Human adipose-derived mesenchymal stem cells systemically injected promote peripheral nerve regeneration in the mouse model of sciatic crush.

Mesenchymal stem cells (MSC) represent a promising therapeutic approach in nerve tissue engineering. To date, local implantation of MSC in injured nerves has been the only route of administration used. In case of multiple sites of injury, the systemic administration of cells capable of reaching damaged nerves would be advisable. In this regard, we found that intravenous administration of adipose-derived MSC (ASC) one week after sciatic nerve crush injury, a murine model of acute axonal damage, significantly accelerated the functional recovery. Sciatic nerves from ASC-treated mice showed the presence of a restricted number of undifferentiated ASC together with, significant improvement of fiber sprouting and reduction of inflammatory infiltrates for up to 3 weeks. Besides the immune modulatory effect, our results show that ASC may contribute to peripheral nerve regeneration because of their ability to produce in culture neuroprotective factors like IGF-I, BDNF or bFGF. In addition to this production in vitro, we interestingly found that the concentration of GDNF was significantly increased in sciatic nerves from mice treated with ASC. Since no detectable levels of GDNF were observed in ASC cultures, we hypothesize that ASC induced the local production of GDNF by Schwann cells. In conclusion, we show that systemically injected ASC have a clear therapeutic potential in an acute model of axonal damage. Among the possible mechanisms promoting nerve regeneration, our results rule out a process of trans-differentiation and rather suggest the relevance of a bystander effect, including the production in situ of molecules which, directly or indirectly through a cross-talk with local glial cells, may modulate the local environment with down-regulation of inflammation and promotion of axonal regeneration.