Spinal cord injury target-immunotherapy with TNF-α autoregulated and feedback-controlled human umbilical cord mesenchymal stem cell derived exosomes remodelled by CRISPR/Cas9 plasmid.

Abstract

Human umbilical cord mesenchymal stem cell (hucMSC) derived exosomes (EXOs) have been investigated as a new treatment for spinal cord injury (SCI) because of their anti-inflammatory, anti-apoptotic, angiogenesis-promoting, and axonal regeneration properties. The CAQK peptide found in the brains of mice and humans after trauma has recently been found to specifically bind to the injured site after SCI. Thus, we developed a nanocarrier system called EXO-C@P based on hucMSC exosomes remodelled by the CRISPR/Cas9 plasmid to control inflammation and modified by the CAQK peptide. EXO-C@P was shown to effectively accumulate at the injury site and saturate the macrophages to significantly reduce the expression of inflammatory cytokines in a mouse model of SCI. Moreover, EXO-C@P treatment improved the performance of mice in behavioural assessments and upregulated soluble tumour necrosis factor receptor-1 (sTNFR1) in serum and at the trauma site after SCI surgery, but lowered the proportion of iNOS+ cells and the concentration of proinflammatory factors. In conclusion, EXO-C@P provides an effective alternative to multiple topical administration and drug delivery approaches for the treatment of SCI. STATEMENT OF SIGNIFICANCE: SCI is a serious disease characterised by a high incidence, high disability rate, and high medical costs, and has become a global medical problem. Several studies have shown that the inflammatory response is the critical inducer of secondary injury after SCI. The inflammatory cytokine TNF-α is considered to be one of the most significant therapeutic targets for autoimmune diseases. Antibodies targeting TNF-α and sTNFR1 are capable of neutralising free TNF-α. In this study, exosomes in the CRISPR/Cas9 system were used to establish stem cells with an autoregulated and feedback-controlled TNF-α response, with these cells secreting sTNFR1, which neutralised TNF-α and antagonised the inflammation stimulated by TNF-α. Moreover, the plasmid was combined with CAQK, which targeted the injury site and promoted the recovery of SCI function.

• Authors: Baocheng Wang, Minmin Chang, Renwen Zhang, Jin Wo, Bowen Wu, Hua Zhang, Zhigang Zhou, Zhizhong Li, Feng Zhang, Cheng Zhong, Shujie Tang, Shuxian Yang, Guodong Sun
• Journal: Biomaterials advances (Biomater Adv) Vol. 133 Pg. 112624 (Feb 2022) ISSN: 2772-9508 [Electronic] Netherlands
• PMID: 35525736 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• Cytokines
• Immunologic Factors
• Tumor Necrosis Factor-alpha

Topics

• CRISPR-Cas Systems
• Cytokines (metabolism)
• Exosomes (metabolism)
• Feedback
• Humans
• Immunologic Factors (metabolism)
• Immunotherapy
• Inflammation (metabolism)
• Mesenchymal Stem Cells (metabolism)
• Plasmids
• Spinal Cord Injuries (therapy)
• Tumor Necrosis Factor-alpha (metabolism)
• Umbilical Cord (metabolism)