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
Authors
Johnson, William Eustace BasilWatanabe, Shuji
Uchida, Kenzo
Nakajima, Hideaki
Matsuo, Hideaki
Sugita, Daisuke
Yoshida, Ai
Honjoh, Kazuya
Baba, Hisatoshi
Affiliation
Aston University, University of Fukui
Metadata
Show full item recordAbstract
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-γ 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-α, 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.Citation
Watanabe, S., Uchida, K., Nakajima, H., Matsuo, H., Sugita, D., Yoshida, A., . . . Baba, H. (2015). 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. Stem Cells, 33(6), 1902-1914Publisher
AlphaMed Press/WileyJournal
Stem CellsType
ArticleDescription
This novel study demonstrated that mesenchymal stem cell transplants after spinal cord injury reduce neuropathic pain, giving details of reduced pain signalling pathways affected. The work is essential in the translation of stem cell therapies for CNS regeneration.ISSN
1066-5099EISSN
1549-4918Collections
Except where otherwise noted, this item's license is described as https://creativecommons.org/licenses/by-nc-nd/4.0/