Schwann Cell Transplantation Subdues the Pro-Inflammatory Innate Immune Cell Response after Spinal Cord Injury

Abstract

The transplantation of Schwann cells (SCs) has been shown to provide tissue preservation and support axon growth and remyelination as well as improve functional recovery across a diverse range of experimental spinal cord injury (SCI) paradigms. The autologous use of SCs has progressed to Phase 1 SCI clinical trials in humans where their use has been shown to be both feasible and safe. The contribution of immune modulation to the protective and reparative actions of SCs within the injured spinal cord remains largely unknown. In the current investigation, the ability of SC transplants to alter the innate immune response after contusive SCI in the rat was examined. SCs were intraspinally transplanted into the lesion site at 1 week following a thoracic (T8) contusive SCI. Multicolor flow cytometry and immunohistochemical analysis of specific phenotypic markers of pro- and anti-inflammatory microglia and macrophages as well as cytokines at 1 week after SC transplantation was employed. The introduction of SCs significantly attenuated the numbers of cluster of differentiation molecule 11B (CD11b)+, cluster of differentiation molecule 68 (CD68)+, and ionized calcium-binding adapter molecule 1 (Iba1)+ immune cells within the lesion implant site, particularly those immunoreactive for the pro-inflammatory marker, inducible nitric oxide synthase (iNOS). Whereas numbers of anti-inflammatory CD68+ Arginase-1 (Arg1+) iNOS− cells were not altered by SC transplantation, CD68+ cells of an intermediate, Arg1+ iNOS+ phenotype were increased by the introduction of SCs into the injured spinal cord. The morphology of Iba1+ immune cells was also markedly altered in the SC implant, being elongated and in alignment with SCs and in-growing axons versus their amoeboid form after SCI alone. Examination of pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and anti-inflammatory cytokines, interleukin-4 (IL-4) and interleukin-10 (IL-10), by multicolor flow cytometry analysis showed that their production in CD11b+ cells was unaltered by SC transplantation at 1 week post-transplantation. The ability of SCs to subdue the pro-inflammatory iNOS+ microglia and macrophage phenotype after intraspinal transplantation may provide an important contribution to the neuroprotective effects of SCs within the sub-acute SCI setting.

Intravenous transplantation of olfactory ensheathing cells reduces neuroinflammation after spinal cord injury via interleukin-1 receptor antagonist

“…A lateral hemisection was performed at T12; initially, an angled needle punctured the spinal cord dorsoventrally at the midline, avoiding the dorsal spinal artery, and then pulled to cut the left half of the spinal cord. This operation was repeated three times to ensure completeness of the hemisection 24 . For pain management, Rimadyl (5 mg/kg, Zoetis, Florham Park, NJ) and Temgesic (0.3 mg/mL, Intervet International, Boxmer, the Netherlands) was administered subcutaneously before surgery and every 8 h for 3 consecutive days after establishing the SCI model.…”

Transplantation of Skin Precursor-Derived Schwann Cells Yields Better Locomotor Outcomes and Reduces Bladder Pathology in Rats with Chronic Spinal Cord Injury

“…These cellular conduits align rostro-caudally and attract and guide the growth of axons into and across the site of SCI ( Bastidas et al., 2017 , Bunge, 2016 ). In addition, SCs myelinate regenerating and spared CNS axons, provide neuroprotection ( Pearse et al., 2018 ), and promote axonal growth/plasticity and concomitant functional recovery ( Bunge et al., 2017 , Wiliams and Bunge, 2012 ). Finally, because SCs can be harvested from peripheral nerves and expanded in vitro , they are well suited for transplantation in the autologous setting.…”

Modern Trends for Peripheral Nerve Repair and Regeneration: Beyond the Hollow Nerve Guidance Conduit

“…Once expanded and harvested, Schwann cells will help in PNR after introduced in the NGC, which can be attained by a variety of methods: direct injection of a cellular suspension to the lumen (Jesuraj et al, 2011), suspension within an intraluminal hydrogel (Cerqueira et al, 2018), distributed along intraluminal guidance structures (Meyer et al, 2016a) or released from the luminal (Kalbermatten et al, 2008). It has been considered that autograft is the gold standard of PNR and autologous Schwann cells are the gold standard of cellular-based therapies (Pearse et al, 2018). However, the use of Schwann cells comes with a few shortcomings such as the effort of collection, the time-consuming expansion in culture and a inappropriate immunogenicity, thus requiring further immune suppression strategies to be considered.…”