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Abstract
Systemic infusion of bone marrow stromal cells (BMSCs), a major type of multipotent stromal cells, produces pain relief (antihyperalgesia) that lasts for months. However, studies have shown that the majority of BMSCs are trapped in the lungs immediately after intravenous infusion and their survival time in the host is inconsistent with their lengthy antihyperalgesia. Here we show that long-lasting antihyperalgesia produced by BMSCs required their chemotactic factors such as CCL4 and CCR2, the integrations with the monocytes/macrophages population, and BMSC-induced monocyte CXCL1. The activation of central mu-opioid receptors related to CXCL1-CXCR2 signaling plays an important role in BMSC-produced antihyperalgesia. Our findings suggest that the maintenance of antihypergesia can be achieved by immune regulation without actual engraftment of BMSCs. In the capacity of therapeutic use of BMSCs other than structural repair and replacement, more attention should be directed to their role as immune modulators and subsequent alterations in the immune system.
Highlights
Multipotent stromal cells have shown their therapeutic potential in a variety of clinical conditions[1,2,3]
We showed previously that the bone marrow stromal cells (BMSCs)-produced antihyperalgesia was attenuated, or pain hypersensitivity rekindled, by naloxone, an opioid receptors antagonist[5]; and that N-methylD-aspartate receptor-mediated trigeminal nociceptive neuronal hyperexcitability was attenuated by BMSCs, an effect reversed by naloxone[26]
The BMSC-produced antihyperalgesia was attenuated by 6-β-naltrexol (Supplementary Fig. 1a,b). These results suggest that the antihyperalgesia by BMSCs involves the endogenous opioid system
Summary
Multipotent stromal cells have shown their therapeutic potential in a variety of clinical conditions[1,2,3]. Clinical studies show promising long-term pain relief with multipotent stromal cells[9, 10]. A portion of intrathecally injected MSCs migrated to the dorsal root ganglion and survived there for up to 84 days[4]. Recent MSC medicine appreciate that there are sophisticated interactions between implanted cells and the host immune system[19, 20]. Infused MSCs would first encounter circulating immune cells and embolized cells in the lungs interact with the host[13, 21, 22]. Host immune cells, followed by release of immune mediators, leading to activation of the endogenous analgesic system and long-lasting pain relief. We have conducted a series of experiments to test this hypothesis
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