Galectin-3 inhibition reduces fibrotic scarring and promotes functional recovery after spinal cord injury in mice

被引:1
作者
Shan, Fangli [1 ]
Ye, Jianan [1 ,2 ,3 ]
Xu, Xinzhong [1 ]
Liang, Chao [1 ]
Zhao, Yuanzhe [1 ]
Wang, Jingwen [1 ]
Ouyang, Fangru [1 ]
Li, Jianjian [1 ]
Lv, Jianwei [1 ]
Wu, Zhonghan [1 ]
Yao, Fei [1 ,2 ]
Jing, Juehua [1 ,2 ]
Zheng, Meige [1 ,2 ]
机构
[1] Anhui Med Univ, Affiliated Hosp 2, Dept Orthopaed, Hefei 230601, Peoples R China
[2] Anhui Med Univ, Affiliated Hosp 2, Inst Orthopaed, Res Ctr Translat Med, Hefei 230601, Peoples R China
[3] Suzhou 100 Hosp, Dept Orthopaed, Suzhou 215000, Peoples R China
关键词
Spinal cord injury; PDGFR beta; Fibrotic scar; Galectin-3; Macrophage; PDGF; MACROPHAGES; CONTRIBUTES; ACTIVATION;
D O I
10.1186/s13578-024-01310-9
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Background In the context of spinal cord injury (SCI), infiltrating macrophages assume prominence as the primary inflammatory cells within the lesion core, where the fibrotic scar is predominantly orchestrated by platelet-derived growth factor receptor beta (PDGFR beta(+)) fibroblasts. Galectin-3, a carbohydrate-binding protein of the lectin family, is notably expressed by infiltrating hematogenous macrophages and mediates cell-cell interactions. Although Galectin-3 has been shown to contribute to the endocytic internalization of PDGFR beta in vitro, its specific role in driving fibrotic scar formation after SCI has not been determined. Methods We employed a crush mid-thoracic (T10) SCI mouse model. Galectin-3 inhibition after SCI was achieved through intrathecal injection of the Galectin-3 inhibitor TD139 or in situ injection of lentivirus carrying Galectin-3-shRNA (Lv-shLgals3). A fibrosis-induced mice model was established by in situ injection of platelet-derived growth factor D (PDGFD) or recombinant Galectin-3 (rGalectin-3) into the uninjured spinal cord. Galectin-3 internalization experiments were conducted in PDGFR beta(+) fibroblasts cocultured in conditioned medium in vitro. Results We identified the spatial and temporal correlation between macrophage-derived Galectin-3 and PDGFR beta in fibroblasts from 3 to 56 days post-injury (dpi). Administration of TD139 via intrathecal injection or in situ injection of Lv-shLgals3 effectively mitigated fibrotic scar formation and extracellular matrix deposition within the injured spinal cord, leading to better neurological outcomes and function recovery after SCI. Furthermore, the fibrosis-inducing effects of exogenous PDGFD in the uninjured spinal cord could be blocked by TD139. In vitro experiments further demonstrated the ability of PDGFR beta(+) fibroblasts to internalize Galectin-3, with Galectin-3 inhibition resulting in reduced PDGFR beta expression. Conclusions Our finding underscores the pivotal role of macrophage-derived Galectin-3 in modulating the sustained internalized activation of PDGFR beta (+) within fibroblasts, providing a novel mechanistic insight into fibrotic scarring post-SCI.
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页数:18
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