High molecular weight hyaluronic acid limits astrocyte activation and scar formation after spinal cord injury

Abstract

A major hurdle for regeneration after spinal cord injury (SCI) is the ability of axons to penetrate and grow through the scar tissue. After SCI, inflammatory cells, astrocytes and meningeal cells all play a role in developing the glial scar. In addition, degradation of native high molecular weight (MW) hyaluronic acid (HA), a component of the extracellular matrix, has been shown to induce activation and proliferation of astrocytes. However, it is not known if the degradation of native HA actually enhances glial scar formation. We hypothesize that the presence of high MW HA (HA with limited degradation) after SCI will decrease glial scarring. Here, we demonstrate that high MW HA decreases cell proliferation and reduces chondroitin sulfate proteoglycan (CSPG) production in cultured neonatal and adult astrocytes. In addition, stiffness-matched high MW HA hydrogels crosslinked to resist degradation were implanted in a rat model of spinal dorsal hemisection injury. The numbers of immune cells (macrophages and microglia) detected at the lesion site in animals with HA hydrogel implants were significantly reduced at acute time points (one, three and ten days post-injury). Lesioned animals with HA implants also exhibited significantly lower CSPG expression at ten days post-injury. At nine weeks post-injury, animals with HA hydrogel implants exhibited a significantly decreased astrocytic response, but did not have significantly altered CSPG expression. Combined, these data suggest that high MW HA, when stabilized against degradation, mitigates astrocyte activation in vitro and in vivo. The presence of HA implants was also associated with a significant decrease in CSPG deposition at ten days after SCI. Therefore, HA-based hydrogel systems hold great potential for minimizing undesired scarring as part of future repair strategies after SCI.

Schwann-cell cylinders grown inside hyaluronic-acid tubular scaffolds with gradient porosity

“…This must be attributed to the confinement of the channel, which impedes viable but non-adhered cells to leak outside, and maybe also to the fact that the channel surface has a microporosity which is absent in HAf substrates, which had not suffered lyophilization; such a microporosity is frequently beneficial for cell attachment. The overall anti-adherent characteristics of crosslinked HA, however, may be an advantage for preventing glial scarring [39,82], since a quiescent effect of HA has been identified on human astrocytes [83,84]. The evolution with time of the ratio of viable to dead cells in the conduits ( Figure 4B and Figure 5B) suggests that an initial stage dominated by the poor cell attachment typical of HA is followed by a stage of easy proliferation of the viable cells, which retained their phenotypic markers ( Figure 6).…”

The Hyaluronan Receptor for Endocytosis (HARE) Activates NF-κB-mediated Gene Expression in Response to 40–400-kDa, but Not Smaller or Larger, Hyaluronans

“…lHA can prevent scar formation during fetal wound healing and in spinal cord injuries. These biological activities occur in various cell types as altered cell proliferation, infiltration, or glycosaminoglycan synthesis (15,16). oHA or sHA can activate cell proliferation, differentiation, or angiogenesis (17,18).…”

Hyaluronic acid scaffold has a neuroprotective effect in hemisection spinal cord injury

“…21 It has been used in many medical applications and is frequently investigated as a potential biomaterial for tissue engineering. 1,3,11,13,18,19,28,37,54 Hyaluronic acid is highly biocompatible, immunologically and chemically inert, and nontoxic; thus, using it prevents the problem of neural tissue rejection. Furthermore, high-molecular-weight HA promotes neuroprotective cell-signaling cascades.…”