A 3D Fiber-Hydrogel Based Non-Viral Gene Delivery Platform Reveals that microRNAs Promote Axon Regeneration and Enhance Functional Recovery Following Spinal Cord Injury.

Na Zhang,Elaine Guo Yan Chew,Junquan Lin,Vincent Po Hen Lin,Jiah Shin Chin,Kunyu Zhang,Jia Nee Foo,Sing Yian Chew,Michelle Mulan Lian,Ulla Milbreta,Wutian Wu

doi:10.1002/advs.202100805

Abstract

Current treatment approaches toward spinal cord injuries (SCI) have mainly focused on overcoming the inhibitory microenvironment that surrounds lesion sites. Unfortunately, the mere modulation of the cell/tissue microenvironment is often insufficient to achieve desired functional recovery. Therefore, stimulating the intrinsic growth ability of injured neurons becomes crucial. MicroRNAs (miRs) play significant roles during axon regeneration by regulating local protein synthesis at growth cones. However, one challenge of using miRs to treat SCI is the lack of efficient delivery approaches. Here, a 3D fiber‐hydrogel scaffold is introduced which can be directly implanted into a spinal cord transected rat. This 3D scaffold consists of aligned electrospun fibers which provide topographical cues to direct axon regeneration, and collagen matrix which enables a sustained delivery of miRs. Correspondingly, treatment with Axon miRs (i.e., a cocktail of miR‐132/miR‐222/miR‐431) significantly enhances axon regeneration. Moreover, administration of Axon miRs along with anti‐inflammatory drug, methylprednisolone, synergistically enhances functional recovery. Additionally, this combined treatment also decreases the expression of pro‐inflammatory genes and enhance gene expressions related to extracellular matrix deposition. Finally, increased Axon miRs dosage with methylprednisolone, significantly promotes functional recovery and remyelination. Altogether, scaffold‐mediated Axon miR treatment with methylprednisolone is a promising therapeutic approach for SCI.

Highlights

Spinal cord injuries (SCI) result in devastating outcomes of paralysis and functional impairment and are the major causes of morbidity and mortality, in young adults and children.[1]
Prolonged availability of biomolecules is desirable for the treatment of SCI as the injured microenvironment is highly dynamic and requires biochemical guidance in order to achieve nerve regeneration and subsequent functional recovery
The effect of glial cell-derived neurotrophic factor (GDNF) on spinally injured rats was evaluated at week 2 and we demonstrated that as compared to Untreated rats, GDNFtreated rats exhibited significantly more robust axon regeneration (p < 0.01, Figure S1, Supporting Information)

Summary

Introduction

Spinal cord injuries (SCI) result in devastating outcomes of paralysis and functional impairment and are the major causes of morbidity and mortality, in young adults and children.[1] Both intrinsic growth ability of neurons and the microenvironment that surrounds cells/tissues control the process of nerve (axon) regeneration after injuries.[2,3] current SCI treatment approaches mainly focus on overcoming the inhibitory microenvironment that is present after nerve injuries. Results available to date reflect sub-optimal recovery of function in patients. An alternative is to recognize that mature neurons have diminished intrinsic regeneration capability, which is a major cause of regeneration failure. The mere modulation of the microenvironment may be insufficient to achieve the desired regeneration outcomes[4] and stimulating the intrinsic growth ability of mature neurons becomes crucial

Results

Discussion

Conclusion