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

• Published in: Journal of cellular and molecular medicine 2023-02, Vol.27 (4), p.482-495
• Main Authors: Yin, Tsung‐Cheng, Li, Yi‐Chen, Sung, Pei‐Hsun, Chiang, John Y., Shao, Pei‐Lin, Yip, Hon‐Kan, Lee, Mel S.
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Vesicular Transport - metabolism; adipose‐derived mesenchymal stem cells; Animals; CD11b antigen; Cell viability; Disease; FADD protein; Humans; Hydrogen peroxide; Hypotheses; inflammasome; Inflammasomes; Inflammasomes - metabolism; Inflammation; inflammatory signalling; Interleukin 6; Laboratory animals; Lipopolysaccharides; Mesenchymal stem cells; Mesenchymal Stem Cells - metabolism; MyD88 protein; Myeloid Differentiation Factor 88 - metabolism; NF-kappa B - metabolism; NF-κB protein; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Original; Oxidative stress; Plasmids; Pore size; Prion protein; Prions - metabolism; Proteins; Rats; Rats, Sprague-Dawley; Spinal Cord - metabolism; Spinal cord injuries; Spinal Cord Injuries - genetics; Spinal Cord Injuries - metabolism; Spinal Cord Injuries - therapy; spinal cord injury; Stem cell transplantation; Stem cells; Strategic management; TLR4 protein; Toll-like receptors; TRAF6 protein; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-α
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.17620

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 (PrPcOE). Therefore, this study tested whether PrPcOE‐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 PrPcOE‐ADMSCs were significantly enhanced in cellular viability, anti‐oxidative stress and migration against H2O2 and lipopolysaccharide damages. Similarly, PrPcOE‐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 + PrPcOE‐ADMSCs). Compared with SCI group 2, both ADMSCs and PrPcOE‐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, PrPcOE‐ADMSCs significantly attenuated SCI in rodents that could be through suppressing the inflammatory signalling.