Abstract
After spinal cord injury (SCI) chronic inflammation hampers regeneration. Influencing the local microenvironment after SCI may provide a strategy to modulate inflammation and the immune response. The objectives of this work were to determine whether bone or spinal cord derived ECM hydrogels can deliver human mesenchymal stem cells from the apical papilla (SCAP) to reduce local inflammation and provide a regenerative microenvironment. Bone hydrogels (8 and 10 mg/ml, B8 and B10) and spinal cord hydrogels (8 mg/ml, S8) supplemented with fibrin possessed a gelation rate and a storage modulus compatible with spinal cord implantation. S8 and B8 impact on the expression of anti and pro-inflammatory cytokines (Arg1, Nos2, Tnf) in LPS treated microglial cells were assessed using solubilised and solid hydrogel forms. S8 significantly reduced the Nos2/Arg1 ratio and solubilised B8 significantly reduced Tnf and increased Arg1 whereas solid S8 and B8 did not impact inflammation in microglial cells. SCAP incorporation within ECM hydrogels did not impact upon SCAP immunoregulatory properties, with significant downregulation of Nos2/Arg1 ratio observed for all SCAP embedded hydrogels. Tnf expression was reduced with SCAP embedded in B8, reflecting the gene expression observed with the innate hydrogel. Thus, ECM hydrogels are suitable vehicles to deliver SCAP due to their physical properties, preservation of SCAP viability and immunomodulatory capacity.
Highlights
Spinal cord injury (SCI), usually caused by a car crash, fall or violence, drastically influences the quality of life and increases mortality risk by 2–5 times[1]
Comprehensive studies of cellular response show that the inflammatory and proliferative phases of immune response to spinal cord injury (SCI) start as expected, but difficulties occur in later transitions between the pro-inflammatory and pro-resolutive phases[2], that is, the remodeling phase that usually follows the acute pro-inflammatory phase, does not seem to occur[3]
The thermo-responsive nature of Extracellular matrix (ECM) hydrogels provides a potential role for these materials
Summary
Spinal cord injury (SCI), usually caused by a car crash, fall or violence, drastically influences the quality of life and increases mortality risk by 2–5 times[1]. The inflammatory phase, initiated by microglia and led by macrophages and T-lymphocytes, remains chronically predominant[2] This contributes to the secondary injury and has a negative effect on regeneration[3]. Attempts to influence immune response in injured spinal cord, e.g. by macrophage depletion[4], local or systemic delivery of anti-inflammatory drugs[5] or immunoregulatory cytokines[6], or adoptive transfer of “immunoregulatory” (interleukin-4 (IL4), interleukin-10 (IL10) or transforming growth factor beta (TGFβ) stimulated) macrophages[7] have shown positive effects on regeneration in pre-clinical trials. 3.97 ± 0.26A network can protect MSC from the immediate influence of the hostile microenvironment and assist in cell localisation and retention at the injection site[12]. We and others have previously shown that SCAP secrete a broad pallet of neurotrophic and regenerative growth factors[19] and possess immunoregulatory properties[20]
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