Lumbar Myeloid Cell Trafficking into Locomotor Networks after Thoracic Spinal Cord Injury

Abstract

Spinal cord injury (SCI) promotes inflammation along the neuroaxis that jeopardizes plasticity, intrinsic repair and recovery. While inflammation at the injury site is well-established, less is known within remote spinal networks. The presence of bone marrow-derived immune (myeloid) cells in these areas may further impede functional recovery. Previously, high levels of the gelatinase, matrix metalloproteinase-9 (MMP-9) occurred within the lumbar enlargement after thoracic SCI and impeded activity-dependent recovery. Since SCI-induced MMP-9 potentially increases vascular permeability, myeloid cell infiltration may drive inflammatory toxicity in locomotor networks. Therefore, we examined neurovascular reactivity and myeloid cell infiltration in the lumbar cord after thoracic SCI. We show evidence of region-specific recruitment of myeloid cells into the lumbar but not cervical region. Myeloid infiltration occurred with concomitant increases in chemoattractants (CCL2) and cell adhesion molecules (ICAM-1) around lumbar vasculature 24 hours and 7 days post injury. Bone marrow GFP chimeric mice established robust infiltration of bone marrow-derived myeloid cells into the lumbar gray matter 24 hours after SCI. This cell infiltration occurred when the blood-spinal cord barrier was intact, suggesting active recruitment across the endothelium. Myeloid cells persisted as ramified macrophages at 7 days post injury in parallel with increased inhibitory GAD67 labeling. Importantly, macrophage infiltration required MMP-9.

Spinal cord motor neuron plasticity accompanies second‐degree burn injury and chronic pain

“…Damaged skin, scar tissue, and injured intracutaneous nerves release inflammatory factors, such as TNF‐alpha, as well as chemokines and trophic factors. As part of the healing process, many of these molecular factors can remotely signal long‐distances and alter neuronal excitability (Hansen et al, , ; Zhao, Waxman, & Hains, ). Injured peripheral nerve afferents have been shown to misexpress sodium channels following burn‐ or mechanical nerve injury.…”

Consideration of Dose and Timing When Applying Interventions After Stroke and Spinal Cord Injury

“…Within 24 hrs of SCI, green bone-marrow cells appeared in the lumbar cord, 10-12 segments below the injury (Figure 6). 42 Surprisingly, peripheral cells did not invade the cervical cord above the injury which indicates that this is a localized rather than general response after SCI. 42 These infiltrating bone-marrow cells have higher inflammatory profiles than resident cord cells and early treadmill training (2-9 days) primes these invading cells to even higher inflammatory toxic profiles (Figure 7).…”

“…42 Surprisingly, peripheral cells did not invade the cervical cord above the injury which indicates that this is a localized rather than general response after SCI. 42 These infiltrating bone-marrow cells have higher inflammatory profiles than resident cord cells and early treadmill training (2-9 days) primes these invading cells to even higher inflammatory toxic profiles (Figure 7). 43 Thus, the primary source of early, harmful inflammation are bone marrow-derived cells and early rehabilitation worsens inflammation.…”

A cellular spinal cord scaffold seeded with rat adipose‑derived stem cells facilitates functional recovery via enhancing axon regeneration in spinal cord injured rats

“…Reasons why implantation of ASCs seeded with rADSCs promote axon regeneration and reduce reactive gliosis can be ascribed as follows: ( 1 ) rebalance of local disturbed niche, ( 2 ) physical support of allograft, ( 3 ) neurotrophic factors secretion and ( 4 ) inflammation suppression. Excitotoxic damage, high levels of the gelatinase and matrix metalloproteinase-9 (MMP-9) often damages local microenvironment in acute phase after SCI to elicit neuronal loss and severe locomotor impairment ( 27 , 28 ). While, inflammation in subacute phase usually increases vascular permeability and myeloid cell infiltration to deteriorate locomotor networks ( 29 – 32 ).…”