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脂肪间充质干细胞过表达朊病毒通过 NLRP3 炎性小体/DAMP 信号改善大鼠脊髓损伤后的预后。

Adipose-derived mesenchymal stem cells overexpressing prion improve outcomes via the NLRP3 inflammasome/DAMP signalling after spinal cord injury in rat.

机构信息

Department of Orthopaedic Surgery, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung, Taiwan.

Center for General Education, Cheng Shiu University, Kaohsiung, Taiwan.

出版信息

J Cell Mol Med. 2023 Feb;27(4):482-495. doi: 10.1111/jcmm.17620. Epub 2023 Jan 20.

DOI:10.1111/jcmm.17620
PMID:36660907
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9930430/
Abstract

Traumatic spinal cord injury (SCI) is a highly destructive disease in human neurological functions. Adipose-derived mesenchymal stem cells (ADMSCs) have tissue regenerations and anti-inflammations, especially with prion protein overexpression (PrPc ). Therefore, this study tested whether PrPc -ADMSCs therapy offered benefits in improving outcomes via regulating nod-like-receptor-protein-3 (NLRP3) inflammasome/DAMP signalling after acute SCI in rats. Compared with ADMSCs only, the capabilities of PrPc -ADMSCs were significantly enhanced in cellular viability, anti-oxidative stress and migration against H O and lipopolysaccharide damages. Similarly, PrPc -ADMSCs significantly inhibited the inflammatory patterns of Raw264.7 cells. The SD rats (n = 32) were categorized into group 1 (Sham-operated-control), group 2 (SCI), group 3 (SCI + ADMSCs) and group 4 (SCI + PrPc -ADMSCs). Compared with SCI group 2, both ADMSCs and PrPc -ADMSCs significantly improved neurological functions. Additionally, the circulatory inflammatory cytokines levels (TNF-α/IL-6) and inflammatory cells (CD11b/c+/MPO+/Ly6G+) were highest in group 2, lowest in group 1, and significantly higher in group 3 than in group 4. By Day 3 after SCI induction, the protein expressions of inflammasome signalling (HGMB1/TLR4/MyD88/TRIF/c-caspase8/FADD/p-NF-κB/NEK7/NRLP3/ASC/c-caspase1/IL-ß) and by Day 42 the protein expressions of DAMP-inflammatory signalling (HGMB1/TLR-4/MyD88/TRIF/TRAF6/p-NF-κB/TNF-α/IL-1ß) in spinal cord tissues displayed an identical pattern as the inflammatory patterns. In conclusion, PrPc -ADMSCs significantly attenuated SCI in rodents that could be through suppressing the inflammatory signalling.

摘要

创伤性脊髓损伤（SCI）是一种对人类神经功能具有高度破坏性的疾病。脂肪间充质干细胞（ADMSCs）具有组织再生和抗炎作用，特别是在朊病毒蛋白过表达（PrPc）时。因此，本研究测试了 PrPc-ADMSCs 疗法是否通过调节急性 SCI 后大鼠中的核苷酸结合寡聚化结构域样受体蛋白 3（NLRP3）炎性小体/DAMP 信号通路来改善结局。与 ADMSCs 相比，PrPc-ADMSCs 在细胞活力、抗氧化应激和对 H2O2 和脂多糖损伤的迁移能力方面显著增强。同样，PrPc-ADMSCs 显著抑制了 Raw264.7 细胞的炎症模式。32 只 SD 大鼠（n=32）分为第 1 组（假手术对照）、第 2 组（SCI）、第 3 组（SCI+ADMSCs）和第 4 组（SCI+PrPc-ADMSCs）。与 SCI 组 2 相比，ADMSCs 和 PrPc-ADMSCs 均显著改善了神经功能。此外，在第 2 组中循环炎症细胞因子水平（TNF-α/IL-6）和炎症细胞（CD11b/c+/MPO+/Ly6G+）最高，在第 1 组中最低，在第 3 组中明显高于第 4 组。在 SCI 诱导后第 3 天，炎性小体信号蛋白表达（HGMB1/TLR4/MyD88/TRIF/c-caspase8/FADD/p-NF-κB/NEK7/NRLP3/ASC/c-caspase1/IL-ß）和在第 42 天脊髓组织中的 DAM 炎性信号蛋白表达（HGMB1/TLR-4/MyD88/TRIF/TRAF6/p-NF-κB/TNF-α/IL-1ß）呈现出与炎症模式相同的模式。总之，PrPc-ADMSCs 显著减轻了 SCI 模型鼠的 SCI，其机制可能是通过抑制炎症信号。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2450/9930430/76bad6bf9285/JCMM-27-482-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2450/9930430/23cbb950f216/JCMM-27-482-g004.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2450/9930430/76bad6bf9285/JCMM-27-482-g001.jpg

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