Nanoparticle therapy for spinal cord injury and the mechanisms regulating fibrotic scarring after spinal cord injuryPublic Deposited
Spinal cord injury occurs with a worldwide incidence of 13-33 cases per million per year, and more than 2.5 million patients worldwide suffer from spinal cord injury (SCI)-related disability (1, 2). Different methods have been attempted to promote axonal regeneration, including neurotrophin injection, hydrogel injection, olfactory ensheathing cells implantation and nerve grafts. However, only limited success has been achieved, and to date there exists no effective way to restore motor and sensory functions after injury (3-6). In my thesis work, our lab introduces a new technology to the field of SCI, immune-modifying microparticles (IMPs), that has the potential for relatively straightforward translation into a meaningful therapy for human SCI. Intravenously infused IMPs bind to macrophage receptor, MARCO, which is expressed on the surface of circulating monocytes. Monocytes bound to IMPs no longer migrate to inflammatory sites, but instead, they traffic to the spleen where they are sequestered and undergo apoptosis. IMPs have shown remarkable therapeutic potentials in inflammatory diseases including encephalomyelitis, lethal flavivirus encephalitis, myocardial infarction, dextran sodium sulfate–induced colitis, and thioglycollate-induced peritonitis via reducing tissue damage and disease symptoms (7, 8). Interestingly, it has been suggested that the early influx of inflammatory immune cells after SCI is responsible for axonal dieback and differentiate into M1-like (pro-inflammatory) macrophages. Therefore, blocking the early infiltration of monocytes can be a target of clinical intervention. To investigate whether IMP treatment acutely after SCI can improve functional outcome, severe contusion injury was performed in mice, and IMPs were administered 2, 24, and 48 hrs post injury via I.V injection. Excitingly, our study, in collaboration with Dr. Stephen Miller lab at Northwestern University, showed that administration of IMPs during acute phase of SCI successfully reduced infiltration of monocytes into the injured cord, limited chronic fibrotic scar formation, and subsequently improved functional recovery in mice. Our results suggest that the early influx of hematogenous monocytes is a selective contributor to fibrotic scarring, and that inhibiting fibrotic scarring enhances motor recovery after SCI. The most severe forms of human SCI, major compression and laceration injuries, result in the accumulation of permanent fibrotic scar tissue in the injured spinal cord (9). Unfortunately, relatively little is known about what mediates its formation and how it exerts its inhibitory functions after SCI. More detailed examination of the fibrotic response after SCI will allow us to discover a novel molecular target or pathway that can be exploited therapeutically. To determine the exact role of fibrotic scarring and how it is formed, we used a transgenic mouse line that lacks the alternatively-spliced fibronectin isoform containing Extra Domain A (FnEDA-null). The FnEDA isoform is implicated in many pathologic fibrosis conditions including scleroderma, idiopathic pulmonary fibrosis, and skin wound healing (10-13). In this work, we demonstrated that FnEDA-null mice showed a markedly attenuated chronic fibrotic response after SCI and smaller lesion areas. Subsequent analysis of the injured spinal cord tissues revealed significantly reduced amounts of insoluble fibronectin matrix in FnEDA-null mice at sub-acute and chronic time points after SCI. This result shows that the FnEDA isoform is an important switch mediating the fibronectin matrix assembly and maintenance after SCI. More importantly, FnEDA-null mice showed significantly improved motor recovery compared to wildtype mice. In summary, our study shows that IMP is a potential treatment for SCI. We believe that the first injection 2h after the injury is a conservative estimate of a real life therapy that a patient could receive in an emergency room. Since IMPs are stable at room temperature, they could possibly be used in the field by EMTs at even earlier time points. Moreover, our study also provides novel insight into the mechanism of fibrosis after SCI and suggests that inhibiting the fibronectin matrix formation by targeting the FnEDA isoform could represent a new therapeutic strategy for SCI.