title: 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.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Chul-Kyu
authors.initials: CK
authors.lastname: Park
authors.forename: Rou-Gang
authors.initials: RG
authors.lastname: Xie
authors.forename: Ru-Rong
authors.initials: RR
authors.lastname: Ji
mesh_terms: D064591:Allografts; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000378:metabolism; D004195:Disease Models, Animal; D005071:Evoked Potentials; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D009473:Neuronal Plasticity; D019899:Paracrine Communication; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D018125:Receptors, Transforming Growth Factor beta; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I