TY - JOUR
T1 - Nasal administration of mesenchymal stem cells reverses chemotherapy-induced peripheral neuropathy in mice
AU - Boukelmoune, Nabila
AU - Laumet, Geoffroy
AU - Tang, Yongfu
AU - Ma, Jiacheng
AU - Mahant, Itee
AU - Singh, Susmita K.
AU - Nijboer, Cora
AU - Benders, Manon
AU - Kavelaars, Annemieke
AU - Heijnen, Cobi J.
N1 - Funding Information:
This work was supported by the National Institutes of Health [Grants R01CA208371, RO1 NS073939 and RO1CA227064]; and the National Institutes of Health, Cancer Center Support Grant [P30 CA016672]. N.B. A.K. and C.J.H designed research; N.B. G.L. Y.T. J.M. S.K.S and I.M performed research and analyzed data; N.B. A.K. and C.J.H wrote the paper; C.N. and M.B. reviewed and edited the manuscript.
Funding Information:
This work was supported by National Institute of Health Grants R01CA208371 , RO1 NS073939 and RO1CA227064 .
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2021/3
Y1 - 2021/3
N2 - Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most frequently reported adverse effects of cancer treatment. CIPN often persists long after treatment completion and has detrimental effects on patient's quality of life. There are no efficacious FDA-approved drugs for CIPN. We recently demonstrated that nasal administration of mesenchymal stem cells (MSC) reverses the cognitive deficits induced by cisplatin in mice. Here we show that nasal administration of MSC after cisplatin- or paclitaxel treatment- completely reverses signs of established CIPN, including mechanical allodynia, spontaneous pain, and loss of intraepidermal nerve fibers (IENF) in the paw. The resolution of CIPN is associated with normalization of the cisplatin-induced decrease in mitochondrial bioenergetics in DRG neurons. Nasally administered MSC enter rapidly the meninges of the brain, spinal cord and peripheral lymph nodes to promote IL-10 production by macrophages. MSC-mediated resolution of mechanical allodynia, recovery of IENFs and restoration of DRG mitochondrial function critically depends on IL-10 production. MSC from IL-10 knockout animals are not capable of reversing the symptoms of CIPN. Moreover, WT MSC do not reverse CIPN in mice lacking IL-10 receptors on peripheral sensory neurons. In conclusion, only two nasal administrations of MSC fully reverse CIPN and the associated mitochondrial abnormalities via an IL-10 dependent pathway. Since MSC are already applied clinically, we propose that nasal MSC treatment could become a powerful treatment for the large group of patients suffering from neurotoxicities of cancer treatment.
AB - Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most frequently reported adverse effects of cancer treatment. CIPN often persists long after treatment completion and has detrimental effects on patient's quality of life. There are no efficacious FDA-approved drugs for CIPN. We recently demonstrated that nasal administration of mesenchymal stem cells (MSC) reverses the cognitive deficits induced by cisplatin in mice. Here we show that nasal administration of MSC after cisplatin- or paclitaxel treatment- completely reverses signs of established CIPN, including mechanical allodynia, spontaneous pain, and loss of intraepidermal nerve fibers (IENF) in the paw. The resolution of CIPN is associated with normalization of the cisplatin-induced decrease in mitochondrial bioenergetics in DRG neurons. Nasally administered MSC enter rapidly the meninges of the brain, spinal cord and peripheral lymph nodes to promote IL-10 production by macrophages. MSC-mediated resolution of mechanical allodynia, recovery of IENFs and restoration of DRG mitochondrial function critically depends on IL-10 production. MSC from IL-10 knockout animals are not capable of reversing the symptoms of CIPN. Moreover, WT MSC do not reverse CIPN in mice lacking IL-10 receptors on peripheral sensory neurons. In conclusion, only two nasal administrations of MSC fully reverse CIPN and the associated mitochondrial abnormalities via an IL-10 dependent pathway. Since MSC are already applied clinically, we propose that nasal MSC treatment could become a powerful treatment for the large group of patients suffering from neurotoxicities of cancer treatment.
KW - Cisplatin
KW - Interleukin-10 (IL-10)
KW - Meninges
KW - Mesenchymal Stem Cells (MSC)
KW - Mitochondria
KW - Peripheral neuropathy
KW - Sensory neurons
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U2 - 10.1016/j.bbi.2020.12.011
DO - 10.1016/j.bbi.2020.12.011
M3 - Article
C2 - 33316379
AN - SCOPUS:85098617703
SN - 0889-1591
VL - 93
SP - 43
EP - 54
JO - Brain, behavior, and immunity
JF - Brain, behavior, and immunity
ER -