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Updated: Mar 4, 2026
Author Spotlight: Advancements in Cell and Tissue Engineering for Tendon Repair
Published on: March 1, 2024
Inhibiting cGAS-STING to Preserve Mitochondrial-Nuclear Communication and Stemness in Young Tendon Stem Cells: A
Zhuo Zhang1, Weiyong Song1, Heng Yin1
1Department of Orthopedics, Affiliated Hospital of North Sichuan Medical College, Nanchong City, Sichuan Province, P. R. China.
Abstract:
Age-related tendinopathy is common in the elderly. Their refractory nature is linked to low cellular density and poor blood supply of tendons. Key pathological features in aged tendons include the accumulation of senescent tendon-derived stem cells (TDSCs), a decrease in young TDSCs, and an imbalance in the inflammatory microenvironment caused by reactive oxygen species (ROS). Among these, impaired mitochondria-nucleus communication is a central mechanism in disease progression. This study develops a ROS-responsive dual-targeted hydrogel (P/H@Lipo) loaded with selenium nanocatalysts (HPSe) and the STING inhibitor H-151 in liposomes (L-Lipo@H-151). This system releases L-Lipo@H-151 in response to ROS within the inflammatory environment, targeting it to TDSCs to inhibit the cGAS-STING pathway. The simultaneously released HPSe effectively reduces mtDNA leakage and cGAMP production, thereby strengthening the blockade of the cGAS-STING pathway. This process maintains mitochondrial-nuclear communication, which in turn preserves the stemness of young TDSCs by preventing their senescence. Mechanistic studies indicate that HPSe boosts self-renewal and tendinogenic differentiation in young TDSCs by inhibiting the Hippo signaling pathway. In summary, this study develops a novel therapeutic paradigm that targets the mitochondrial-nuclear communication to combat age-related tendinopathy.
Insights
This study developed a novel hydrogel therapy to combat age-related tendinopathy by restoring mitochondrial-nuclear communication in tendon stem cells. The treatment prevents cell senescence and promotes tendon healing.
Area of Science:
- Biomedical Engineering
- Regenerative Medicine
- Stem Cell Biology
Background:
- Age-related tendinopathy presents challenges due to low cellularity and poor vascularity in tendons.
- Key factors include senescent tendon-derived stem cells (TDSCs), reduced young TDSCs, and oxidative stress.
- Impaired mitochondria-nucleus communication is a critical driver of tendinopathy progression.
Purpose of the Study:
- To develop a novel therapeutic strategy targeting mitochondria-nucleus communication in age-related tendinopathy.
- To create a ROS-responsive hydrogel system delivering specific therapeutic agents to TDSCs.
- To investigate the therapeutic potential of this system in preserving TDSC function and promoting tendon repair.
Main Methods:
- Development of a ROS-responsive dual-targeted hydrogel (P/H@Lipo) loaded with selenium nanocatalysts (HPSe) and a STING inhibitor (H-151) in liposomes.
- In vitro and in vivo studies to evaluate the hydrogel's efficacy in reducing inflammation and restoring TDSC function.
- Mechanistic investigations into the effects of HPSe on mitochondrial-nuclear communication, Hippo signaling, and TDSC self-renewal/differentiation.
Main Results:
- The P/H@Lipo system effectively released its payload in response to ROS, targeting TDSCs.
- HPSe reduced mtDNA leakage and cGAMP production, reinforcing the blockade of the cGAS-STING pathway.
- The treatment preserved mitochondrial-nuclear communication, prevented TDSC senescence, and promoted self-renewal and tendinogenic differentiation via Hippo pathway inhibition.
Conclusions:
- This study presents a novel therapeutic paradigm for age-related tendinopathy centered on restoring mitochondria-nucleus communication.
- The developed ROS-responsive hydrogel system offers a promising approach for targeted delivery of therapeutic agents to TDSCs.
- The findings highlight the potential of targeting cellular senescence and inflammatory pathways for effective tendon regeneration.
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