title: 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-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.
authors: Department of Orthopaedics and Rehabilitation Medicine, Faculty of Medical Sciences, University of Fukui, Matsuoka Shimoaizuki, Eiheiji, Fukui, Japan.
authors: Shuji
authors: S
authors: Watanabe
authors: Department of Orthopaedics and Rehabilitation Medicine, Faculty of Medical Sciences, University of Fukui, Matsuoka Shimoaizuki, Eiheiji, Fukui, Japan.
authors: Kenzo
authors: K
authors: Uchida
authors: Department of Orthopaedics and Rehabilitation Medicine, Faculty of Medical Sciences, University of Fukui, Matsuoka Shimoaizuki, Eiheiji, Fukui, Japan.
authors: Hideaki
authors: H
authors: Nakajima
authors: Department of Orthopaedics and Rehabilitation Medicine, Faculty of Medical Sciences, University of Fukui, Matsuoka Shimoaizuki, Eiheiji, Fukui, Japan.
authors: Hideaki
authors: H
authors: Matsuo
authors: Department of Orthopaedics and Rehabilitation Medicine, Faculty of Medical Sciences, University of Fukui, Matsuoka Shimoaizuki, Eiheiji, Fukui, Japan.
authors: Daisuke
authors: D
authors: Sugita
authors: Department of Orthopaedics and Rehabilitation Medicine, Faculty of Medical Sciences, University of Fukui, Matsuoka Shimoaizuki, Eiheiji, Fukui, Japan.
authors: Ai
authors: A
authors: Yoshida
authors: Department of Orthopaedics and Rehabilitation Medicine, Faculty of Medical Sciences, University of Fukui, Matsuoka Shimoaizuki, Eiheiji, Fukui, Japan.
authors: Kazuya
authors: K
authors: Honjoh
authors: Life and Health Sciences, Aston University, Aston Triangle, Birmingham, United Kingdom.
authors: William E B
authors: WE
authors: Johnson
authors: Department of Orthopaedics and Rehabilitation Medicine, Faculty of Medical Sciences, University of Fukui, Matsuoka Shimoaizuki, Eiheiji, Fukui, Japan.
authors: Hisatoshi
authors: H
authors: Baba
mesh_terms: D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007249:Inflammation / Q000517:prevention & control / Q000628:therapy; D008264:Macrophages / Q000378:metabolism; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D009437:Neuralgia / Q000209:etiology*; D009474:Neurons / Q000378:metabolism; D020127:Recovery of Function / Q000502:physiology; D015398:Signal Transduction; D013119:Spinal Cord Injuries / Q000150:complications / Q000473:pathology / Q000628:therapy*
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Blood-spinal cord barrier; Bone marrow-derived mesenchymal stem cells; Central neuropathic pain; Hematogenous macrophages; Mitogen-activated protein kinase (MAPK) pathway; Resident microglia; Spinal cord injury; Transplantation