CD73‐Overexpressing ADSCs Promote Neurogenic Bladder Repair via A2A–JAK1/STAT3‐Mediated Modulation of Inflammation and Macrophage Polarization
Guanqun Zhu, Guoyi Jiang, Jiao Huang, Yuxuan He, Zongliang Zhang, Rui Zhang, Xinbao Yin, Kai Zhao, Xiaokun Yang, Woong Jin Bae, Ke WangBackground
Neurogenic bladder (NB) is characterized by chronic inflammation and bladder tissue injury, and current treatments fail to restore the inflammatory microenvironment or tissue integrity. Although adipose‐derived stem cell (ADSC) therapy shows regenerative potential, its efficacy is limited by inflammation; whether CD73 overexpression enhances ADSC therapeutic effects in NB remains unclear.
Methods
A rat model of NB was established via pelvic nerve (PN) injury and treated with CD73‐overexpressing ADSCs (CD73 + ADSCs). Bladder function, histological remodeling, and apoptosis were evaluated in vivo. In vitro, conditioned medium (CM) from CD73 + ADSCs was applied to LPS‐injured rat bladder transitional epithelial cells (RB‐TECs) and macrophages to assess proliferation, migration, apoptosis, inflammatory responses, and macrophage polarization. Key signaling pathways were examined, and label‐free quantitative (LFQ) proteomics was performed to characterize global molecular reprogramming.
Results
CD73 + ADSCs significantly improved urodynamic function, restored smooth muscle architecture, and reduced apoptosis in NB rats. In vitro, CD73 + ADSC‐CM promoted urothelial cell proliferation and migration while attenuating cell death. Mechanistically, CD73 + ADSCs enhanced extracellular adenosine production, at least partly dependent on pharmacologically sensitive A2A receptor signaling, suppressed NF‐κB activation, reduced proinflammatory cytokine release, promoted macrophage polarization toward an M2 phenotype, and inhibited NLRP3 inflammasome activation. Proteomic analysis revealed a global shift toward antiinflammatory and reparative molecular programs.
Conclusion
Our findings suggest that CD73 contributes to the immunomodulatory and reparative properties of ADSCs under inflammatory conditions. By coordinating adenosinergic signaling, inflammatory suppression, and repair‐associated pathways, CD73 + ADSCs effectively reprogram the NB microenvironment and represent a promising regenerative therapeutic strategy for NB.