Intrathecal bone marrow stromal cells inhibit neuropathic pain via TGF-β secretion
Gang Chen, … , Rou-Gang Xie, Ru-Rong Ji
Gang Chen, … , Rou-Gang Xie, Ru-Rong Ji
Published July 13, 2015
Citation Information: J Clin Invest. 2015;125(8):3226-3240. https://doi.org/10.1172/JCI80883.
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Research Article Neuroscience

Intrathecal bone marrow stromal cells inhibit neuropathic pain via TGF-β secretion

Abstract

Neuropathic pain remains a pressing clinical problem. Here, we demonstrate that a local, intrathecal (i.t.) injection of bone marrow stromal cells (BMSCs) following lumbar puncture alleviates early- and late-phase neuropathic pain symptoms, such as allodynia and hyperalgesia, for several weeks in murine chronic constriction injury (CCI) and spared nerve injury models. Moreover, i.t. BMSCs reduced CCI-induced spontaneous pain and axonal injury of dorsal root ganglion (DRG) neurons and inhibited CCI-evoked neuroinflammation in DRGs and spinal cord tissues. BMSCs secreted TGF-β1 into the cerebrospinal fluid, and neutralization of TGF-β1, but not IL-10, reversed the analgesic effect of BMSCs. Conversely, i.t. administration of TGF-β1 potently inhibited neuropathic pain. TGF-β1 acted as a powerful neuromodulator and rapidly (within minutes) suppressed CCI-evoked spinal synaptic plasticity and DRG neuronal hyperexcitability via TGF-β receptor 1–mediated noncanonical signaling. Finally, nerve injury upregulated CXCL12 in lumbar L4–L6 DRGs, and this upregulation caused migration of i.t.-injected BMSCs to DRGs through the CXCL12 receptor CXCR4, which was expressed on BMSCs. BMSCs that migrated from the injection site survived at the border of DRGs for more than 2 months. Our findings support a paracrine mechanism by which i.t. BMSCs target CXCL12-producing DRGs to elicit neuroprotection and sustained neuropathic pain relief via TGF-β1 secretion.

Authors

Gang Chen, Chul-Kyu Park, Rou-Gang Xie, Ru-Rong Ji

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Figure 1

Inhibition of CCI-induced evoked and ongoing neuropathic pain in mice by a single i.t. injection of BMSCs.

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Inhibition of CCI-induced evoked and ongoing neuropathic pain in mice by...
(A and B) Prolonged inhibition of mechanical allodynia (A) and thermal hyperalgesia (B) for 5 weeks by early treatment with i.t. injection of BMSCs (1.0 or 2.5 × 105 cells), given 4 days after CCI. *P < 0.05, compared with vehicle (PBS); n = 6 mice/group. (C and D) Reversal of mechanical allodynia (C) and thermal hyperalgesia (D) by late treatment with i.t. BMSCs (1.0 or 2.5 × 105 cells), given 14 days after CCI. Arrows in A–D indicate the time of BMSC injection. *P < 0.05, compared with vehicle; #P < 0.05; n = 6 mice/group. (E) Paradigm for measuring ongoing pain using a 2-chamber CPP test. (F) CCI-induced ongoing pain was abolished by treatment with BMSCs. *P < 0.05, compared with saline; n = 5 mice/group. Statistical significance was determined by 2-way repeated-measures ANOVA, followed by Bonferroni’s post-hoc test (A–D) or Student’s t test (F). All data are expressed as the mean ± SEM. BL, baseline.