Background & Aims
Chemotherapy-induced peripheral neuropathy (CIPN) is a common, often severe side effect that considerably reduces the quality of life of cancer survivors [1-3]. Neuronal mitochondrial dysfunction is a key pathogenic mechanism involved in CIPN [4-7]. Currently, there are no effective FDA-approved drugs to prevent or treat this condition. We previously showed that nasal administration of mesenchymal stem cells (MSC) reverses CIPN in mice and that IL-10 signaling is critical for resolution of CIPN [8]. The aim of this study is to investigate the cellular mechanisms underlying the therapeutic effects of MSC on neuropathic pain after chemotherapy.
Methods
Mice received cisplatin or saline for 2 cycles of 5 daily injections of 2.3 mg/kg with 5 days of rest in between. Adoptive transfer of T cells and/or B cells to mice deficient in T cells and/or B cells was performed 2 weeks before cisplatin treatment. MSC were administered nasally at 48 and 96 h after the last dose of cisplatin. CIPN was monitored before and after chemotherapy and MSC administration. Mechanical allodynia was evaluated using von Frey tests; spontaneous pain was measured using a conditioned place preference operant test. Mitochondrial function of dorsal root ganglia (DRG) was determined by Seahorse Flux analysis. Intracellular IL-10 production after MSC treatment was assessed by flow cytometry.
Results
Nasal MSC administration resolved cisplatin-induced mechanical allodynia, spontaneous pain and restored mitochondrial function in DRG of wild-type mice. In contrast, MSCs did not resolve these symptoms in mice deficient in B cells (muMt-), or both B and T cells (Rag2-/-). Adoptive transfer of T cells but not B cells to Rag2-/- mice prior to cisplatin treatment partially reversed mechanical allodynia but not DRG mitochondrial dysfunction . Reconstitution of muMt- mice with B cells and Rag2-/- mice with B and T cells was necessary for MSCs to fully resolve CIPN symptoms. Whereas administration of IL-10-/- B cells to muMt- mice failed to reverse cisplatin-induced mechanical allodynia, suggesting a role for B cell-derived IL-10 in resolving CIPN.
Conclusions
Nasal administration of MSCs resolves CIPN via a mechanism involving B cells and T cells that is dependent on IL-10 signaling.
References
1.Zajaczkowska, R., et al., Mechanisms of Chemotherapy-Induced Peripheral Neuropathy. Int J Mol Sci, 2019. 20(6).
2.Seretny, M., et al., Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis. Pain, 2014. 155(12): p. 2461-2470.
3.Molassiotis, A., et al., Are we mis-estimating chemotherapy-induced peripheral neuropathy? Analysis of assessment methodologies from a prospective, multinational, longitudinal cohort study of patients receiving neurotoxic chemotherapy. BMC Cancer, 2019. 19(1): p. 132.
4.Ma, J., et al., Beyond symptomatic relief for chemotherapy-induced peripheral neuropathy: Targeting the source. Cancer, 2018. 124(11): p. 2289-2298.
5.Bennett, G.J., T. Doyle, and D. Salvemini, Mitotoxicity in distal symmetrical sensory peripheral neuropathies. Nat Rev Neurol, 2014. 10(6): p. 326-36.
6.Flatters, S.J., The contribution of mitochondria to sensory processing and pain. Prog Mol Biol Transl Sci, 2015. 131: p. 119-46.
7.Trecarichi, A. and S.J.L. Flatters, Mitochondrial dysfunction in the pathogenesis of chemotherapy-induced peripheral neuropathy. Int Rev Neurobiol, 2019. 145: p. 83-126.
8.Boukelmoune, N., et al., Nasal administration of mesenchymal stem cells reverses chemotherapy-induced peripheral neuropathy in mice. Brain Behav Immun, 2021. 93: p. 43-54.
Presenting Author
Nabila Boukelmoune
Poster Authors
Nabila Boukelmoune
PhD
The University of Texas MD Anderson Cancer Center
Lead Author
Anand Singh
PhD
The University of Texas MD Anderson Cancer Center
Lead Author
Jixiang Zhang
PhD
The University of Texas MD Anderson Cancer Center
Lead Author
Peter Grace
University of Texas MD Anderson Cancer Center
Lead Author
Cobi J. Heijnen
PhD
Rice University
Lead Author
Topics
- Specific Pain Conditions/Pain in Specific Populations: Neuropathic Pain - Peripheral