Advances in mesenchymal stem cells and their derivatives for promoting peripheral nerve regeneration

Abstract

Peripheral nerve injury constitutes a complex neurotraumatic pathology characterized by mechanical disruption of neural integrity, manifesting as multimodal sensorimotor deficits and impaired neuromuscular coordination. The primary clinical interventions include surgical tension-free suturing of the severed nerve ends and autologous nerve transplantation. Despite these interventions, patients often experience complications, and the outcomes are not entirely satisfactory for either patients or clinicians. Mesenchymal stem cells (MSCs) have gradually become a novel therapeutic option, with burgeoning preclinical evidence elucidating their multimodal therapeutic potential in peripheral nerve reconstruction. This research has produced promising outcomes, contributing to both fundamental research and translational medicine. However, a comprehensive synthesis of the roles of MSCs and their derivatives in nerve regeneration is still lacking. This article presents a review of the current research advancements in this area, aiming to encourage further investigations and therapeutic applications of MSCs and their derivatives in peripheral nerve injury and regenerative medicine.

References

[1] Lopes B, Sousa P, Alvites R, Branquinho M, Sousa AC, Mendonça C. et al. Peripheral nerve injury treatments and advances: one health perspective. Int J Mol Sci. 2022; 23: 918. https://doi.org/10.3390/ijms23020918.

[2] Hussain G, Wang J, Rasul A, Anwar H, Qasim M, Zafar S. et al. Current status of therapeutic approaches against peripheral nerve injuries: a detailed story from injury to recovery. Int J Biol Sci. 2020; 16: 116-34. https://doi.org/10.7150/ijbs.35653.

[3] Zhang RC, Du WQ, Zhang JY, Yu SX, Lu FZ, Ding HM. et al. Mesenchymal stem cell treatment for peripheral nerve injury: a narrative review. Neural Regen Res. 2021; 16: 2170-6. https://doi.org/10.4103/1673-5374.310941.

[4] Shin YH, Choi SJ, Kim JK. Mechanisms of Wharton’s jelly-derived MSCS in enhancing peripheral nerve regeneration. Sci Rep. 2023; 13: 21214. https://doi.org/10.1038/s41598-023-48495-6.

[5] Lavorato A, Raimondo S, Boido M, Muratori L, Durante G, Cofano F. et al. Mesenchymal stem cell treatment perspectives in peripheral nerve regeneration: systematic review. Int J Mol Sci. 2021; 22: 572. https://doi.org/10.3390/ijms22020572.

[6] Li X, Guan Y, Li C, Zhang T, Meng F, Zhang J. et al. Immunomodulatory effects of mesenchymal stem cells in peripheral nerve injury. Stem Cell Res Ther. 2022; 13: 18. https://doi.org/10.1186/s13287-021-02690-2.

[7] Fan XL, Zhang Y, Li X, Fu QL. Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy. Cell Mol Life Sci. 2020; 77: 2771-94. https://doi.org/10.1007/s00018-020-03454-6.

[8] Contreras E, Bolívar S, Navarro X, Udina E. New insights into peripheral nerve regeneration: the role of secretomes. Exp Neurol. 2022; 354: 114069. https://doi.org/10.1016/j.expneurol.2022.114069.

[9] Carrillo, González NJ, Reyes Gutierrez GS, Campos-Ordoñez T, Castro-Torres RD, Beas Zárate C, Gudiño-Cabrera G. GFAPβ and GFAPδ isoforms expression in mesenchymal stem cells, MSCs differentiated towards Schwann-like, and olfactory ensheathing cells. Curr Issues Mol Biol. 2025; 47: 35. https://doi.org/10.3390/cimb47010035.

[10] Siwak M, Piotrzkowska D, Skrzypek M, Majsterek I. Effects of PEMF and LIPUS therapy on the expression of genes related to peripheral nerve regeneration in Schwann cells. Int J Mol Sci. 2024; 25: 12791. https://doi.org/10.3390/ijms252312791.

[11] Saffari S, Saffari TM, Ulrich DJO, Hovius SER, Shin AY. The interaction of stem cells and vascularity in peripheral nerve regeneration. Neural Regen Res. 2021; 16: 1510-7. https://doi.org/10.4103/1673-5374.303009.

[12] Yuan Y, Ni S, Zhuge A, Li L, Li B. Adipose-derived mesenchymal stem cells reprogram M1 macrophage metabolism via PHD2/HIF-1α pathway in colitis mice. Front Immunol. 2022; 13: 859806. https://doi.org/10.3389/fimmu.2022.859806.

[13] Yi W, Xue Y, Qing W, Cao Y, Zhou L, Xu M. et al. Effective treatment of optic neuropathies by intraocular delivery of MSC-SEVS through augmenting the G-CSF-macrophage pathway. Proc Natl Acad Sci USA. 2024; 121: e2305947121. https://doi.org/10.1073/pnas.2305947121.

[14] Andrzejewska A, Dabrowska S, Lukomska B, Janowski M. Mesenchymal stem cells for neurological disorders. Adv Sci (Weinh). 2021; 8: 2002944. https://doi.org/10.1002/advs.202002944.

[15] Kubiak CA, Grochmal J, Kung TA, Cederna PS, Midha R, Kemp SWP. Stem-cell-based therapies to enhance peripheral nerve regeneration. Muscle Nerve. 2020; 61: 449-59. https://doi.org/10.1002/mus.26760.

[16] Liu F, Han R, Nie S, Cao Y, Zhang X, Gao F. et al. Metformin rejuvenates Nap1l2-impaired immunomodulation of bone marrow mesenchymal stem cells via metabolic reprogramming. Cell Prolif. 2024; 57: e13612. https://doi.org/10.1111/cpr.13612.

[17] Chu DT, Phuong TNT, Tien NLB, Tran DK, Thanh VV, Quang TL. et al. An update on the progress of isolation, culture, storage, and clinical application of human bone marrow mesenchymal stem/stromal cells. Int J Mol Sci. 2020; 21: 708. https://doi.org/10.3390/ijms21030708.

[18] Redondo J, Bailey S, Kemp KC, Scolding NJ, Rice CM. The bone marrow microenvironment in immune-mediated inflammatory diseases: implications for mesenchymal stromal cell-based therapies. Stem Cells Transl Med. 2024; 13: 219-29. https://doi.org/10.1093/stcltm/szad086.

[19] Yurie H, Ikeguchi R, Aoyama T, Tanaka M, Oda H, Takeuchi H. et al. Bio 3D conduits derived from bone marrow stromal cells promote peripheral nerve regeneration. Cell Transplant. 2020; 29: 096368972095155. https://doi.org/10.1177/0963689720951551.

[20] Li X, Xu H, Li C, Guan Y, Liu Y, Zhang T. et al. Biological characteristics of tissue engineered-nerve grafts enhancing peripheral nerve regeneration. Stem Cell Res Ther. 2024; 15: 215. https://doi.org/10.1186/s13287-024-03827-9.

[21] Zhang W, Fang XX, Li QC, Pi W, Han N. Reduced graphene oxide-embedded nerve conduits loaded with bone marrow mesenchymal stem cell-derived extracellular vesicles promote peripheral nerve regeneration. Neural Regen Res. 2023; 18: 200-6. https://doi.org/10.4103/1673-5374.343889.

[22] Zhao J, Ding Y, He R, Huang K, Liu L, Jiang C. et al. Dose-effect relationship and molecular mechanism by which BMSC-derived exosomes promote peripheral nerve regeneration after crush injury. Stem Cell Res Ther. 2020; 11: 360. https://doi.org/10.1186/s13287-020-01872-8.

[23] Wang S, Zhu C, Zhang B, Hu J, Xu J, Xue C. et al. BMSC-derived extracellular matrix better optimizes the microenvironment to support nerve regeneration. Biomaterials. 2022; 280: 121251. https://doi.org/10.1016/j.biomaterials.2021.121251.

[24] Yang Z, Zheng C, Zhang F, Lin B, Cao M, Tian X. et al. Magnetic resonance imaging of enhanced nerve repair with mesenchymal stem cells combined with microenvironment immunomodulation in neurotmesis. Muscle Nerve. 2020; 61: 815-25. https://doi.org/10.1002/mus.26862.

[25] Chen G, Park CK, Xie RG, Ji RR. Intrathecal bone marrow stromal cells inhibit neuropathic pain via TGF-β secretion. J Clin Invest. 2015; 125: 3226-40. https://doi.org/10.1172/JCI80883.

[26] Zhong Z, Chen A, Fa Z, Ding Z, Xiao L, Wu G. et al. Bone marrow mesenchymal stem cells upregulate pi3k/Akt pathway and down-regulate NF-κb pathway by secreting glial cell-derived neurotrophic factors to regulate microglial polarization and alleviate deafferentation pain in rats. Neurobiol Dis. 2020; 143: 104945. https://doi.org/10.1016/j.nbd.2020.104945.

[27] Rhode SC, Beier JP, Ruhl T. Adipose tissue stem cells in peripheral nerve regeneration-in vitro and in vivo. J Neurosci Res. 2021; 99: 545-60. https://doi.org/10.1002/jnr.24738.

[28] Yi S, Zhang Y, Gu X, Huang L, Zhang K, Qian T. et al. Application of stem cells in peripheral nerve regeneration. Burns Trauma. 2020; 8: tkaa002.

[29] Romano IR, D’Angeli F, Gili E, Fruciano M, Lombardo GAG, Mannino G. et al. Melatonin enhances neural differentiation of adipose-derived mesenchymal stem cells. Int J Mol Sci. 2024; 25: 4891. https://doi.org/10.3390/ijms25094891.

[30] Soto PA, Vence M, Piñero GM, Coral DF, Usach V, Muraca D. et al. Sciatic nerve regeneration after traumatic injury using magnetic targeted adipose-derived mesenchymal stem cells. Acta Biomater. 2021; 130: 234-47. https://doi.org/10.1016/j.actbio.2021.05.050.

[31] Rodríguez Sánchez DN, de Lima Resende LA, Boff Araujo Pinto G, de Carvalho Bovolato AL, Possebon FS, Deffune E. et al. Canine adipose-derived mesenchymal stromal cells enhance neuroregeneration in a rat model of sciatic nerve crush injury. Cell Transplant. 2019; 28: 47-54. https://doi.org/10.1177/0963689718809045.

[32] Liu CY, Yin G, Sun YD, Lin YF, Xie Z, English AW. et al. Effect of exosomes from adipose-derived stem cells on the apoptosis of Schwann cells in peripheral nerve injury. CNS Neurosci Ther. 2020; 26: 189-96. https://doi.org/10.1111/cns.13187.

[33] Lewis M, David G, Jacobs D, Kuczwara P, Woessner AE, Kim JW. et al. Neuro-regenerative behavior of adipose-derived stem cells in aligned collagen I hydrogels. Mater Today Bio. 2023; 22: 100762. https://doi.org/10.1016/j.mtbio.2023.100762.

[34] Sun Y, Chi X, Meng H, Ma M, Wang J, Feng Z. et al. Polylysine-decorated macroporous microcarriers laden with adipose-derived stem cells promote nerve regeneration in vivo. Bioact Mater. 2021; 6: 3987-98. https://doi.org/10.1016/j.bioactmat.2021.03.029.

[35] Zhu Y, Yi D, Wang J, Zhang Y, Li M, Ma J. et al. Harnessing three-dimensional porous chitosan microsphere embedded with adipose-derived stem cells to promote nerve regeneration. Stem Cell Res Ther. 2024; 15: 158. https://doi.org/10.1186/s13287-024-03753-w.

[36] Palombella S, Guiotto M, Higgins GC, Applegate LL, Raffoul W, Cherubino M. et al. Human platelet lysate as a potential clinical-translatable supplement to support the neurotrophic properties of human adipose-derived stem cells. Stem Cell Res Ther. 2020; 11: 432. https://doi.org/10.1186/s13287-020-01949-4.

[37] Brambilla S, Guiotto M, Torretta E, Armenia I, Moretti M, Gelfi C. et al. Human platelet lysate stimulates neurotrophic properties of human adipose-derived stem cells better than Schwann cell-like cells. Stem Cell Res Ther. 2023; 14: 179. https://doi.org/10.1186/s13287-023-03407-3.

[38] Saffari TM, Saffari S, Vyas KS, Mardini S, Shin AY. Role of adipose tissue grafting and adipose-derived stem cells in peripheral nerve surgery. Neural Regen Res. 2022; 17: 2179-84. https://doi.org/10.4103/1673-5374.336870.

[39] Huang CW, Lu SY, Huang TC, Huang BM, Sun HS, Yang SH. et al. FGF9 induces functional differentiation to Schwann cells from human adipose derived stem cells. Theranostics. 2020; 10: 2817-31. https://doi.org/10.7150/thno.38553.

[40] Wang W, Gu MF, Wang ZF, Shen XM, Zhang J, Yang L. Let-7a-5p regulated by lncRNA-MEG3 promotes functional differentiation to Schwann cells from adipose derived stem cells via directly inhibiting RBPJ-mediating Notch pathway. Apoptosis. 2021; 26: 548-60. https://doi.org/10.1007/s10495-021-01685-x.

[41] Hoang DM, Pham PT, Bach TQ, Ngo ATL, Nguyen QT, Phan TTK. et al. Stem cell-based therapy for human diseases. Signal Transduct Target Ther. 2022; 7: 272. https://doi.org/10.1038/s41392-022-01134-4.

[42] Choi SJ, Park SY, Shin YH, Heo SH, Kim KH, Lee HI. et al. Mesenchymal stem cells derived from Wharton’s jelly can differentiate into Schwann cell-like cells and promote peripheral nerve regeneration in acellular nerve grafts. Tissue Eng Regen Med. 2021; 18: 467-78. https://doi.org/10.1007/s13770-020-00329-6.

[43] Bojanic C, To K, Zhang B, Mak C, Khan WS. Human umbilical cord derived mesenchymal stem cells in peripheral nerve regeneration. World J Stem Cells. 2020; 12: 288-302. https://doi.org/10.4252/wjsc.v12.i4.288.

[44] Lin YJ, Lee YW, Chang CW, Huang CC. 3D spheroids of umbilical cord blood MSC-derived Schwann cells promote peripheral nerve regeneration. Front Cell Dev Biol. 2020; 8: 604946. https://doi.org/10.3389/fcell.2020.604946.

[45] Guan Y, Ren Z, Yang B, Xu W, Wu W, Li X. et al. Dual-bionic regenerative microenvironment for peripheral nerve repair. Bioact Mater. 2023; 26: 370-86. https://doi.org/10.1016/j.bioactmat.2023.02.002.

[46] Zhang Y, Yi D, Hong Q, Cao J, Geng X, Liu J. et al. Platelet-rich plasma-derived exosomes boost mesenchymal stem cells to promote peripheral nerve regeneration. J Control Release. 2024; 367: 265-82. https://doi.org/10.1016/j.jconrel.2024.01.043.

[47] Ülger M, Sezer G, Özyazgan İ, Özocak H, Yay A, Balcıoğlu E. et al. The effect of erythropoietin and umbilical cord-derived mesenchymal stem cells on nerve regeneration in rats with sciatic nerve injury. J Chem Neuroanat. 2021; 114: 101958. https://doi.org/10.1016/j.jchemneu.2021.101958.

[48] Zhu Z, Zhang Y, Huang Z, Hao H, Yan M. Hypoxic culture of umbilical cord mesenchymal stem cell-derived sEVs prompts peripheral nerve injury repair. Front Cell Neurosci. 2022; 16: 897224. https://doi.org/10.3389/fncel.2022.897224.

[49] Li P, Ou Q, Shi S, Shao C. Immunomodulatory properties of mesenchymal stem cells/dental stem cells and their therapeutic applications. Cell Mol Immunol. 2023; 20: 558-69. https://doi.org/10.1038/s41423-023-00998-y.

[50] Karbalaie KH, Tanhaei S, Rabiei F, Kiani-Esfahani A, Masoudi NS, Nasr-Esfahani MH. et al. Stem cells from human exfoliated deciduous tooth exhibit stromal-derived inducing activity and lead to generation of neural crest cells from human embryonic stem cells. Cell J. 2021; 23: 140-2. https://doi.org/10.22074/cellj.2021.7931.

[51] Gan L, Liu Y, Cui D, Pan Y, Zheng L, Wan M. Dental tissue-derived human mesenchymal stem cells and their potential in therapeutic application. Stem Cells Int. 2020; 2020: 1-17. https://doi.org/10.1155/2020/8864572.

[52] Chen Y, Huang H, Li G, Yu J, Fang F, Qiu W. Dental-derived mesenchymal stem cell sheets: a prospective tissue engineering for regenerative medicine. Stem Cell Res Ther. 2022; 13: 38. https://doi.org/10.1186/s13287-022-02716-3.

[53] Liu J, Yu F, Sun Y, Jiang B, Zhang W, Yang J. et al. Concise reviews: characteristics and potential applications of human dental tissue-derived mesenchymal stem cells. Stem Cells. 2015; 33: 627-38. https://doi.org/10.1002/stem.1909.

[54] Banavar SR, Rawal SY, Paterson IC, Singh G, Davamani F, Khoo SP. et al. Establishing a technique for isolation and characterization of human periodontal ligament derived mesenchymal stem cells. Saudi Dent J. 2021; 33: 693-701. https://doi.org/10.1016/j.sdentj.2020.04.007.

[55] Mohebichamkhorami F, Fattahi R, Niknam Z, Aliashrafi M, Khakpour Naeimi S, Gilanchi S. et al. Periodontal ligament stem cells as a promising therapeutic target for neural damage. Stem Cell Res Ther. 2022; 13: 273. https://doi.org/10.1186/s13287-022-02942-9.

[56] Luo H, Birjandi AA, Ren F, Sun T, Sharpe PT, Sun H. et al. Advances in oral mesenchymal stem cell-derived extracellular vesicles in health and disease. Genes Dis. 2024; 11: 346-57. https://doi.org/10.1016/j.gendis.2023.03.015.

[57] Zhang Q, Burrell JC, Zeng J, Motiwala FI, Shi S, Cullen DK. et al. Implantation of a nerve protector embedded with human GMSC-derived Schwann-like cells accelerates regeneration of crush-injured rat sciatic nerves. Stem Cell Res Ther. 2022; 13: 263. https://doi.org/10.1186/s13287-022-02947-4.

[58] Yu Z, Wen Y, Jiang N, Li Z, Guan J, Zhang Y. et al. TNF-α stimulation enhances the neuroprotective effects of gingival MSCs derived exosomes in retinal ischemia-reperfusion injury via the meg3/mir-21a-5p axis. Biomaterials. 2022; 284: 121484. https://doi.org/10.1016/j.biomaterials.2022.121484.

[59] Liuyang S, Wang G, Wang Y, He H, Lyu Y, Cheng L. et al. Highly efficient and rapid generation of human pluripotent stem cells by chemical reprogramming. Cell Stem Cell. 2023; 30: 450-59.e9. https://doi.org/10.1016/j.stem.2023.02.008.

[60] Xie L, Yin Y, Jayakar S, Kawaguchi R, Wang Q, Peterson S. et al. The oncomodulin receptor armc10 enables axon regeneration in mice after nerve injury and neurite outgrowth in human iPSC-derived sensory neurons. Sci Transl Med. 2023; 15:eadg6241. https://doi.org/10.1126/scitranslmed.adg6241.

[61] Nishijima T, Okuyama K, Shibata S, Kimura H, Shinozaki M, Ouchi T. et al. Novel artificial nerve transplantation of human iPSC-derived neurite bundles enhanced nerve regeneration after peripheral nerve injury. Inflamm Regen. 2024; 44: 6. https://doi.org/10.1186/s41232-024-00319-4.

[62] Hirano M, Huang Y, Vela Jarquin D, De la Garza Hernández RL, Jodat YA, Luna Cerón E. et al. 3D bioprinted human iPSC-derived somatosensory constructs with functional and highly purified sensory neuron networks. Biofabrication. 2021; 13: 035046. https://doi.org/10.1088/1758-5090/abff11.

[63] Pan J, Zhao M, Yi X, Tao J, Li S, Jiang Z. et al. Acellular nerve grafts supplemented with induced pluripotent stem cell-derived exosomes promote peripheral nerve reconstruction and motor function recovery. Bioact Mater. 2022; 15: 272-87. https://doi.org/10.1016/j.bioactmat.2021.12.004.

[64] Tam KW, Wong CY, Wu KL, Lam G, Liang X, Wong WT. et al. IPSC-derived sensory neurons directing fate commitment of human BMSC-derived Schwann cells: applications in traumatic neural injuries. Cells. 2023; 12: 12. https://doi.org/10.3390/cells12111479.

[65] Mitsuzawa S, Zhao C, Ikeguchi R, Aoyama T, Kamiya D, Ando M. et al. Pro-angiogenic scaffold-free bio three-dimensional conduit developed from human induced pluripotent stem cell-derived mesenchymal stem cells promotes peripheral nerve regeneration. Sci Rep. 2020; 10: 12034. https://doi.org/10.1038/s41598-020-68745-1.

[66] Kim HS, Kim JY, Song CL, Jeong JE, Cho YS. Directly induced human Schwann cell precursors as a valuable source of Schwann cells. Stem Cell Res Ther. 2020; 11: 257. https://doi.org/10.1186/s13287-020-01772-x.

[67] Manion J, Khuong T, Harney D, Littleboy JB, Ruan T, Loo L. et al. Human induced pluripotent stem cell-derived GABAergic interneuron transplants attenuate neuropathic pain. Pain. 2020; 161: 379-87. https://doi.org/10.1097/j.pain.0000000000001733.

[68] Bosch-Queralt M, Fledrich R, Stassart RM. Schwann cell functions in peripheral nerve development and repair. Neurobiol Dis. 2023; 176: 105952. https://doi.org/10.1016/j.nbd.2022.105952.

[69] Guo X, Bu X, Li Z, Yan Z, Jiang J, Zhou Z. Comparison of autologous bone marrow mononuclear cells transplantation and mobilization by granulocyte colony-stimulating factor in experimental spinal injury. Int J Neurosci. 2012; 122: 723-33. https://doi.org/10.3109/00207454.2012.716109.

[70] Mendonça MV, Larocca TF, de Freitas Souza BS, Villarreal CF, Silva LF, Matos AC. et al. Safety and neurological assessments after autologous transplantation of bone marrow mesenchymal stem cells in subjects with chronic spinal cord injury. Stem Cell Res Ther. 2014; 5: 126. https://doi.org/10.1186/scrt516.

[71] Dai G, Liu X, Zhang Z, Yang Z, Dai Y, Xu R. Transplantation of autologous bone marrow mesenchymal stem cells in the treatment of complete and chronic cervical spinal cord injury. Brain Res. 2013; 1533: 73-9. https://doi.org/10.1016/j.brainres.2013.08.016.

[72] Akhlaghpasand M, Tavanaei R, Allameh F, Hosseinpoor M, Toreyhi H, Golmohammadi M. et al. Improvement of neurogenic bladder dysfunction following combined cell therapy with mesenchymal stem cell and Schwann cell in spinal cord injury: a randomized, open-label, phase ii clinical trial. World Neurosurg. 2024; 194: 123402. https://doi.org/10.1016/j.wneu.2024.10.131.

[73] Oraee-Yazdani S, Akhlaghpasand M, Golmohammadi M, Hafizi M, Zomorrod MS, Kabir NM. et al. Combining cell therapy with human autologous Schwann cell and bone marrow-derived mesenchymal stem cell in patients with subacute complete spinal cord injury: safety considerations and possible outcomes. Stem Cell Res Ther. 2021; 12: 445. https://doi.org/10.1186/s13287-021-02515-2.

[74] Bydon M, Qu W, Moinuddin FM, Hunt CL, Garlanger KL, Reeves RK. et al. Intrathecal delivery of adipose-derived mesenchymal stem cells in traumatic spinal cord injury: phase i trial. Nat Commun. 2024; 15: 2201. https://doi.org/10.1038/s41467-024-46259-y.

[75] Awidi A, Al Shudifat A, El Adwan N, Alqudah M, Jamali F, Nazer F. et al. Safety and potential efficacy of expanded mesenchymal stromal cells of bone marrow and umbilical cord origins in patients with chronic spinal cord injuries: a phase I/II study. Cytotherapy. 2024; 26: 825-31. https://doi.org/10.1016/j.jcyt.2024.03.480.

[76] Honmou O, Yamashita T, Morita T, Oshigiri T, Hirota R, Iyama S. et al. Intravenous infusion of auto serum-expanded autologous mesenchymal stem cells in spinal cord injury patients: 13 case series. Clin Neurol Neurosurg. 2021; 203: 106565. https://doi.org/10.1016/j.clineuro.2021.106565.

[77] Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020; 367: eaau6977. https://doi.org/10.1126/science.aau6977.

[78] Nakazaki M, Morita T, Lankford KL, Askenase PW, Kocsis JD. Small extracellular vesicles released by infused mesenchymal stromal cells target m2 macrophages and promote tgf-β upregulation, microvascular stabilization and functional recovery in a rodent model of severe spinal cord injury. J Extracell Vesicles. 2021; 10: e12137. https://doi.org/10.1002/jev2.12137.

[79] Tang Y, Zhou Y, Li HJ. Advances in mesenchymal stem cell exosomes: a review. Stem Cell Res Ther. 2021; 12: 71. https://doi.org/10.1186/s13287-021-02138-7.

[80] Isaac R, Reis FCG, Ying W, Olefsky JM. Exosomes as mediators of intercellular crosstalk in metabolism. Cell Metab. 2021; 33: 1744-62. https://doi.org/10.1016/j.cmet.2021.08.006.

[81] Hade MD, Suire CN, Suo Z. Mesenchymal stem cell-derived exosomes: applications in regenerative medicine. Cells. 2021; 10: 10. https://doi.org/10.3390/cells10081959.

[82] Chen SH, Kao HK, Wun JR, Chou PY, Chen ZY, Chen SH. et al. Thermosensitive hydrogel carrying extracellular vesicles from adipose-derived stem cells promotes peripheral nerve regeneration after microsurgical repair. APL Bioeng. 2022; 6: 046103. https://doi.org/10.1063/5.0118862.

[83] Wang Y, Yu T, Hu F. Hypocapnia stimuli-responsive engineered exosomes delivering mir-218 facilitate sciatic nerve regeneration. Front Bioeng Biotechnol. 2022; 10: 825146. https://doi.org/10.3389/fbioe.2022.825146.

[84] Zhao Y, Liu J, Liu S, Yang P, Liang Y, Ma J. et al. Fibroblast exosomal TFAP2C induced by chitosan oligosaccharides promotes peripheral axon regeneration via the mir-132-5p/CAMKK1 axis. Bioact Mater. 2023; 26: 249-63. https://doi.org/10.1016/j.bioactmat.2023.03.002.

[85] Ye K, Li Z, Yin Y, Zhou J, Li D, Gan Y. et al. LIPUS-SCS-Exo promotes peripheral nerve regeneration in cavernous nerve crush injury-induced ED rats via PI3K/Akt/FoxO signaling pathway. CNS Neurosci Ther. 2023; 29: 3239-58. https://doi.org/10.1111/cns.14256.

[86] Zeng X, Bian W, Liu Z, Li J, Ren S, Zhang J. et al. Muscle-derived stem cell exosomes with overexpressed miR-214 promote the regeneration and repair of rat sciatic nerve after crush injury to activate the JAK2/STAT3 pathway by targeting PTEN. Front Mol Neurosci. 2023; 16: 1146329. https://doi.org/10.3389/fnmol.2023.1146329.

[87] Park KK, Liu K, Hu Y, Smith PD, Wang C, Cai B. et al. Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science. 2008; 322: 963-6. https://doi.org/10.1126/science.1161566.

[88] Sang X, Tang L, Zhao L, Xu N, Liu F, Shen Y. et al. Umbilical cord mesenchymal stem cell-derived exosomes promote axon regeneration during optic nerve injury through microRNA-dependent mtorc1 signalling. Clin Transl Med. 2023; 13: e1319. https://doi.org/10.1002/ctm2.1319.

[89] Namini MS, Ebrahimi-Barough S, Ai J, Jahromi HK, Mikaeiliagah E, Azami M. et al. Tissue-engineered core-shell silk-fibroin/poly-l-lactic acid nerve guidance conduit containing encapsulated exosomes of human endometrial stem cells promotes peripheral nerve regeneration. ACS Biomater Sci Eng. 2023; 9: 3496-511. https://doi.org/10.1021/acsbiomaterials.3c00157.

[90] Yang Z, Yang Y, Xu Y, Jiang W, Shao Y, Xing J. et al. Biomimetic nerve guidance conduit containing engineered exosomes of adipose-derived stem cells promotes peripheral nerve regeneration. Stem Cell Res Ther. 2021; 12: 442. https://doi.org/10.1186/s13287-021-02528-x.

[91] Wang H, Zhao H, Chen Z, Cai X, Wang X, Zhou P. et al. Hypoxic bone mesenchymal stem cell-derived exosomes direct Schwann cells proliferation, migration, and paracrine to accelerate facial nerve regeneration via circRNA_Nkd2/mir-214-3p/MED19 axis. Int J Nanomedicine. 2024; 19: 1409-29. https://doi.org/10.2147/IJN.S443036.

[92] Fan B, Chopp M, Zhang ZG, Liu XS. Treatment of diabetic peripheral neuropathy with engineered mesenchymal stromal cell-derived exosomes enriched with microRNA-146a provide amplified therapeutic efficacy. Exp Neurol. 2021; 341: 113694. https://doi.org/10.1016/j.expneurol.2021.113694.

[93] Hu T, Chang S, Qi F, Zhang Z, Chen J, Jiang L. et al. Neural grafts containing exosomes derived from Schwann cell-like cells promote peripheral nerve regeneration in rats. Burns Trauma. 2023; 11: tkad013. https://doi.org/10.1093/burnst/tkad013.

[94] Chen J, Ren S, Duscher D, Kang Y, Liu Y, Wang C. et al. Exosomes from human adipose-derived stem cells promote sciatic nerve regeneration via optimizing Schwann cell function. J Cell Physiol. 2019; 234: 23097-110. https://doi.org/10.1002/jcp.28873.

[95] Huang J, Zhang G, Li S, Li J, Wang W, Xue J. et al. Endothelial cell-derived exosomes boost and maintain repair-related phenotypes of Schwann cells via miR199-5p to promote nerve regeneration. J Nanobiotechnology. 2023; 21: 10. https://doi.org/10.1186/s12951-023-01767-9.

[96] Chen W, Chang S, Yang C, Zhou J, Zhang H, Nie K. et al. Schwann cell-like cells derived from human amniotic mesenchymal stem cells promote sciatic nerve repair through an exosome-induced SOX2/FN1 pathway in vitro. Int J Mol Med. 2022; 49: 80. https://doi.org/10.3892/ijmm.2022.5136.

[97] Zhang X, Zhang W, Sun H, Wang H. The effects of exosomes originating from different cell sources on the differentiation of bone marrow mesenchymal stem cells into Schwann cells. J Nanobiotechnology. 2024; 22: 220. https://doi.org/10.1186/s12951-024-02450-3.

[98] Wang H, Jia Y, Li J, Liu Q. Schwann cell-derived exosomes induce bone marrow-derived mesenchymal stem cells to express Schwann cell markers in vitro. Mol Med Rep. 2020; 21: 1640-6. https://doi.org/10.3892/mmr.2020.10960.

[99] Yu M, Gu G, Cong M, Du M, Wang W, Shen M. et al. Repair of peripheral nerve defects by nerve grafts incorporated with extracellular vesicles from skin-derived precursor Schwann cells. Acta Biomater. 2021; 134: 190-203. https://doi.org/10.1016/j.actbio.2021.07.026.

[100] Yu M, Shen M, Chen D, Li Y, Zhou Q, Deng C. et al. Chitosan/PLGA-based tissue engineered nerve grafts with SKP-SC-EVs enhance sciatic nerve regeneration in dogs through miR-30b-5p-mediated regulation of axon growth. Bioact Mater. 2024; 40: 378-95. https://doi.org/10.1016/j.bioactmat.2024.06.011.

[101] Zhou X, Yu M, Chen D, Deng C, Zhang Q, Gu X. et al. Chitosan nerve grafts incorporated with SKP-SC-EVs induce peripheral nerve regeneration. Tissue Eng Regen Med. 2023; 20: 309-22. https://doi.org/10.1007/s13770-022-00517-6.

[102] Segarra M, Aburto MR, Hefendehl J, Acker-Palmer A. Neurovascular interactions in the nervous system. Annu Rev Cell Dev Biol. 2019; 35: 615- 35. https://doi.org/10.1146/annurev-cellbio-100818-125142.

[103] Cattin AL, Burden JJ, Van Emmenis L, Mackenzie FE, Hoving JJ, Garcia Calavia N. et al. Macrophage-induced blood vessels guide Schwann cell-mediated regeneration of peripheral nerves. Cell. 2015; 162: 1127-39. https://doi.org/10.1016/j.cell.2015.07.021.

[104] Muangsanit P, Roberton V, Costa E, Phillips JB. Engineered aligned endothelial cell structures in tethered collagen hydrogels promote peripheral nerve regeneration. Acta Biomater. 2021; 126: 224-37. https://doi.org/10.1016/j.actbio.2021.03.039.

[105] Saffari TM, Bedar M, Hundepool CA, Bishop AT, Shin AY. The role of vascularization in nerve regeneration of nerve graft. Neural Regen Res. 2020; 15: 1573-9. https://doi.org/10.4103/1673-5374.276327.

[106] Gong M, Wang M, Xu J, Yu B, Wang YG, Liu M. et al. Nano-sized extracellular vesicles secreted from GATA-4 modified mesenchymal stem cells promote angiogenesis by delivering Let-7 miRNAs. Cells. 2022; 11: 11. https://doi.org/10.3390/cells11091573.

[107] Heo JS, Kim S. Human adipose mesenchymal stem cells modulate inflammation and angiogenesis through exosomes. Sci Rep. 2022; 12: 2776. https://doi.org/10.1038/s41598-022-06824-1.

[108] Zhang Y, Xie Y, Hao Z, Zhou P, Wang P, Fang S. et al. Umbilical mesenchymal stem cell-derived exosome-encapsulated hydrogels accelerate bone repair by enhancing angiogenesis. ACS Appl Mater Interfaces. 2021; 13: 18472-87. https://doi.org/10.1021/acsami.0c22671.

[109] Phelps J, Hart DA, Mitha AP, Duncan NA, Sen A. Physiological oxygen conditions enhance the angiogenic properties of extracellular vesicles from human mesenchymal stem cells. Stem Cell Res Ther. 2023; 14: 218. https://doi.org/10.1186/s13287-023-03439-9.

[110] Sun J, Shen H, Shao L, Teng X, Chen Y, Liu X. et al. HIF-1α overexpression in mesenchymal stem cell-derived exosomes mediates cardioprotection in myocardial infarction by enhanced angiogenesis. Stem Cell Res Ther. 2020; 11: 373. https://doi.org/10.1186/s13287-020-01881-7.

[111] Serger E, Luengo-Gutierrez L, Chadwick JS, Kong G, Zhou L, Crawford G. et al. The gut metabolite indole-3 propionate promotes nerve regeneration and repair. Nature. 2022; 607: 585-92. https://doi.org/10.1038/s41586-022-04884-x.

[112] Xia Y, Cai M, Zhou Y, Yao Y, Jiang M, Gu D. et al. Immune cell biology in peripheral nervous system injury. Neurorehabil Neural Repair. 2025; 39: 230-240.

[113] Wang JY, Yuan Y, Zhang SY, Lu SY, Han GJ, Bian MX. et al. Remodeling of the intra-conduit inflammatory microenvironment to improve peripheral nerve regeneration with a neuromechanical matching protein-based conduit. Adv Sci (Weinh). 2024; 11: e2302988. https://doi.org/10.1002/advs.202302988.

[114] Wei J, Su W, Zhao Y, Wei Z, Hua Y, Xue P. et al. Maresin 1 promotes nerve regeneration and alleviates neuropathic pain after nerve injury. J Neuroinflammation. 2022; 19: 32. https://doi.org/10.1186/s12974-022-02405-1.

[115] Zhang J, Buller BA, Zhang ZG, Zhang Y, Lu M, Rosene DL. et al. Exosomes derived from bone marrow mesenchymal stromal cells promote remyelination and reduce neuroinflammation in the demyelinating central nervous system. Exp Neurol. 2022; 347: 113895. https://doi.org/10.1016/j.expneurol.2021.113895.

[116] Li C, Li X, Shi Z, Wu P, Fu J, Tang J. et al. Exosomes from LPS-preconditioned bone marrow MSCs accelerated peripheral nerve regeneration via m2 macrophage polarization: involvement of TSG-6/NF-κb/NLRP3 signaling pathway. Exp Neurol. 2022; 356: 114139. https://doi.org/10.1016/j.expneurol.2022.114139.

[117] Xue R, Xie M, Wu Z, Wang S, Zhang Y, Han Z. et al. Mesenchymal stem cell-derived exosomes promote recovery of the facial nerve injury through regulating macrophage M1 and M2 polarization by targeting the p38 MAPK/NF-κb pathway. Aging Dis. 2024; 15: 851-68. https://doi.org/10.14336/AD.2023.0719-1.

[118] Zhai K, Duan H, Wang W, Zhao S, Khan GJ, Wang M. et al. Ginsenoside Rg1 ameliorates blood-brain barrier disruption and traumatic brain injury via attenuating macrophages derived exosomes miR-21 release. Acta Pharm Sin B. 2021; 11: 3493-507. https://doi.org/10.1016/j.apsb.2021.03.032.

[119] Finnerup NB, Kuner R, Jensen TS. Neuropathic pain: from mechanisms to treatment. Physiol Rev. 2021; 101: 259-301. https://doi.org/10.1152/physrev.00045.2019.

[120] Buchheit T, Huh Y, Breglio A, Bang S, Xu J, Matsuoka Y. et al. Intrathecal administration of conditioned serum from different species resolves chemotherapy-induced neuropathic pain in mice via secretory exosomes. Brain Behav Immun. 2023; 111: 298-311. https://doi.org/10.1016/j.bbi.2023.04.013.

[121] Shiue SJ, Rau RH, Shiue HS, Hung YW, Li ZX, Yang KD. et al. Mesenchymal stem cell exosomes as a cell-free therapy for nerve injury-induced pain in rats. Pain. 2019; 160: 210-23. https://doi.org/10.1097/j.pain.0000000000001395.

[122] Li S, Huang C, Tu C, Chen R, Ren X, Qi L. et al. Bone marrow mesenchymal stem cell-derived exosomes shuttling mir-150-5p alleviates mechanical allodynia in rats by targeting notch2 in microglia. Mol Med. 2022; 28: 133. https://doi.org/10.1186/s10020-022-00561-x.

[123] Schäfer JA, Sutandy FXR, Münch C. Omics-based approaches for the systematic profiling of mitochondrial biology. Mol Cell. 2023; 83: 911-26. https://doi.org/10.1016/j.molcel.2023.02.015.

[124] Delgado de la Herran HC, Cheng Y, Perocchi F. Towards a systems-level understanding of mitochondrial biology. Cell Calcium. 2021; 95: 102364. https://doi.org/10.1016/j.ceca.2021.102364.

[125] Heine KB, Hood WR. Mitochondrial behaviour, morphology, and animal performance. Biol Rev Camb Philos Soc. 2020; 95: 730-7. https://doi.org/10.1111/brv.12584.

[126] Choong CJ, Okuno T, Ikenaka K, Baba K, Hayakawa H, Koike M. et al. Alternative mitochondrial quality control mediated by extracellular release. Autophagy. 2021; 17: 2962-74. https://doi.org/10.1080/15548627.2020.1848130.

[127] Sundaram VK, Schütza V, Schröter NH, Backhaus A, Bilsing A, Joneck L. et al. Adipo-glial signaling mediates metabolic adaptation in peripheral nerve regeneration. Cell Metab. 2023; 35: 2136-52.e9. https://doi.org/10.1016/j.cmet.2023.10.017.

[128] Cheng XT, Huang N, Sheng ZH. Programming axonal mitochondrial maintenance and bioenergetics in neurodegeneration and regeneration. Neuron. 2022; 110: 1899-923. https://doi.org/10.1016/j.neuron.2022.03.015.

[129] Borcherding N, Brestoff JR. The power and potential of mitochondria transfer. Nature. 2023; 623: 283-91. https://doi.org/10.1038/s41586-023-06537-z.

[130] Lin RZ, Im GB, Luo AC, Zhu Y, Hong X, Neumeyer J. et al. Mitochondrial transfer mediates endothelial cell engraftment through mitophagy. Nature. 2024; 629: 660-8. https://doi.org/10.1038/s41586-024-07340-0.

[131] Liu D, Liao P, Li H, Tong S, Wang B, Lu Y. et al. Regulation of blood-brain barrier integrity by Dmp1-expressing astrocytes through mitochondrial transfer. Sci Adv. 2024; 10: eadk2913. https://doi.org/10.1126/sciadv.adk2913.

[132] Jiang D, Xiong G, Feng H, Zhang Z, Chen P, Yan B. et al. Donation of mitochondria by iPSC-derived mesenchymal stem cells protects retinal ganglion cells against mitochondrial complex I defect-induced degeneration. Theranostics. 2019; 9: 2395-410. https://doi.org/10.7150/thno.29422.

[133] Tseng N, Lambie SC, Huynh CQ, Sanford B, Patel M, Herson PS. et al. Mitochondrial transfer from mesenchymal stem cells improves neuronal metabolism after oxidant injury in vitro: the role of Miro1. J Cereb Blood Flow Metab. 2021; 41: 761-70. https://doi.org/10.1177/0271678X20928147.

[134] Hayakawa K, Esposito E, Wang X, Terasaki Y, Liu Y, Xing C. et al. Transfer of mitochondria from astrocytes to neurons after stroke. Nature. 2016; 535: 551-5. https://doi.org/10.1038/nature18928.

[135] Zhou J, Zhang L, Peng J, Zhang X, Zhang F, Wu Y. et al. Astrocytic LRP1 enables mitochondria transfer to neurons and mitigates brain ischemic stroke by suppressing ARF1 lactylation. Cell Metab. 2024; 36: 2054-2068.e14. https://doi.org/10.1016/j.cmet.2024.05.016.

[136] Yao S, Pang M, Wang Y, Wang X, Lin Y, Lv Y. et al. Mesenchymal stem cell attenuates spinal cord injury by inhibiting mitochondrial quality control-associated neuronal ferroptosis. Redox Biol. 2023; 67: 102871. https://doi.org/10.1016/j.redox.2023.102871.

[137] Kuo CC, Su HL, Chang TL, Chiang CY, Sheu ML, Cheng FC. et al. Prevention of axonal degeneration by perineurium injection of mitochondria in a sciatic nerve crush injury model. Neurosurgery. 2017; 80: 475-88. https://doi.org/10.1093/neuros/nyw090.

[138] Nascimento-Dos-Santos G, de Souza-Ferreira E, Lani R, Faria CC, Araújo VG, Teixeira-Pinheiro LC. et al. Neuroprotection from optic nerve injury and modulation of oxidative metabolism by transplantation of active mitochondria to the retina. Biochim Biophys Acta Mol basis Dis. 2020; 1866: 165686. https://doi.org/10.1016/j.bbadis.2020.165686.

[139] Sheu ML, Shen CC, Tsou HK, Yang MY, Su HL, Sheehan J. et al. Dual regeneration of muscle and nerve by intramuscular infusion of mitochondria in a nerve crush injury model. Neurosurgery. 2021; 89: E49-e59. https://doi.org/10.1093/neuros/nyab105.

[140] Bai J, Yu B, Li C, Cheng H, Guan Y, Ren Z. et al. Mesenchymal stem cell-derived mitochondria enhance extracellular matrix-derived grafts for the repair of nerve defect. Adv Healthc Mater. 2024; 13: e2302128.

[141] Zhang Y, Xu T, Xie J, Wu H, Hu W, Yuan X. MSC-derived mitochondria promote axonal regeneration via Atf3 gene upregulation by ROS induced DNA double strand breaks at transcription initiation region. Cell Commun Signal. 2024; 22: 240. https://doi.org/10.1186/s12964-024-01617-7.

[142] Ledderose C, Liu K, Kondo Y, Slubowski CJ, Dertnig T, Denicoló S. et al. Purinergic P2X4 receptors and mitochondrial ATP production regulate T cell migration. J Clin Invest. 2018; 128: 3583-94. https://doi.org/10.1172/JCI120972.

[143] Clayton SA, Daley KK, MacDonald L, Fernandez-Vizarra E, Bottegoni G, O’Neil JD. et al. Inflammation causes remodeling of mitochondrial cytochrome c oxidase mediated by the bifunctional gene C15orf48. Sci Adv. 2021; 7:eabl5182. https://doi.org/10.1126/sciadv.abl5182.

[144] Lyu Y, Wang T, Huang S, Zhang Z. Mitochondrial damage-associated molecular patterns and metabolism in the regulation of innate immunity. J Innate Immun. 2023; 15: 665-79. https://doi.org/10.1159/000533602.

[145] Vringer E, Tait SWG. Mitochondria and cell death-associated inflammation. Cell Death Differ. 2023; 30: 304-12. https://doi.org/10.1038/s41418-022-01094-w.

[146] Gulen MF, Samson N, Keller A, Schwabenland M, Liu C, Glück S. et al. cGAS-STING drives ageing-related inflammation and neurodegeneration. Nature. 2023; 620: 374-80. https://doi.org/10.1038/s41586-023-06373-1.

[147] Tigano M, Vargas DC, Tremblay-Belzile S, Fu Y, Sfeir A. Nuclear sensing of breaks in mitochondrial DNA enhances immune surveillance. Nature. 2021; 591: 477-81. https://doi.org/10.1038/s41586-021-03269-w.

[148] Riley JS, Tait SW. Mitochondrial DNA in inflammation and immunity. EMBO Rep. 2020; 21: e49799. https://doi.org/10.15252/embr.201949799.

[149] Jiménez-Loygorri JI, Villarejo-Zori B, Viedma-Poyatos Á, Zapata-Muñoz J, Benítez-Fernández R, Frutos-Lisón MD. et al. Mitophagy curtails cytosolic mtDNA-dependent activation of cGAS/STING inflammation during aging. Nat Commun. 2024; 15: 830. https://doi.org/10.1038/s41467-024-45044-1.

[150] Onishi M, Yamano K, Sato M, Matsuda N, Okamoto K. Molecular mechanisms and physiological functions of mitophagy. EMBO J. 2021; 40:e104705. https://doi.org/10.15252/embj.2020104705.

[151] Shao S, Xu CB, Chen CJ, Shi GN, Guo QL, Zhou Y. et al. Divanillyl sulfone suppresses nlrp3 inflammasome activation via inducing mitophagy to ameliorate chronic neuropathic pain in mice. J Neuroinflammation. 2021; 18: 142. https://doi.org/10.1186/s12974-021-02178-z.

[152] Li B, Zhang Z, Wang H, Zhang D, Han T, Chen H. et al. Melatonin promotes peripheral nerve repair through parkin-mediated mitophagy. Free Radic Biol Med. 2022; 185: 52-66. https://doi.org/10.1016/j.freeradbiomed.2022.04.016.

[153] Sliter DA, Martinez J, Hao L, Chen X, Sun N, Fischer TD. et al. Parkin and PINK1 mitigate sting-induced inflammation. Nature. 2018; 561: 258-62. https://doi.org/10.1038/s41586-018-0448-9.

[154] Yang J, Wei Y, Zhao T, Li X, Zhao X, Ouyang X. et al. Magnolol effectively ameliorates diabetic peripheral neuropathy in mice. Phytomedicine. 2022; 107: 154434. https://doi.org/10.1016/j.phymed.2022.154434.

[155] Khwaja B, Thankam FG, Agrawal DK. Mitochondrial DAMPs and altered mitochondrial dynamics in oxLDL burden in atherosclerosis. Mol Cell Biochem. 2021; 476: 1915-28. https://doi.org/10.1007/s11010-021-04061-0.

[156] Lv L, Sheng C, Zhou Y. Extracellular vesicles as a novel therapeutic tool for cell-free regenerative medicine in oral rehabilitation. J Oral Rehabil. 2020; 47: 29-54. https://doi.org/10.1111/joor.12885.

[157] Raoofi A, Sadeghi Y, Piryaei A, Sajadi E, Aliaghaei A, Rashidiani-Rashidabadi A. et al. Bone marrow mesenchymal stem cell condition medium loaded on PCL nanofibrous scaffold promoted nerve regeneration after sciatic nerve transection in male rats. Neurotox Res. 2021; 39: 1470-86. https://doi.org/10.1007/s12640-021-00391-5.

[158] Ghasemi M, Talebi A, Ghanbari A, Hayat P, Yousefi B, Mohammadi M. et al. Bone marrow stromal cell-conditioned medium regenerates injured sciatic nerve by increasing expression of MPZ and NGF and decreasing apoptosis. Iran J Basic Med Sci. 2024; 27: 596-602. https://doi.org/10.22038/IJBMS.2024.74267.16133.

[159] Reboussin É, Buffault J, Brignole-Baudouin F, Réaux-Le Goazigo A, Riancho L, Olmiere C. et al. Evaluation of neuroprotective and immunomodulatory properties of mesenchymal stem cells in an ex vivo retinal explant model. J Neuroinflammation. 2022; 19: 63. https://doi.org/10.1186/s12974-022-02418-w.

[160] Amodeo G, Niada S, Moschetti G, Franchi S, Savadori P, Brini AT. et al. Secretome of human adipose-derived mesenchymal stem cell relieves pain and neuroinflammation independently of the route of administration in experimental osteoarthritis. Brain Behav Immun. 2021; 94: 29-40. https://doi.org/10.1016/j.bbi.2021.03.011.

[161] Liu Y, Kano F, Hashimoto N, Xia L, Zhou Q, Feng X. et al. Conditioned medium from the stem cells of human exfoliated deciduous teeth ameliorates neuropathic pain in a partial sciatic nerve ligation model. Front Pharmacol. 2022; 13: 745020. https://doi.org/10.3389/fphar.2022.745020.

[162] Petrenko Y, Vackova I, Kekulova K, Chudickova M, Koci Z, Turnovcova K. et al. A comparative analysis of multipotent mesenchymal stromal cells derived from different sources, with a focus on neuroregenerative potential. Sci Rep. 2020; 10: 4290. https://doi.org/10.1038/s41598-020-61167-z.

[163] Bar JK, Lis-Nawara A, Grelewski PG. Dental pulp stem cell-derived secretome and its regenerative potential. Int J Mol Sci. 2021; 22: 12018. https://doi.org/10.3390/ijms222112018.

[164] Yi SA, Zhang Y, Rathnam C, Pongkulapa T, Lee KB. Bioengineering approaches for the advanced organoid research. Adv Mater. 2021; 33:e2007949. https://doi.org/10.1002/adma.202007949.

[165] Garreta E, Kamm RD, de Sousa C, Lopes SM, Lancaster MA, Weiss R. et al. Rethinking organoid technology through bioengineering. Nat Mater. 2021; 20: 145-55. https://doi.org/10.1038/s41563-020-00804-4.

[166] Van Lent J, Vendredy L, Adriaenssens E, Da Silva AT, Asselbergh B, Kaji M. et al. Downregulation of PMP22 ameliorates myelin defects in iPSC-derived human organoid cultures of CMT1A. Brain. 2023; 146: 2885-96. https://doi.org/10.1093/brain/awac475.

[167] Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE. et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature. 2009; 459: 262-5. https://doi.org/10.1038/nature07935.

[168] Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006; 126: 663-76. https://doi.org/10.1016/j.cell.2006.07.024.

[169] Huijbers MG, Marx A, Plomp JJ, Le Panse R, Phillips WD. Advances in the understanding of disease mechanisms of autoimmune neuromuscular junction disorders. Lancet Neurol. 2022; 21: 163-75. https://doi.org/10.1016/S1474-4422(21)00357-4.

[170] Sirago G, Pellegrino MA, Bottinelli R, Franchi MV, Narici MV. Loss of neuromuscular junction integrity and muscle atrophy in skeletal muscle disuse. Ageing Res Rev. 2023; 83: 101810. https://doi.org/10.1016/j.arr.2022.101810.

[171] Guo X, Gonzalez M, Stancescu M, Vandenburgh HH, Hickman JJ. Neuromuscular junction formation between human stem cell-derived motoneurons and human skeletal muscle in a defined system. Biomaterials. 2011; 32: 9602-11. https://doi.org/10.1016/j.biomaterials.2011.09.014.

[172] Steinbeck JA, Jaiswal MK, Calder EL, Kishinevsky S, Weishaupt A, Toyka KV. et al. Functional connectivity under optogenetic control allows modeling of human neuromuscular disease. Cell Stem Cell. 2016; 18: 134-43. https://doi.org/10.1016/j.stem.2015.10.002.

[173] Lin CY, Yoshida M, Li LT, Ikenaka A, Oshima S, Nakagawa K. et al. iPSC-derived functional human neuromuscular junctions model the pathophysiology of neuromuscular diseases. JCI Insight. 2019; 4: 4. https://doi.org/10.1172/jci.insight.124299.

[174] Afshar Bakooshli M, Lippmann ES, Mulcahy B, Iyer N, Nguyen CT, Tung K. et al. A 3D culture model of innervated human skeletal muscle enables studies of the adult neuromuscular junction. elife. 2019; 8: 8. https://doi.org/10.7554/eLife.44530.

[175] Martin NR, Passey SL, Player DJ, Mudera V, Baar K, Greensmith L. et al. Neuromuscular junction formation in tissue-engineered skeletal muscle augments contractile function and improves cytoskeletal organization. Tissue Eng Part A. 2015; 21: 2595-604. https://doi.org/10.1089/ten.tea.2015.0146.

[176] Mazaleyrat K, Badja C, Broucqsault N, Chevalier R, Laberthonnière C, Dion C. et al. Multilineage differentiation for formation of innervated skeletal muscle fibers from healthy and diseased human pluripotent stem cells. Cells. 2020; 9: 9. https://doi.org/10.3390/cells9061531.

[177] Brown M, Li J, Moraes C, Tabrizian M, Li-Jessen NYK. Decellularized extracellular matrix: new promising and challenging biomaterials for regenerative medicine. Biomaterials. 2022; 289: 121786. https://doi.org/10.1016/j.biomaterials.2022.121786.

[178] Chaudhuri O, Cooper-White J, Janmey PA, Mooney DJ, Shenoy VB. Effects of extracellular matrix viscoelasticity on cellular behaviour. Nature. 2020; 584: 535-46. https://doi.org/10.1038/s41586-020-2612-2.

[179] Karamanos NK, Theocharis AD, Piperigkou Z, Manou D, Passi A, Skandalis SS. et al. A guide to the composition and functions of the extracellular matrix. FEBS J. 2021; 288: 6850-912. https://doi.org/10.1111/febs.15776.

[180] Zhang H, Tsui CK, Garcia G, Joe LK, Wu H, Maruichi A. et al. The extracellular matrix integrates mitochondrial homeostasis. Cell. 2024; 187: 4289-4304.e26.

[181] Contreras E, Traserra S, Bolívar S, Forés J, Jose-Cunilleras E, García F. et al. Repair of long nerve defects with a new decellularized nerve graft in rats and in sheep. Cells. 2022; 11: 4074.

[182] Wei S, Hu Q, Ma J, Dai X, Sun Y, Han G. et al. Acellular nerve xenografts based on supercritical extraction technology for repairing long-distance sciatic nerve defects in rats. Bioact Mater. 2022; 18: 300-20. https://doi.org/10.1016/j.bioactmat.2022.03.014.

[183] Jin B, Yu Y, Chen X, Yang Y, Xiong Y, Im YJ. et al. Microtubes with gradient decellularized porcine sciatic nerve matrix from microfluidics for sciatic nerve regeneration. Bioact Mater. 2023; 21: 511-9. https://doi.org/10.1016/j.bioactmat.2022.08.027.

[184] Meder T, Prest T, Skillen C, Marchal L, Yupanqui VT, Soletti L. et al. Nerve-specific extracellular matrix hydrogel promotes functional regeneration following nerve gap injury. NPJ Regen Med. 2021; 6: 69. https://doi.org/10.1038/s41536-021-00174-8.

[185] Qiu S, Deng PJ, He FL, Yan LW, Tu ZH, Liu XL. et al. A decellularized nerve matrix scaffold inhibits neuroma formation in the stumps of transected peripheral nerve after peripheral nerve injury. Neural Regen Res. 2023; 18: 664-70. https://doi.org/10.4103/1673-5374.350213.

[186] Wang X, Yao X, Sun Z, Jin Y, Yan Z, Jiang H. et al. An extracellular matrix mimicking alginate hydrogel scaffold manipulates an inflammatory microenvironment and improves peripheral nerve regeneration by controlled melatonin release. J Mater Chem B. 2023; 11: 11552-61. https://doi.org/10.1039/D3TB01727C.

[187] Zheng C, Yang Z, Chen S, Zhang F, Rao Z, Zhao C. et al. Nanofibrous nerve guidance conduits decorated with decellularized matrix hydrogel facilitate peripheral nerve injury repair. Theranostics. 2021; 11: 2917-31. https://doi.org/10.7150/thno.50825.

[188] Wang S, Wang H, Lu P, Gong L, Gu X, Li M. Mechanisms underlying the cell-matrixed nerve grafts repairing peripheral nerve defects. Bioact Mater. 2024; 31: 563-77. https://doi.org/10.1016/j.bioactmat.2023.09.002.

[189] Li T, Javed R, Ao Q. Xenogeneic decellularized extracellular matrix-based biomaterials for peripheral nerve repair and regeneration. Curr Neuropharmacol. 2021; 19: 2152-63. https://doi.org/10.2174/1570159X18666201111103815.

[190] Wang Y, Wang S, He JH. Transcriptomic analysis reveals essential microRNAs after peripheral nerve injury. Neural Regen Res. 2021; 16: 1865-70. https://doi.org/10.4103/1673-5374.306092.

[191] Ma X, Wang Y, Shi Y, Li S, Liu J, Li X. et al. Exosomal miR-132-3p from mesenchymal stromal cells improves synaptic dysfunction and cognitive decline in vascular dementia. Stem Cell Res Ther. 2022; 13: 315. https://doi.org/10.1186/s13287-022-02995-w.

[192] Wang H, Wang F, Wang Y, Li X, Di C, Liang C. et al. Study on the mechanism of BMSCs in regulating NF-κB signal pathway by targeting mir-449a to improve the inflammatory response to peripheral nerve injury. J Musculoskelet Neuronal Interact. 2022; 22: 546-61.

[193] Bassett C, Triplett H, Lott K, Howard KM, Kingsley K. Differential expression of microRNA (miR-27, miR-145) among dental pulp stem cells (DPSCs) following neurogenic differentiation stimuli. Biomedicines. 2023; 11: 11. https://doi.org/10.3390/biomedicines11113003.

[194] Chen QQ, Liu QY, Wang P, Qian TM, Wang XH, Yi S. et al. Potential application of let-7a antagomir in injured peripheral nerve regeneration. Neural Regen Res. 2023; 18: 1584-90. https://doi.org/10.4103/1673-5374.357914.

[195] Sun Y, Zhang C, Ma Q, Yu X, Gao X, Zhang H. et al. MiR-34a-HK1 signal axis retards bone marrow mesenchymal stem cell senescence via ameliorating glycolytic metabolism. Stem Cell Res Ther. 2024; 15: 238. https://doi.org/10.1186/s13287-024-03857-3.

[196] Li K, Liu Z, Wu P, Chen S, Wang M, Liu W. et al. Micro electrical fields induced MSC-sEVs attenuate neuronal cell apoptosis by activating autophagy via lncRNA MALAT1/miR-22-3p/SIRT1/AMPK axis in spinal cord injury. J Nanobiotechnology. 2023; 21: 451. https://doi.org/10.1186/s12951-023-02217-2.

[197] Grabundzija I, Wang J, Sebe A, Erdei Z, Kajdi R, Devaraj A. et al. Sleeping beauty transposon-based system for cellular reprogramming and targeted gene insertion in induced pluripotent stem cells. Nucleic Acids Res. 2013; 41: 1829-47. https://doi.org/10.1093/nar/gks1305.

[198] López-Leal R, Díaz-Viraqué F, Catalán RJ, Saquel C, Enright A, Iraola G. et al. Schwann cell reprogramming into repair cells increases miRNA-21 expression in exosomes promoting axonal growth. J Cell Sci. 2020; 133: jcs239004. https://doi.org/10.1242/jcs.239004.

[199] Ning XJ, Lu XH, Luo JC, Chen C, Gao Q, Li ZY. et al. Molecular mechanism of microRNA-21 promoting Schwann cell proliferation and axon regeneration during injured nerve repair. RNA Biol. 2020; 17: 1508-19. https://doi.org/10.1080/15476286.2020.1777767.

[200] Borger A, Stadlmayr S, Haertinger M, Semmler L, Supper P, Millesi F. et al. How miRNAs regulate Schwann cells during peripheral nerve regeneration-a systemic review. Int J Mol Sci. 2022; 23: 3440. https://doi.org/10.3390/ijms23073440.

[201] Cong M, Hu JJ, Yu Y, Li XL, Sun XT, Wang LT. et al. miRNA-21-5p is an important contributor to the promotion of injured peripheral nerve regeneration using hypoxia-pretreated bone marrow-derived neural crest cells. Neural Regen Res. 2025; 20: 277-90. https://doi.org/10.4103/1673-5374.390956.

[202] Liu X, Cui X, Guan G, Dong Y, Zhang Z. microRNA-192-5p is involved in nerve repair in rats with peripheral nerve injury by regulating XIAP. Cell Cycle. 2020; 19: 326-38. https://doi.org/10.1080/15384101.2019.1710916.

[203] Milbreta U, Lin J, Pinese C, Ong W, Chin JS, Shirahama H. et al. Scaffold-mediated sustained, non-viral delivery of miR-219/miR-338 promotes CNS remyelination. Mol Ther. 2019; 27: 411-23. https://doi.org/10.1016/j.ymthe.2018.11.016.

[204] Sugimura-Wakayama Y, Katagiri W, Osugi M, Kawai T, Ogata K, Sakaguchi K. et al. Peripheral nerve regeneration by secretomes of stem cells from human exfoliated deciduous teeth. Stem Cells Dev. 2015; 24: 2687-99. https://doi.org/10.1089/scd.2015.0104.

[205] Song P, Han T, Wu Z, Fang H, Liu Y, Ying W. et al. Transplantation of neural stem cells loaded in an IGF-1 bioactive supramolecular nanofiber hydrogel for the effective treatment of spinal cord injury. Adv Sci (Weinh). 2024; 11: e2306577.

[206] Garcia G, Pinto S, Cunha M, Fernandes A, Koistinaho J, Brites D. Neuronal dynamics and miRNA signaling differ between SH-SY5Y APPSwe and PSEN1 mutant iPSC-derived AD models upon modulation with miR-124 mimic and inhibitor. Cells. 2021; 10: 2424.

[207] Song Y, Shi R, Liu Y, Cui F, Han L, Wang C. et al. M2 microglia extracellular vesicle miR-124 regulates neural stem cell differentiation in ischemic stroke via AAK1/NOTCH. Stroke. 2023; 54: 2629-39. https://doi.org/10.1161/STROKEAHA.122.041611.