ABSTRACT
Title
Intravenous human adipose stem cells reverse neuropathic pain symptoms and restore pro-anti inflammatory cytokine balance in the chronic constriction injury murine model
Authors
A. Rossi1, E. Arrigoni1, S. Niada1, S. Franchi1, M. Colleoni1, A.E. Panerai1, P. Sacerdote1, A. T. Brini1
1Dipartimento di Farmacologia, Chemioterapia e Tossicologia medica, Università degli Studi di Milano, Milano
1Dipartimento di Farmacologia, Chemioterapia e Tossicologia medica, Università degli Studi di Milano, Milano
Abstract
We previously demonstrated that murine neural stem cells, systemically administered, were able to contrast neuropathic pain symptoms in a murine model of peripheral lesion. In this work we tested the effect of human mesenchymal stem cells from adipose tissue (hASC) in sciatic nerve chronic constriction injury (CCI) model in the mouse. These cells are characterized by easy availability, fast proliferation rate, marked clonogenic ability and low immunogenicity. We correlated their effect on pain reduction with some biochemical changes induced at the lesion site. We chose 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 is possible.
We isolated hASCs from woman subcutaneous adipose tissue, characterized them phenotipically and evaluated their clonogenic and differentiative potential in order to verify their stemness [1].
hASCs (1x106) were injected into mice caudal vein 7 days after CCI, when pain was maximal, and at 1, 3, 7, 14, 21 and 28 days since injection their effect on mechanical allodynia (Dynamic Plantar Aesthesiomether) and thermal hyperalgesia was assessed (Plantar test) and correlated 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 administration was able to completely reverse hyperalgesia and reduce allodynia starting 24 hours after the injection. The effect began to fade 21 days after administration and was 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, the murine pro-inflammatory cytokines IL-1βand IL-6, increased by the injury, returned to physiological levels. 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 murine model. We hypothesize that a bidirectional interaction between stem cells and the lesioned nerve is at the basis of the positive modulation of pain and inflammation.
[1] De Girolamo L et al. (2009) Human adipose-derived stem cells isolated from young and elderly women:their differentiation potential and scaffold interaction during in vitro osteoclastic differentiation. Cytotherapy 11:793-803
We isolated hASCs from woman subcutaneous adipose tissue, characterized them phenotipically and evaluated their clonogenic and differentiative potential in order to verify their stemness [1].
hASCs (1x106) were injected into mice caudal vein 7 days after CCI, when pain was maximal, and at 1, 3, 7, 14, 21 and 28 days since injection their effect on mechanical allodynia (Dynamic Plantar Aesthesiomether) and thermal hyperalgesia was assessed (Plantar test) and correlated 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 administration was able to completely reverse hyperalgesia and reduce allodynia starting 24 hours after the injection. The effect began to fade 21 days after administration and was 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, the murine pro-inflammatory cytokines IL-1βand IL-6, increased by the injury, returned to physiological levels. 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 murine model. We hypothesize that a bidirectional interaction between stem cells and the lesioned nerve is at the basis of the positive modulation of pain and inflammation.
[1] De Girolamo L et al. (2009) Human adipose-derived stem cells isolated from young and elderly women:their differentiation potential and scaffold interaction during in vitro osteoclastic differentiation. Cytotherapy 11:793-803