Sustained MicroRNA delivery enhanced remyelination and functional recovery after spinal cord injury

Myelination by oligodendrocytes (OLs) is critical for central nervous system (CNS) function. It facilitates rapid electrical conduction and supports neuronal metabolism. Unfortunately, spinal cord injury (SCI) disrupts this process by causing OL loss and axonal demyelination. Consequently, profound functional deficits are frequently observed. Although myelination is important, the role of remyelination remains a topic of debate. Numerous studies strongly support the role of remyelination in restoring function after chemically induced demyelination. However, reducing OL-mediated remyelination does not appear to impede functional recovery in the contusion SCI model. Importantly, although several studies have shown that promoting remyelination can aid functional recovery, its specific contribution in severe injuries, such as complete transection SCI remains less well understood. This study tackles this question by deploying a bio-mimicking drug delivery scaffold to enhance remyelination in a severe complete transection SCI model in mice. Extending our prior work, we now demonstrate that our fiber-hydrogel scaffold loaded with miR-219/miR-338 could effectively promote the rate and extent of oligodendrocyte precursor cell (OPC) differentiation into mature OLs as compared to non-functional microRNA (Neg miR) treatment after SCI. Notably, the proportion of myelinated axons within these scaffolds was significantly greater with miR-219/miR-338 treatment (p < 0.001 vs. Neg miR). Furthermore, treatment with miR-219/miR-338 significantly improved sensory and locomotor recovery of injured mice starting 4 weeks post-treatment, and kinematic analysis further demonstrated enhanced motor coordination and gait patterns. Collectively, these findings suggest that enhanced OL remyelination improves functional recovery even in a more challenging complete transection SCI paradigm when mice were treated with fiber-hydrogel scaffolds loaded with miR-219/miR-338.