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 10

Prolonged inhibition of SNI-induced mechanical allodynia by i.t. BMSCs in the early or late phase and its reversal by TGF-β1 Abs.

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Prolonged inhibition of SNI-induced mechanical allodynia by i.t. BMSCs i...
(A and B) Long-term inhibition of mechanical allodynia by early treatment with BMSCs (2.5 × 105 cells) via i.t. injection, given 4 days after SNI. Mechanical allodynia was tested using the paw withdrawal threshold (A) and by the frequency of response (percentage of response) to a single 0.16 gf filament (10 times) (B). *P < 0.05, compared with vehicle (PBS); n = 6 mice/group. (C and D) Sustained inhibition of mechanical allodynia by late treatment with i.t. BMSCs (2.5 × 105 cells), given 21 days after SNI. *P < 0.05, compared with vehicle; n = 6 mice/group. (E) Reversal of BMSC-induced inhibition of mechanical allodynia by i.t. TGF-β1–neutralizing Abs (4 μg), given 3 weeks after SNI. Arrows in A–E indicate the time of injection. *P < 0.05, compared with the IgG control group; n = 5 mice/group. All data are expressed as the mean ± SEM. Statistical significance was determined by 2-way ANOVA, followed by Bonferroni’s post-hoc test.