Spinal Cord Injury Results in Chronic Mechanical Stiffening

Abstract

Gliosis and fibrosis after spinal cord injury (SCI) lead to formation of a scar that is thought to present both molecular and mechanical barriers to neuronal regeneration. The scar consists of a meshwork of reactive glia and deposited, cross-linked, extracellular matrix (ECM) that has long been assumed to present a mechanically ''stiff'' blockade. However, remarkably little quantitative information is available about the rheological properties of chronically injured spinal tissue. In this study we utilize atomic force microscopy microindentation to provide quantitative evidence of chronic mechanical stiffening after SCI. Using the results of this tissue characterization, we assessed the sensitivity of both mouse and human astrocytes in vitro and determined that they are exquisitely mechanosensitive within the relevant range of substrate stiffness observed in the injured/uninjured spinal cord. We then utilized a novel immune modifying nanoparticle (IMP) treatment as a tool to reveal fibrotic scarring as one of the key drivers of mechanical stiffening after SCI in vivo. We also demonstrate that glial scar-forming astrocytes form a highly aligned, anisotropic network of glial fibers after SCI, and that IMP treatment mitigates this pathological alignment. Taken together, our results identify chronic mechanical stiffening as a critically important aspect of the complex lesion milieu after SCI that must be considered when assessing and developing potential clinical interventions for SCI.

Effect of Velocity and Contact Stress Area on the Dynamic Behavior of the Spinal Cord Under Different Testing Conditions

“…These differences were not statistically significant (Figure 7B). This indicates that normal SCPC tissue stiffness was spatially relatively homogeneous with low variation in elastic values, which is consistent with past findings (Cooper et al, 2020). The stiffness of regions one and two did not differ significantly across specimens (p ≥ 0.05, Supplementary Figure S4, Supplementary Table S5).…”

“…Although numerous studies found that gray matter was stiffer than white matter (Prange and Margulies, 2002;Christ et al, 2010;van Dommelen et al, 2010;Koser et al, 2015), others found the opposite (Ozawa et al, 2001;Kruse et al, 2008;Budday et al, 2015), whereas others observed no significant differences in the moduli of white and gray matter (Maikos et al, 2008b;Finan et al, 2012). This was a challenging question to answer because of the high complexity of neural tissue with anisotropic and inhomogeneous mechanical properties (Koser et al, 2015;Cooper et al, 2020). Furthermore, different experimental techniques had unique strengths and limitations and operated at divergent length scales (Budday et al, 2015).…”

Mechanical properties of the spinal cord and brain: Comparison with clinical-grade biomaterials for tissue engineering and regenerative medicine

“…However, in contrast to other parts of the body where scar tissue is traditionally stiffer than the surrounding healthy tissue [28,29], recent data have indicated that CNS tissue may in fact soften after injury but display increased viscosity [30,31]. Whether these softening changes are retained over time remains unclear though, and chronic CNS injury may still be associated with tissue stiffening [32].…”

Exosomes derived from human placental mesenchymal stem cells enhanced the recovery of spinal cord injury by activating endogenous neurogenesis

“…Specifically, the survival rate of the transplanted stem cells is very low due to severe inflammatory responses or other factors in the injured microenvironment [ 10 – 12 ]. Additionally, the scar-forming gliosis prevents the integration, differentiation, and axon outgrowth of grafted stem cells in the lesion area [ 13 , 14 ]. Moreover, there are also still some concerns regarding the safety of these cells [ 15 , 16 ].…”