Reducing neuroinflammation by delivery of IL‐10 encoding lentivirus from multiple‐channel bridges

Abstract

The spinal cord is unable to regenerate after injury largely due to growth‐inhibition by an inflammatory response to the injury that fails to resolve, resulting in secondary damage and cell death. An approach that prevents inhibition by attenuating the inflammatory response and promoting its resolution through the transition of macrophages to anti‐inflammatory phenotypes is essential for the creation of a growth permissive microenvironment. Viral gene delivery to induce the expression of anti‐inflammatory factors provides the potential to provide localized delivery to alter the host inflammatory response. Initially, we investigated the effect of the biomaterial and viral components of the delivery system to influence the extent of cell infiltration and the phenotype of these cells. Bridge implantation reduces antigen‐presenting cell infiltration at day 7, and lentivirus addition to the bridge induces a transient increase in neutrophils in the spinal cord at day 7 and macrophages at day 14. Delivery of a lentivirus encoding IL‐10, an anti‐inflammatory factor that inhibits immune cell activation and polarizes the macrophage population towards anti‐inflammatory phenotypes, reduced neutrophil infiltration at both day 7 and day 28. Though IL‐10 lentivirus did not affect macrophages number, it skewed the macrophage population toward an anti‐inflammatory M2 phenotype and altered macrophage morphology. Additionally, IL‐10 delivery resulted in improved motor function, suggesting reduced secondary damage and increased sparing. Taken together, these results indicate that localized expression of anti‐inflammatory factors, such as IL‐10, can modulate the inflammatory response following spinal cord injury, and may be a key component of a combinatorial approach that targets the multiple barriers to regeneration and functional recovery.

Heterogeneous fate choice of genetically modulated adult neural stem cells in gray and white matter of the central nervous system

“…However, we also found that the number of p57kip2 suppressed cells was severely reduced upon grafting into lesioned CNS tissue suggesting that a promoted oligodendroglial fate acquisition on the one hand facilitates successful tissue integration but on the other hand might come with an increased sensitivity toward hostile cues as described before (Casha, Yu, & Fehlings, ; Crowe, Bresnahan, Shuman, Masters, & Beattie, ; Pfeifer et al, ; Rowland, Hawryluk, Kwon, & Fehlings, ; Vroemen, Aigner, Winkler, & Weidner, ). An influence of spinal cord infiltrating peripheral immune cells (Anderson, ; Margul et al, ) can also not be excluded yet. Such an impact could only be addressed by future transplantation experiments into subacute spinal cord injuries at later time points featuring reduced inflammation and beyond secondary cell death.…”

Regulation of Inflammatory Cytokines for Spinal Cord Injury Repair Through Local Delivery of Therapeutic Agents

“…IL‐10 has been demonstrated to promote functional recovery in SCI models in rats66, 67, 68, 69, 72, 73, 74 and mice 58, 64, 65, 70, 71. IL‐10 affects inflammation through regulation of activation of microglia/macrophages70, 71 and astrocytes,72 as well as reducing the production of TNF‐α,72, 73 IL‐1β, S100β, and inducible nitric oxide synthase (iNOS) 65.…”

“…Local applications of lentivirus‐mediated regulation of both TNF‐α228 and IL‐1071 promoted functional recovery. In addition to inflammatory cytokines, local lentivirus‐mediated regulation of other proteins also affected inflammation and facilitated neurorepair.…”

Take a deep breath and digest the material: organoids and biomaterials of the respiratory and digestive systems

“…In this context, biomaterials may be used as platforms to deliver factors specific to reduce the immune response and to minimize the role of the injury and inflammatory response on organoid engraftment. [133,134] Collectively, biomaterial systems have the potential to recapitulate the physical and chemical properties of the native organ in order to maintain and mature organoid models of the respiratory and digestive systems. [18,21,129] Creating an environment with the necessary properties for tissue maintenance and maturation will allow for further manipulation to enhance organoid growth and maturation in vitro, or may promote specific structures and engraftment in vivo.…”