Comparative evaluation of the effectiveness of systemic and local administration of mesenchymal stem cells in experimental neuropathy

Objective. Compare the effectiveness of systemic and local administration of adipose-derived mesenchymal stem cells (ADMSC) at a dose of 1х106 cells/kg on nociceptive sensitivity to mechanical and thermal stimuli in rats and changes in histostructure of sciatic nerve and surrounded tissues of affected hind paw in experimental model of peripheral neuropathy of sciatic nerve.
Materials and methods. 26 male Wistar rats were used to perform a model of peripheral neuropathy by axotomy of the sciatic nerve. On the 7th day, the experimental animals underwent systemic or local transplantation of ADMSC at a dose of 1x10⁶ cells/kg. Nociceptive responses to mechanical and thermal stimuli were assessed for 90 days, and the histostructure of the sciatic nerve and surrounding tissues was analyzed after systemic and local transplantation of ADMSC.
Results. Systemic administration of ADMSC at a dose of 1x10⁶ cells/kg to rats with sciatic nerve axotomy increased the mechanical withdrawal threshold (MWT) by 17.1% and had no effect on the thermal withdrawal latency (TWL). Local administration of ADMSCs in an equivalent dose contributed to the full recovery of the MWT and TWL by the 21^st day of the experiment, as well as suppressed the inflammatory reaction in the soft tissues of the operated hind paw of experimental animals.
Conclusion. Intramuscular administration of ADMSC into the area of sciatic nerve axotomy of rats was significantly more effective than systemic administration of an equivalent dose of a cell transplant. This method of administration is more appropriate for further studies of the mechanisms of antinociceptive and reparative effects of ADMSCs.

1. Scholz J, Finnerup NB, Attal N, et al. The IASP classification of chronic pain for ICD-11: chronic neuropathic pain. Pain. 2019;160(1):53-59. DOI: https://doi.org/10.1097/j.pain.0000000000001365

2. Finnerup NB, Kuner R, Jensen TS. Neuropathic pain: from mechanisms to treatment. Physiol Rev. 2021;101(1):259-301. DOI: https://doi.org/10.1152/physrev.00045.2019

3. Smith BH, Hébert HL, Veluchamy A. Neuropathic pain in the community: prevalence, impact, and risk factors Pain. 2020;161 Suppl 1:S127-S137. DOI: https://doi.org/10.1097/j.pain.0000000000001824

4. Sacerdote P, Niada S, Franchi S, et al. Systemic administration of human adipose-derived stem cells reverts nociceptive hypersensitivity in an experimental model of neuropathy. Stem Cells Dev. 2013;22(8):1252-1263. DOI: https://doi.org/10.1089/scd.2012.0398

5. Guo W, Wang H, Zou S, et al. Bone marrow stromal cells produce long-term pain relief in rat models of persistent pain. Stem Cells. 2011;29(8):1294-1303. DOI: https://doi.org/10.1002/stem.667

6. Siniscalco D, Giordano C, Galderisi U, et al. Long-lasting effects of human mesenchymal stem cell systemic administration on pain-like behaviors, cellular, and biomolecular modifications in neuropathic mice. Front Integr Neurosci. 2011;5:79. DOI: https://doi.org/10.3389/fnint.2011.00079

7. Naruse K, Sato J, Funakubo M, et al. Transplantation of bone marrow-derived mononuclear cells improves mechanical hyperalgesia, cold allodynia and nerve function in diabetic neuropathy. PLoS One. 2011;6(11):e27458. DOI: https://doi.org/10.1371/journal.pone.0027458

8. Li J, Deng G, Wang H, Yang M, et al. Interleukin-1β pre-treated bone marrow stromal cells alleviate neuropathic pain through CCL7-mediated inhibition of microglial activation in the spinal cord. Sci Rep. 2017;7:42260. DOI: https://doi.org/10.1038/srep42260

9. Yerofeyeva AMV, Zhavaranak IP, Antipova OA, Schastnaya NI, Siamionik IA, Rjabceva SN, Molchanova AY. Assesment of Anti-Nociceptive Actions of Adipose-Derived Mesemchymal Stem Cells in Experimental Peripheral Neuropathic Pain. Novosti Khirurgii. 2021;29(5):527-534. (In Russ.). DOI: https://dx.doi.org/10.18484/2305-0047.2021.5.527

10. Yerofeyeva AMV, Molchanova AYu. Impact of adipose-derived allogeneic mesenchymal stem cell transplantation on nociceptive reactions and gait parameters in rats with experimental peripheral neuropathy. Proceedings of the National Academy of Sciences of Belarus, Medical series. 2022;19(4):404-412. (In Russ.). DOI: https://doi.org/10.29235/1814-6023-2022-19-4-404-412

11. Deuis JR, Dvorakova LS, Vetter I. Methods Used to Evaluate Pain Behaviors in Rodents. Front Mol Neurosci. 2017;10:284. DOI: https://doi.org/10.3389/fnmol.2017.00284

12. Huh Y, Ji RR, Chen G. Neuroinflammation, Bone Marrow Stem Cells, and Chronic Pain. Front Immunol. 2017;8:1014. DOI: https://doi.org/10.3389/fimmu.2017.01014

13. Ruhl T, Corsten C, Beier JP, Kim BS. The immunosuppressive effect of the endocannabinoid system on the inflammatory phenotypes of macrophages and mesenchymal stromal cells: a comparative study. Pharmacol Rep. 2021;73(1):143-153. DOI: https://doi.org/10.1007/s43440-020-00 166-3