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

Watanabe, Shuji, Uchida, Kenzo, Nakajima, Hideaki, Matsuo, Hideaki, Sugita, Daisuke, Yoshida, Ai, Honjoh, Kazuya, Johnson, William E.B. and Baba, Hisatoshi (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), pp. 1902-1914.

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.

Publication DOI: https://doi.org/10.1002/stem.2006
Divisions: Life & Health Sciences > Biosciences
Life & Health Sciences
Life & Health Sciences > Cellular and Molecular Biomedicine
Life & Health Sciences > Cell & Tissue Biomedical Research
Additional Information: © 2015 The Authors STEM CELLS published by Wiley Periodicals, Inc. on behalf of AlphaMed Press This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. Funding: Ministry of Education, Science and Culture of Japan (B-24791530 and B-24390351), from the Japan Orthopaedics and Traumatology Foundation, Inc. (#297).
Uncontrolled 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,Cell Biology,Developmental Biology,Molecular Medicine
Full Text Link:
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
Published Date: 2015-06-30
Authors: Watanabe, Shuji
Uchida, Kenzo
Nakajima, Hideaki
Matsuo, Hideaki
Sugita, Daisuke
Yoshida, Ai
Honjoh, Kazuya
Johnson, William E.B.
Baba, Hisatoshi

Export / Share Citation


Statistics

Additional statistics for this record