Early Transplantation of Mesenchymal Stem Cells After Spinal Cord Injury Relieves Pain Hypersensitivity Through Suppression of Pain-Related Signaling Cascades and Reduced Inflammatory Cell Recruitment

Abstract

Bone marrow-derived mesenchymal stem cells (BMSC) modulate inflammatory/immune responses and promote motor functional recovery after spinal cord injury (SCI). However, the effects of BMSC transplantation on central neuropathic pain and neuronal hyperexcitability after SCI remain elusive. This is of importance because BMSC-based therapies have been proposed for clinical treatment. We investigated the effects of BMSC transplantation on pain hypersensitivity in green fluorescent protein (GFP)-positive bone marrow-chimeric mice subjected to a contusion SCI, and the mechanisms of such effects. BMSC transplantation at day 3 post-SCI improved motor function and relieved SCI-induced hypersensitivities to mechanical and thermal stimulation. The pain improvements were mediated by suppression of protein kinase C-c and phosphocyclic AMP response element binding protein expression in dorsal horn neurons. BMSC transplants significantly reduced levels of p-p38 mitogen-activated protein kinase and extracellular signal-regulated kinase (p-ERK1/2) in both hematogenous macrophages and resident microglia and significantly reduced the infiltration of CD11b and GFP double-positive hematogenous macrophages without decreasing the CD11b-positive and GFP-negative activated spinal-microglia population. BMSC transplants prevented hematogenous macrophages recruitment by restoration of the blood-spinal cord barrier (BSCB), which was associated with decreased levels of (a) inflammatory cytokines (tumor necrosis factor-a, interleukin-6); (b) mediators of early secondary vascular pathogenesis (matrix metallopeptidase 9); (c) macrophage recruiting factors (CCL2, CCL5, and CXCL10), but increased levels of a microglial stimulating factor (granulocyte-macrophage colony-stimulating factor). These findings support the use of BMSC transplants for SCI treatment. Furthermore, they suggest that BMSC reduce neuropathic pain through a variety of related mechanisms that include neuronal sparing and restoration of the disturbed BSCB, mediated through modulation of the activity of spinal-resident microglia and the activity and recruitment of hematogenous macrophages.

Adipose-derived stem cells decrease pain in a rat model of oxaliplatin-induced neuropathy: Role of VEGF-A modulation

“…Adult MSCs are not only a pluripotent cellular source for replacing injured tissues but also represent a source of neuroprotective and anti-inflammatory mediators. MSCs are able to modulate the inflammatory cascade associated with immune-related diseases, such as rheumatoid arthritis (Gonzalez-Rey et al, 2010), but also painful neuropathies consequent to nerve trauma (Sacerdote et al, 2013;Watanabe et al, 2015), or to metabolic alterations (Shibata et al, 2008). MSCs can be isolated from fetal liver, umbilical cord blood, bone marrow and stromal vascular cell fraction of adipose tissue which is an abundant and easily accessible source.…”

Anti-inflammatory effect of stem cells against spinal cord injury via regulating macrophage polarization

“…[76][77][78][79] There is a large body of evidence demonstrating that the effects of MSCs on macrophages are critical for inflammatory response and tissue repair after SCI. [80][81][82][83][84] Nakajima et al observed that BM-MSCs altered macrophages into anti-inflammatory M2 and beneficially modulated the immune system. 80 When human BM-derived macrophages were cocultured with human BM-MSCs, these macrophages showed high expression of a well-known marker of alternatively activated M2 macrophages (CD206) and expressed low levels of TNF-α and IL-12 and high levels of IL-6 and IL-10.…”

Regulation of Inflammatory Cytokines for Spinal Cord Injury Repair Through Local Delivery of Therapeutic Agents

“…Cells transplanted directly into the lesion site in SCI animal models reduce the expression of TNF‐α,198, 199, 200, 201, 202, 203, 204 IL‐1β,200, 201, 203 IL‐6,198, 199, 200, 202 IL‐2, IL‐4, IL‐12,199 IFN‐α,200 IL‐10, TGF‐β1,201 MMP‐9,202, 204 CCL2, CCL5, CCL10,202 GM‐CSF, and tissue inhibitor of metalloproteinases,203 and increase the expression of IL‐4,198, 201 IL‐13,198 CCL5,199 GM‐CSF,202 leptin, and ciliary neurotrophic factor 203…”