miR-155 Deletion in Mice Overcomes Neuron-Intrinsic and Neuron-Extrinsic Barriers to Spinal Cord Repair

Abstract

Axon regeneration after spinal cord injury (SCI) fails due to neuron-intrinsic mechanisms and extracellular barriers including inflammation. microRNA (miR)-155-5p is a small, noncoding RNA that negatively regulates mRNA translation. In macrophages, miR-155-5p is induced by inflammatory stimuli and elicits a response that could be toxic after SCI. miR-155 may also independently alter expression of genes that regulate axon growth in neurons. Here, we hypothesized that miR-155 deletion would simultaneously improve axon growth and reduce neuroinflammation after SCI by acting on both neurons and macrophages. New data show that miR-155 deletion attenuates inflammatory signaling in macrophages, reduces macrophage-mediated neuron toxicity, and increases macrophage-elicited axon growth by ϳ40% relative to control conditions. In addition, miR-155 deletion increases spontaneous axon growth from neurons; adult miR-155 KO dorsal root ganglion (DRG) neurons extend 44% longer neurites than WT neurons. In vivo, miR-155 deletion augments conditioning lesion-induced intraneuronal expression of SPRR1A, a regeneration-associated gene; ϳ50% more injured KO DRG neurons expressed SPRR1A versus WT neurons. After dorsal column SCI, miR-155 KO mouse spinal cord has reduced neuroinflammation and increased peripheral conditioning-lesion-enhanced axon regeneration beyond the epicenter. Finally, in a model of spinal contusion injury, miR-155 deletion improves locomotor function at postinjury times corresponding with the arrival and maximal appearance of activated intraspinal macrophages. In miR-155 KO mice, improved locomotor function is associated with smaller contusion lesions and decreased accumulation of inflammatory macrophages. Collectively, these data indicate that miR-155 is a novel therapeutic target capable of simultaneously overcoming neuron-intrinsic and neuron-extrinsic barriers to repair after SCI.

Comparative Morphometry of the Wisconsin Miniature Swine^TM Thoracic Spine for Modeling Human Spine in Translational Spinal Cord Injury Research

“…To date, drug-based therapies for SCI and NP management have had limited efficacy in humans [23]. The heavy reliance on mouse [3][4][5][6]24] and rat [7][8][9][10] models for SCI research has led to inaccurate assessment of the effectiveness of therapies and delivery methods, especially of those administered into the spinal cord. The large surface area to volume ratio and the small axial plane of the spinal cord in small animals result in the distribution of therapies that is significantly different from that in humans.…”

“…While many promising molecular, gene, and cell therapies are being explored for SCI, advancement of these therapies to the clinical setting is hampered by a gap that exists between early research and clinical testing. Most SCI research occurs in small animal models such as mice [3][4][5][6] and rats [7][8][9][10]. However, no therapy shown to be safe and effective in rodent studies has advanced through clinical trials for treating human SCI [11].…”

MiR-463-3p inhibits tibial nerve regeneration via post-transcriptional suppression of SPRR1A

“…Some studies also suggest that SPRR1A is expressed during development and constitutively by some cells in the adult. Recently, miR-155 deletion in mice overcomes neuron-intrinsic and neuron-extrinsic barriers to spinal cord repair via targeting SPRR1A [24]. Thus, SPRR1A was identified as a promoter of nerve regeneration.…”

The Dorsal Column Lesion Model of Spinal Cord Injury and Its Use in Deciphering the Neuron‐Intrinsic Injury Response

“…5 forceps to a depth of 2 mm. Gaudet et al () selected a more specific and severe paradigm where they injured axons to a depth of 0.6 mm and held a pair of forceps tightly together for 10 s and repeated this three times (Puttagunta et al, ).…”