwen Wu,
  • Hao Fang

摘要

Background

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) remains a critical respiratory condition with limited effective treatments.

Methods

This study investigated whether mesenchymal stem cells (MSCs) preconditioned with supernatant from hypoxia-cultured telocytes (TCs) could enhance therapeutic efficacy in ALI through regulatory T cell (Treg) modulation.

Results

MSCs preconditioned with 5% hypoxic TC supernatant demonstrated superior efficacy in ameliorating LPS-induced lung injury compared to conventional MSCs or TC monotherapy, as evidenced by preserved alveolar architecture, reduced inflammatory infiltration, and decreased pro-inflammatory cytokines. Mechanistically, these preconditioned MSCs significantly enhanced Treg recruitment to injured lung tissues and improved their immunosuppressive function through the CXCL5/6-CXCR1 axis, an effect that was substantially attenuated upon siRNA-mediated disruption of this pathway, and was further corroborated in a humanized ALI mouse model where preconditioned-MSC treatment improved survival, reduced lung injury severity, and enhanced Treg recruitment and function in a CXCL5/6 signaling-dependent manner.

Conclusions

These findings reveal a novel mechanism by which hypoxic TC supernatant enhances MSC therapeutic efficacy in ALI through the CXCL5/6-CXCR1 axis, providing a promising strategy for optimizing cellular therapy in inflammatory pulmonary disorders.