Aaron Mackie

Background: Facial nerve palsy is the partial or complete inability to move the affected side of the muscles of facial expression through damage to the facial nerve.¹ There are various causes of facial nerve palsy including idiopathic facial paralysis, infection, neoplasm, developmental, metabolic, toxic, trauma, and iatrogenic.² Facial paralysis usually resolves on its own, however, in approximately 25% of patients, moderate to severe facial asymmetry persists leading to symptoms such as oral insufficiency and permanent eye injury.³ For patients with moderate to severe facial paralysis who are not suspected to make a spontaneous recovery, surgical intervention is used to restore nerve function. Surgical restoration, however, is often unsatisfactory and can lead to abnormal regenerative side effects such as synkinesis.^4,5  Recent studies demonstrated that mesenchymal stem cells (MSCs) improve tissue regeneration in peripheral nerve injuries by modulating inflammatory responses, suggesting MSCs as a new potential therapeutic agent for the recovery of facial nerve palsy.⁶

Objective: In this narrative review, the mechanisms by which MSCs promote nerve recovery through modulation of the inflammatory responses were explored.

Search Methods: An online search using the PubMed database was conducted from 2018 to 2023 using the following keywords: “facial nerve palsy,” “nerve regeneration,” “mesenchymal stem cells,” “macrophage polarization.”

Results: Studies show that peripheral nerve injury-induced inflammatory responses, including increased macrophage infiltration, can inhibit peripheral nerve regeneration.⁷ Accelerated recovery with enhanced remyelination of nerves was observed in sciatic nerve crush injured mice when given acetylsalicylic acid which decreased macrophage levels, showing that modulation of macrophage levels is a potential therapeutic target for peripheral nerve repair.⁷ Administration of human umbilical cord mesenchymal stem cells (hUCMSCs) improved sensory and motor function in mice compared to control mice following spinal cord injury.⁸ In addition, hUCMSCs elevated levels of Arginase+ and reduced levels of iNOS+, markers for anti-inflammatory M2 and pro-inflammatory M1 macrophage phenotypes respectively.⁸ In vitro coculture studies of MSCs with mouse peritoneal cell macrophages demonstrated that MSCs increased the anti-inflammatory cytokine TGF-β1 and IL-10 as well as ARG-1 in lipopolysaccharide (LPS) stimulated macrophages while reducing pro-inflammatory cytokine levels of IL-6, IL-1β, and iNOS. However, these effects were significantly reduced when a TGF-β receptor inhibitor was introduced to the coculture system.⁹ MSC secreted TGF-β increased phosphorylation of Akt and FoxO1, which caused the translocation of FoxO1 into the cytoplasm leading to an increase in M2 macrophage markers and a decrease in M1 macrophage markers.⁹

Conclusions: Studies have shown that MSCs improve regeneration in facial nerve palsy.^10,11 Mechanistically, MSCs promote M2 macrophage polarization through secretion of TGF-β via the Akt/FoxO1 pathway. Further research should evaluate which MSC type is most effective for optimization of therapy.

Work Cited:

1. Owusu JA, Stewart CM, Boahene K. Facial Nerve Paralysis. Med Clin North Am. 2018;102(6):1135-1143. doi:10.1016/j.mcna.2018.06.011
2. Bengur FB, Stoy C, Binko MA, et al. Facial Nerve Repair: Bioengineering Approaches in Preclinical Models. Tissue Eng Part B Rev. 2022;28(2):364-378. doi:10.1089/ten.TEB.2020.0381
3. Zhang W, Xu L, Luo T, Wu F, Zhao B, Li X. The etiology of Bell’s palsy: a review. J Neurol. 2020;267(7):1896-1905. doi:10.1007/s00415-019-09282-4
4. Tollefson TT, Hadlock TA, Lighthall JG. Facial Paralysis Discussion and Debate. Facial Plast Surg Clin North Am. 2018;26(2):163-180. doi:10.1016/j.fsc.2017.12.004
5. Ge Y, Zhang Y, Tang Q, et al. Mechanisms of the Immunomodulation Effects of Bone Marrow-Derived Mesenchymal Stem Cells on Facial Nerve Injury in Sprague-Dawley Rats. Stem Cells Dev. 2019;28(7):489-496. doi:10.1089/scd.2018.0104
6. Li X, Guan Y, Li C, et al. Immunomodulatory effects of mesenchymal stem cells in peripheral nerve injury. Stem Cell Res Ther. 2022;13(1):18. Published 2022 Jan 15. doi:10.1186/s13287-021-02690-2
7. Büttner R, Schulz A, Reuter M, et al. Inflammaging impairs peripheral nerve maintenance and regeneration. Aging Cell. 2018;17(6):e12833. doi:10.1111/acel.12833
8. Bao, C. S., Li, X. L., Liu, L., Wang, B., Yang, F. B., & Chen, L. G. (2018). Transplantation of Human umbilical cord mesenchymal stem cells promotes functional recovery after spinal cord injury by blocking the expression of IL-7. European review for medical and pharmacological sciences, 22(19), 6436–6447.
9. Liu F, Qiu H, Xue M, et al. MSC-secreted TGF-β regulates lipopolysaccharide-stimulated macrophage M2-like polarization via the Akt/FoxO1 pathway. Stem Cell Res Ther. 2019;10(1):345. Published 2019 Nov 26. doi:10.1186/s13287-019-1447-y
10. Ge Y, Zhang Y, Tang Q, et al. Mechanisms of the Immunomodulation Effects of Bone Marrow-Derived Mesenchymal Stem Cells on Facial Nerve Injury in Sprague-Dawley Rats. Stem Cells Dev. 2019;28(7):489-496. doi:10.1089/scd.2018.0104
11. Wu L, Han D, Jiang J, et al. Co-transplantation of bone marrow mesenchymal stem cells and monocytes in the brain stem to repair the facial nerve axotomy. Eur J Histochem. 2020;64(s2):3136. Published 2020 Jun 19. doi:10.4081/ejh.2020.3136