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 4

BMSCs administered i.t. inhibit CCI-induced glial activation and neuroinflammation in lumbar DRGs and the spinal cord dorsal horn.

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BMSCs administered i.t. inhibit CCI-induced glial activation and neuroin...
(A) Paradigm showing the timing of BMSC treatment (CCI day 4) and tissue collection (CCI day 8). (B) Inhibition of CCI-induced upregulation of the macrophage marker IBA-1 in L4–L5 DRGs by i.t. injection of BMSCs (2.5 × 105 cells). Scale bar: 50 μm. (C) Quantification of IBA-1 staining. *P < 0.05, compared with the sham group; #P < 0.05; n = 4 mice/group. (D) qPCR showing expression levels of Gfap, Il1b, Il6, and Tnf mRNAs in L4–L5 DRGs and the effects of BMSCs. *P < 0.05, compared with the contralateral group; #P < 0.05; n = 4 mice/group. (E and F) BMSC inhibition of CCI-induced upregulation of the microglial marker IBA-1 and the astrocyte marker GFAP in the L4–L5 dorsal horn. Graph in F shows the quantification of GFAP and IBA-1 staining. Scale bar: 200 μm (top panels) and 50 μm (bottom panels). Bottom panels are enlarged images of the top panels. *P < 0.05, compared with the contralateral group; #P < 0.05; n = 4 mice/group. (G) qPCR showing the expression levels of Iba1, Il1b, Il6, and Tnf mRNAs and the effects of BMSCs. *P < 0.05, compared with the contralateral group; #P < 0.05; n = 4–5 mice/group. Statistical significance was determined by 1-way ANOVA, followed by Bonferroni’s post-hoc test. All data are expressed as the mean ± SEM.