Human adipose stem cells reverse neuropathic pain symptoms and restore pro-anti inflammatory cytokine balance in the chronic constriction injury mouse model

We previously demonstrated that murine neural stem cells, systemically administered, were able to contrast neuropathic pain symptoms in a mouse model of peripheral lesion. In this work we test the effect of human mesenchymal stem cells from adipose tissue (hASCs) in sciatic nerve chronic constriction injury (CCI) model in the mouse. These cells are characterized by easier availability, faster proliferation rate, marked clonogenic ability and low immunogenicity. We correlate their effect on pain reduction with some biochemical changes induced at the lesion site. We choose the sciatic nerve chronic constriction injury model in mouse (CCI) because it produces a robust Wallerian degeneration with additional inflammation. Moreover, since some nerve fibres survive the injury, behavioural testing to assess pain possible. We isolated hASCs from subcutaneous adipose tissue of 5 women; we characterized them phenotipically and evaluated their clonogenic and differentiative potential in order to verify their stemness. hASCs (1x106) were injected into mice caudal vein 7 days after CCI, when pain was already maximal, and at 1,3,7,14,21 and 28 days since injection we assessed their effect on mechanical allodynia (Dynamic Plantar Aesthesiomether) and thermal hyperalgesia (Plantar test) and correlated it with the alterations in pro and anti inflammatory cytokines and nerve growth factor (NGF) in the lesioned sciatic nerve. Cytokines and NGF were measured by ELISA. hASCs were able to completely reverse hyperalgesia and reduce allodynia starting 24 hours after the injection. The effect began to fade 21 days after administration, but could be restored by a new cell injection (1x106). These effects on pain well correlated with changes of the cytokine levels at the lesion site. In fact 3 and 7 days after cells administration, hASCs restored to physiological levels the murine pro-inflammatory cytokines IL-1β and IL-6 that were increased by the injury. The anti-inflammatory cytokine IL-10, that appeared reduced in CCI mice, was significantly increased in cell treated animals. Interestingly, no human IL-10 was detectable in the sciatic nerve tissue of cell injected mice, suggesting that hASCs exerted a modulation of endogenously produced cytokines. A similar effect was evident also for NGF, in fact the treatment restored the levels decreased by the pathology. In conclusion, the peripheral administration of hASCs therapeutically reversed neuropathic pain symptoms in the CCI mouse model. We hypothesize that a bidirectional interaction between stem cells and the lesioned-inflamed nerve is at the basis of the positive modulation of pain and inflammation.