B33-18 Human Umbilical Cord-derived Mesenchymal Stem Cells And Their Exosomes Modulate Asthma Through The CGAS/STING/NF-κB Signaling Pathway

Rationale

Asthma causes chronic airway inflammation, airway hyperreactivity, and airway remodeling. Epithelial–mesenchymal transition (EMT) plays a key role in airway remodeling. The cyclic guanosine monophosphate–adenosine monophosphate synthase–stimulator of interferon genes–nuclear factor kappa B (cGAS/STING/NF-κB) pathway regulates chronic inflammatory responses in many diseases. The role of this pathway in asthma remains unclear. Human umbilical cord–derived mesenchymal stem cells (hUCMSCs) show strong anti-inflammatory and immune-regulating effects. Exosomes derived from hUCMSCs show similar properties. Both approaches may provide benefit in asthma. However, few studies directly compare these two treatments. Few studies also examine how this pathway regulates airway inflammation and EMT in asthma.

Methods

We established a mouse asthma model using ovalbumin (OVA) sensitization and challenge. We randomly assigned mice to six groups: Control, Model, Model+hUCMSCs, Model+hUCMSCs+5,6-dimethylxanthenone-4-acetic acid (DMXAA), Model+Exosomes, and Model+Exosomes+DMXAA. DMXAA served as an activator of the cGAS/STING pathway. We evaluated asthma severity by observing mouse behavior. We measured serum levels of tumor necrosis factor alpha, interleukin-1 beta, interleukin-6, and interleukin-17A. We analyzed bronchoalveolar lavage fluid (BALF) for total and differential inflammatory cell counts. We assessed lung inflammation using hematoxylin and eosin staining. We assessed collagen deposition using Masson’s trichrome staining. We performed immunohistochemistry to detect E-cadherin and alpha-smooth muscle actin. We measured EMT-related markers and pathway-related proteins using Western blotting and quantitative real-time polymerase chain reaction.

Results

OVA exposure induced clear asthma features in mice. Model mice showed marked airway inflammation and epithelial injury. Model mice also showed increased collagen deposition and higher fibrosis scores. Treatment with hUCMSCs significantly improved airway structure and reduced airway inflammation. Treatment with exosomes produced similar improvements. Both treatments significantly reduced inflammatory cell counts in BALF. Both treatments significantly lowered serum pro-inflammatory cytokine levels. Both treatments significantly increased E-cadherin expression. Both treatments significantly reduced alpha-smooth muscle actin and other mesenchymal markers. DMXAA significantly reversed these protective effects. Asthma significantly increased expression of cGAS, STING, and nuclear factor kappa B in lung tissue. hUCMSCs and exosomes significantly suppressed activation of this pathway. DMXAA restored pathway activation and worsened EMT-related changes.

Conclusion

hUCMSCs and their exosomes reduce airway inflammation and airway remodeling in a mouse model of asthma. Both treatments inhibit EMT in vivo. Suppression of the cGAS/STING/NF-κB pathway mediates these effects. Activation of this pathway weakens therapeutic benefit. This pathway represents a potential therapeutic target for asthma.

This abstract is funded by: National Clinical Key Specialty Construction Project, Tianjin Key Medical Discipline Construction Project, TJYXZDXK-3-032C; Tianjin Science and Technology Project, Haihe Laboratory of Cell Ecosystem, HH24KYZX0009; Tianjin Natural Science Foundation, 25JCZDJC01400