Intravenous neural stem cells abolish nociceptive hypersensitivity and trigger nerve regeneration in experimental neuropathy.
A nonphysiological repair of the lesioned nerve leading to the formation of neurinomas, altered nerve conduction, and spontaneous firing is considered the main cause of the events underlying neuropathic pain. It was investigated whether neural stem cell (NSCs) administration could lead to a physiological nerve repair, thus to a reduction of neuropathic pain symptoms such as hyperalgesia and allodynia in a well-established model of this pain (sciatic nerve chronic constriction injury [CCI]). Moreover, since we and others showed that the peripheral nerve lesion starts a cascade of neuroinflammation-related events that may maintain and worsen the original lesion, the effect of NSCs on sciatic nerve pro- and antiinflammatory cytokines in CCI mice was investigated. NSCs injected intravenously, when the pathology was already established, induced a significant reduction in allodynia and hyperalgesia already 3 days after administration, demonstrating a therapeutic effect that lasted for at least 28 days. Responses changed with the number of administered NSCs, and the effect on hyperalgesia could be boosted by a new NSC administration. Treatment significantly decreased proinflammatory, activated antiinflammatory cytokines in the sciatic nerve, and reduced spinal cord Fos expression in laminae I-VI. Moreover, in NSC-treated animals, a reparative process and an improvement of nerve morphology is present at a later time. Since NSC effect on pain symptoms preceded nerve repair and was maintained after cells had disappeared from the lesion site, we suggest that regenerative, behavioral, and immune NSC effects are largely due to microenvironmental changes they might induce at the lesion site.
Dipartimento di Farmacologia Chemioterapia e Tossicologia Medica, Università degli Studi di Milano, Milano, Italy Divisione di Anatomia Umana, Dipartimento di Scienze Biomediche e Biotecnologie, Università di Brescia, Brescia, Italy Dipartimento di Morfologia Umana e Scienze Biomediche, Università degli Studi di Milano, Milano, Italy Dipartimento di Biotecnologie e Bioscienze, Università Milano-Bicocca, Milano, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy Dipartimento di Medicina Sperimentale - Sezione di Farmacologia "L. Donatelli", Seconda Università di Napoli, Napoli, Italy.
Silvia
S
Franchi
Anna E
AE
Valsecchi
Elisa
E
Borsani
Patrizia
P
Procacci
Daniela
D
Ferrari
Cristina
C
Zaffa
Patrizia
P
Sartori
Luigi F
LF
Rodella
Angelo
A
Vescovi
Sabatino
S
Maione
Francesco
F
Rossi
Paola
P
Sacerdote
Mariapia
M
Colleoni
Alberto E
AE
Panerai
D000818:Animals; D006930:Hyperalgesia / Q000150:complications / Q000473:pathology / Q000601:surgery*; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D009416:Nerve Regeneration / Q000502:physiology*; D058953:Neural Stem Cells / Q000473:pathology / Q000502:physiology; D010147:Pain Measurement / Q000379:methods; D020426:Sciatic Neuropathy / Q000150:complications / Q000473:pathology / Q000601:surgery*; D033581:Stem Cell Transplantation / Q000379:methods