title: Human adipose-derived mesenchymal stem cells systemically injected promote peripheral nerve regeneration in the mouse model of sciatic crush.
abstract: Mesenchymal stem cells (MSCs) represent a promising therapeutic approach in nerve tissue engineering. To date, the 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 an intravenous administration of adipose-derived MSC (ASC) 1 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 a significant improvement in fiber sprouting and the 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 such as insulin-like growth factor I, brain-derived neurotrophic factor, or basic fibroblast growth factor. In addition to this production in vitro, we interestingly found that the concentration of glial-derived neurotrophic factor (GDNF) was significantly increased in the sciatic nerves in 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 of in situ molecules, which, directly or indirectly through a cross-talk with local glial cells, may modulate the local environment with the down-regulation of inflammation and the promotion of axonal regeneration.
authors.affiliation: Department of Neurological, Neuropsychological, Morphological and Movement Sciences, Neurology Section, University of Verona, Verona, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Marconi
authors.forename: Giusy
authors.initials: G
authors.lastname: Castiglione
authors.forename: Ermanna
authors.initials: E
authors.lastname: Turano
authors.forename: Guido
authors.initials: G
authors.lastname: Bissolotti
authors.forename: Stefano
authors.initials: S
authors.lastname: Angiari
authors.forename: Alessia
authors.initials: A
authors.lastname: Farinazzo
authors.forename: Gabriela
authors.initials: G
authors.lastname: Constantin
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bedogni
authors.forename: Alberto
authors.initials: A
authors.lastname: Bedogni
authors.forename: Bruno
authors.initials: B
authors.lastname: Bonetti
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007249:Inflammation / Q000473:pathology; D007267:Injections; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity; D009409:Nerve Crush; D009414:Nerve Growth Factors / Q000378:metabolism; D009416:Nerve Regeneration / Q000502:physiology*; D055495:Neurogenesis; D020127:Recovery of Function; D012584:Sciatic Nerve / Q000473:pathology* / Q000503:physiopathology*
chemical_list: D009414:Nerve Growth Factors