Intrathecal bone marrow stromal cells inhibit neuropathic pain via TGF-β secretion
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2015-07-13
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(A) Selective targeting of i.t.-injected BMSCs (CM-Dil labeled) to ipsilateral L4–L6 DRGs 3 days after i.t. injection (day 7 after CCI). Scale bar: 100 μm. Note that there was only limited migration of BMSCs to contralateral DRGs. (B) ELISA analysis showing CXCL12 expression in contralateral and ipsilateral L4–L6 DRGs on days 4 and 14 after CCI. *P < 0.05; n = 4 mice/group. (C) Chemotaxis (Transwell invasion) assay showing the migration of BMSCs in response to CXCL12 (0–100 ng/ml) and the inhibitory effect of the CXCR4 antagonist AMD3100 (5 mg/ml, 30 min). *P < 0.05, compared with the control group (no treatment); #P < 0.05; n = 4 wells from separate cultures. (D) Reduction of Cxcr4 mRNA levels in BMSCs treated with Cxcr4 siRNA (1 μg/ml for 18 h). *P < 0.05; n = 3 separate cultures. (E) Antiallodynic effect of i.t. BMSCs (2.5 × 105 cells) was compromised by pretreatment of BMSCs with Cxcr4 siRNA, but not with nontargeting control siRNA. Arrow indicates BMSC injection on day 14 after CCI. *P < 0.05, compared with the vehicle group; #P < 0.05; n = 5 mice/group. (F) Migration of CM-Dil–labeled BMSCs to ipsilateral L5 DRGs 7 days after i.t. injection (day 21 after CCI). Note that this migration was blocked by Cxcr4 siRNA. Scale bar: 50 μm. (G) Number of CM-Dil–labeled BMSCs in ipsilateral L4–L6 DRGs after the treatment shown in F. *P < 0.05; n = 5 mice/group. Statistical significance was determined by 1-way ANOVA, followed by Bonferroni’s post-hoc test (B and C), 2-way, repeated-measures ANOVA, followed by Bonferroni’s post-hoc test (E), or Student’s t test (D and G). All data are expressed as the mean ± SEM.
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Chen, G, C-K Park, R-G Xie and R Ji (2015). Intrathecal bone marrow stromal cells inhibit neuropathic pain via TGF-β secretion. Journal of Clinical Investigation. 10.1172/JCI80883 Retrieved from https://hdl.handle.net/10161/10285.
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Ru-Rong Ji
I have been doing neuroscience and pain research for over 25 years in multiple academic institutes, including Duke University (2012-current), Harvard Medical School (1998-2012), Johns Hopkins Medical School, Karolinska Institute, and Peking University. The long-term goal of my lab is to identify molecular and cellular mechanisms that underlie the induction and resolution of pathological pain and develop novel pain therapeutics that can target these mechanisms, with specific focus on neuroimmune interactions. We are interested in the following scientific questions. (1) How does inflammation induce and resolve pain via immune cell interaction with primary sensory neurons? (2) How does neuroinflammation drive chronic pain via activation of glial cells in the CNS (microglia and astrocytes) and PNS (satellite glial cells) and regulation of sensory neuron plasticity (peripheral sensitization) and spinal cord synaptic plasticity (central sensitization)? (3) How do specialized pro-resolution mediators (SPMs, e.g., resolvins, protectins, and maresins) control pain via GPCR signaling? (4) How do immunotherapies through the PD-L1/PD-1 and STING/IFN pathways regulate pain, cognition, and neuronal activities? (5) How do secreted miRNAs regulate pain and itch via direct activation of surface receptors and ion channels? (6) How do nerve terminals interact with cancers in chronic pain and itch? (7) How do Toll-like receptors (TLR) in primary sensory neurons sense danger signals and regulate pain and itch? (8) How do regenerative approaches such as autologous conditioned serum (ACS) and bone marrow stromal cells (MSCs) produce long-term pain relief via secreting anti-inflammatory factors and exosomes? We employ a multidisciplinary approach that covers in vitro, ex vivo, and in vivo studies for animal behaviors, electrophysiology, molecular biology, cell biology, and transgenic animals. We have identified numerous therapeutic targets and filed many patents for translational studies. As the Director of the Center for Translational Pain Medicine (CTPM) and a highly cited researcher (Cross Field, Clarivate), I have both administrative and scientific leadership for successful completion of many research projects.
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