Materials today. Bio · 2026
Multi-omics-guided targeting of the CD14-NF-κB axis with PGA1-loaded liposomes restores CD14hi TSPCs function and promotes tendon-bone healing in diabetes.
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Tong Minghao, Liu Liyan, Liu Wanshun, Qin Haocheng, Mai Zhixuan, Qian Pingkang, Qian Yinhua, Huang Haoqiang, Yang Quan, Wu Xiaofeng, Kuang Chen, He Yanwei, Wan Renwen, Luo Wei, Ou Yuxi, Xu Feng, Cheng Xiaolan, Luo Zhiwen, Wang Qing
Аннотация
BACKGROUND: Type 2 diabetes mellitus (T2DM) is common in patients with rotator cuff tears (RCTs) and is associated with poor tendon-bone healing and high retear rates. Tendon stem/progenitor cells (TSPCs) are central to tendon-bone integration, but how T2DM reprograms TSPCs and whether this can be reversed remain unclear.
METHODS: T2DM was induced in rodents, followed by tendon single-cell RNA sequencing, serum metabolomics and tendon proteomics. TSPCs were isolated for functional assays and analysis of underlying signaling. CD14-overexpressing (CD14hi) TSPCs modeled diabetic-like dysfunction. Free PGA1 and Lipo@PGA1 were evaluated in vitro and in a diabetic RCT model, alongside liposome characterization and safety assessment.
RESULTS: Multi-omics analysis revealed that T2DM induced marked remodeling of the tendon-resident cell landscape, with TSPCs exhibiting upregulated CD14 expression and enrichment of NF-κB-related inflammatory and apoptotic pathways, alongside systemic depletion of serum PGA1. Diabetic and CD14hi TSPCs showed reduced progenitor-like functional properties, accompanied by activation of the CD14-NF-κB axis. PGA1 supplementation or CD14 silencing attenuated NF-κB activation and restored TSPC stemness. PGA1-loaded liposomes showed favorable physicochemical properties, good local retention at the tendon-bone interface, and acceptable systemic and cellular biocompatibility. In the diabetic RCT model, Lipo@PGA1 significantly increased TSPCs, improved tendon-bone healing, and enhanced biomechanical properties and forelimb function.
CONCLUSION: T2DM reprograms tendon-resident TSPCs through a CD14-PGA1-NF-κB axis, driving apoptosis and reducing progenitor-like functional properties. Multi-omics-guided targeting of this axis with PGA1-loaded liposomes restores CD14hi TSPCs function and enhances tendon-bone repair in diabetic RCT, supporting a mechanism-based therapeutic strategy.
METHODS: T2DM was induced in rodents, followed by tendon single-cell RNA sequencing, serum metabolomics and tendon proteomics. TSPCs were isolated for functional assays and analysis of underlying signaling. CD14-overexpressing (CD14hi) TSPCs modeled diabetic-like dysfunction. Free PGA1 and Lipo@PGA1 were evaluated in vitro and in a diabetic RCT model, alongside liposome characterization and safety assessment.
RESULTS: Multi-omics analysis revealed that T2DM induced marked remodeling of the tendon-resident cell landscape, with TSPCs exhibiting upregulated CD14 expression and enrichment of NF-κB-related inflammatory and apoptotic pathways, alongside systemic depletion of serum PGA1. Diabetic and CD14hi TSPCs showed reduced progenitor-like functional properties, accompanied by activation of the CD14-NF-κB axis. PGA1 supplementation or CD14 silencing attenuated NF-κB activation and restored TSPC stemness. PGA1-loaded liposomes showed favorable physicochemical properties, good local retention at the tendon-bone interface, and acceptable systemic and cellular biocompatibility. In the diabetic RCT model, Lipo@PGA1 significantly increased TSPCs, improved tendon-bone healing, and enhanced biomechanical properties and forelimb function.
CONCLUSION: T2DM reprograms tendon-resident TSPCs through a CD14-PGA1-NF-κB axis, driving apoptosis and reducing progenitor-like functional properties. Multi-omics-guided targeting of this axis with PGA1-loaded liposomes restores CD14hi TSPCs function and enhances tendon-bone repair in diabetic RCT, supporting a mechanism-based therapeutic strategy.