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Bone Marrow Stem Cells Relieve Pain Symptoms Following Spinal Cord Injury

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Review of “Early transplantation of MSCs after spinal cord injury relieves pain hypersensitivity through suppression of pain-related signaling cascade” from Stem Cells by Stuart P. Atkinson

Bone marrow‐derived mesenchymal stem cells (BMSC) are currently being investigated as a treatment for the debilitating effects of spinal cord injury (SCI). However, these studies usually concentrate on sensory recovery and not SCI‐induced chronic neuropathic pain/neuronal hyperexcitability, which are known to develop in up to 80% of SCI patients. Studies which have attempted to address this clinical feature have found led to some improvements, although this remains a contentious point in this field of research [1-4]. To further our understanding of the effects of BMSC transplantation on post‐SCI chronic neuropathic pain/neuronal hyperexcitability, the group of Kenzo Uchida (University of Fukui, Japan) have focused on microglia [5], inflammatory macrophages and MAPK signaling [6], and report that BMSCs can reduce pain through a mechanism which includes neuronal sparing and the restoration of the disturbed blood‐spinal cord barrier [7].

The study firsts assessed the effects of BMSC transplantation at differing time points after injury, finding that animals treated at day 3 post‐SCI displayed the greatest improvements in locomotor, mechanical and thermal sensitivity scores, and so all subsequent data came from analysis at this time point. Subsequent detailed investigation found that SCI mediated an increase in hyperexcitability markers (PKC‐ and p‐CREB) in neurons of the dorsal horn of the spinal cord around the injury site, in the control non-transplanted group. However, BMSC transplantation diminished these signals, therefore increasing neuronal sparing and bringing a beneficial effect on neuropathic pain caused by neural overstimulation.

MAPK family members (pp38 MAPK, p‐ERK1/2 and p‐JNK) are all activated and crucial to activate the mechanisms leading to neuropathic pain after SCI, and this study demonstrated higher levels of these markers in CD11b-positive hematogenous macrophages and resident microglia within the dorsal horn after SCI. BMSC transplantation reduced these signals, and also inhibited the recruitment of harmful inflammatory macrophages to the lesion site. Co‐expression of p‐p38 MAPK and p‐ERK1/2 in macrophages was also reduced, but BMSC transplantation did not affect the activated spinal microglia population. Additionally, BMSC transplantation improved the function of the blood‐spinal cord barrier (BSCB) as observed by less albumin (See Figure - Red staining) and PDGFR‐α leakage into the parenchyma at day 7, a likely mechanism by which macrophage recruitment is inhibited. This also led to the reduction of inflammatory cytokines (TNF‐α, IL‐6), mediators of early secondary vascular pathogenesis (MMP‐9), and macrophage recruiting factors (CCL2, CCL5, CXCL10).

Overall, this suggests that BMSC have a beneficial effect in treating pain hypersensitivity following SCI in this animal model, and that delineation of some of the mechanisms behind this reduction will further guide therapeutic interventions. Small molecule modulation of some of the pathways described here may function synergistically with BMSCs in the treatment of SCI, promoting both the recovery of sensation and a reduction in pain.

References

  1. Abrams MB, Dominguez C, Pernold K, et al. Multipotent mesenchymal stromal cells attenuate chronic inflammation and injury-induced sensitivity to mechanical stimuli in experimental spinal cord injury. Restor Neurol Neurosci 2009;27:307-321.
  2. Furuya T, Hashimoto M, Koda M, et al. Treatment of rat spinal cord injury with a Rho-kinase inhibitor and bone marrow stromal cell transplantation. Brain research 2009;1295:192-202.
  3. Kumagai G, Tsoulfas P, Toh S, et al. Genetically modified mesenchymal stem cells (MSCs) promote axonal regeneration and prevent hypersensitivity after spinal cord injury. Experimental neurology 2013;248:369-380.
  4. Ritfeld GJ, Nandoe Tewarie RD, Vajn K, et al. Bone marrow stromal cell-mediated tissue sparing enhances functional repair after spinal cord contusion in adult rats. Cell transplantation 2012;21:1561-1575.
  5. Tsuda M, Inoue K, and Salter MW Neuropathic pain and spinal microglia: a big problem from molecules in "small" glia. Trends in neurosciences 2005;28:101-107.
  6. Hulsebosch CE, Hains BC, Crown ED, et al. Mechanisms of chronic central neuropathic pain after spinal cord injury. Brain Res Rev 2009;60:202-213.
  7. Watanabe S, Uchida K, Nakajima H, et al. 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 2015;33:1902-1914.