Abstract
Unlike the central nervous system, the peripheral one has the ability to regenerate itself after injury; however, this natural regeneration process is not always successful. In fact, even with some treatments, the prognosis is poor, and patients consequently suffer with the functional loss caused by injured nerves, generating several impacts on their quality of life. In the present review we aimed to address two strategies that may considerably potentiate peripheral nerve regeneration: stem cells and tissue engineering. In vitro studies have shown that pluripotent cells associated with neural scaffolds elaborated by tissue engineering can increase functional recovery, revascularization, remyelination, neurotrophin expression and reduce muscle atrophy. Although these results are very promising, it is important to note that there are some barriers to be circumvented: the host's immune response, the oncogenic properties attributed to stem cells and the duration of the pro-regenerative effects. After all, more studies are still needed to overcome the limitations of these treatments; those that address techniques for manipulating the lesion microenvironment combining different therapies seem to be the most promising and proactive ones.
Graphical Abstract
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data Availability
All data are given herein.
References
Adams AM, VanDusen KW, Kostrominova TY, Mertens JP, Larkin LM (2017) Scaffoldless tissue-engineered nerve conduit promotes peripheral nerve regeneration and functional recovery after tibial nerve injury in rats. Neural Regen Res 12(9):1529–1537. https://doi.org/10.4103/1673-5374.215265
Armaiz Flores A, Wang H (2018) The use and delivery of stem cells in nerve regeneration: preclinical evidence and regulatory considerations. Ann Plast Surg 80(4):448–456. https://doi.org/10.1097/SAP.0000000000001259
Battiston B, Papalia I, Tos P, Geuna S (2009) Chapter 1 peripheral nerve repair and regeneration research. A historical note. Int. Rev. Neurobiol 87:1–7
Bojanic C, To K, Zhang B, Mak C, Khan WS (2020) Human umbilical cord derived mesenchymal stem cells in peripheral nerve regeneration. World J Stem Cells 12(4):288–302. https://doi.org/10.4252/wjsc.v12.i4.288
Bucan V, Vaslaitis D, Peck CT, Strauß S, Vogt PM, Radtke C (2019) Effect of exosomes from rat adipose-derived mesenchymal stem cells on neurite outgrowth and sciatic nerve regeneration after crush injury. Mol Neurobiol 56(3):1812–1824. https://doi.org/10.1007/s12035-018-1172-z
Burnett MG, Zager EL (2004) Pathophysiology of peripheral nerve injury: a brief review. Neurosurg Focus 16(5):E1. https://doi.org/10.3171/foc.2004.16.5.2
Büttner R, Schulz A, Reuter M et al (2018) Inflammaging impairs peripheral nerve maintenance and regeneration. Aging Cell 17(6):e12833. https://doi.org/10.1111/acel.12833
Cartarozzi LP, Spejo AB, Ferreira RS et al (2015) Mesenchymal stem cells engrafted in a fibrin scaffold stimulate Schwann cell reactivity and axonal regeneration following sciatic nerve tubulization. Brain Res Bull 112:14–24. https://doi.org/10.1016/j.brainresbull.2015.01.005
Chang W, Shah MB, Zhou G et al (2020) Polymeric nanofibrous nerve conduits coupled with laminin for peripheral nerve regeneration. Biomed Mater 15(3):035003. https://doi.org/10.1088/1748-605X/ab6994
Cuevas P, Carceller F, Dujovny M, Garcia-Gómez I, Cuevas B, González-Corrochano R, Diaz-González D, Reimers D (2002) Peripheral nerve regeneration by bone marrow stromal cells. Neurol Res 24(7):634–638. https://doi.org/10.1179/016164102101200564
Cui L, Jiang J, Wei L et al (2009) Transplantation of embryonic stem cells improves nerve repair and functional recovery after severe sciatic nerve axotomy in rats. Stem Cells 21:1356–1365. https://doi.org/10.1634/stemcells.2007-0333
Deumens R, Bozkurt A, Meek MF et al (2010) Repairing injured peripheral nerves: bridging the gap. Prog Neurobiol 92:245–276
Dezawa M, Takahashi I, Esaki M, Takano M, Sawada H (2001) Sciatic nerve regeneration in rats induced by transplantation of in vitro differentiated bone-marrow stromal cells. Eur J Neurosci 14:1771–1776. https://doi.org/10.1046/j.0953-816x.2001.01814.x
di Summa PG, Kalbermatten DF, Pralong E et al (2011) Long-term in vivo regeneration of peripheral nerves through bioengineered nerve grafts. Neuroscience 181:278–291. https://doi.org/10.1016/j.neuroscience.2011.02.052
Dong C, Lv Y (2016) Application of collagen scaffold in tissue engineering: recent advances and new perspectives. Polymers (basel) 8(2):42. https://doi.org/10.3390/polym8020042
Esaki S, Katsumi S, Hamajima Y, Nakamura Y, Murakami S (2019) Transplantation of olfactory stem cells with biodegradable hydrogel accelerates facial nerve regeneration after crush injury. Stem Cells Transl Med 8(2):169–178. https://doi.org/10.1002/sctm.15-0399
Fex Svennigsen A, Dahlin LB (2013) Repair of the peripheral nerve-remyelination that works. Brain Sci 3(3):1182–1197. https://doi.org/10.3390/brainsci3031182
Geremia NM, Pettersson LME, Hasmatali JC et al (2010) Endogenous BDNF regulates induction of intrinsic neuronal growth programs in injured sensory neurons. Exp Neurol 223:128–142. https://doi.org/10.1016/j.expneurol.2009.07.022
Geuna S, Gnavi S, Perroteau I et al (2013) Tissue engineering and peripheral nerve reconstruction: an overview. Int Rev Neurobiol 108:35–57. https://doi.org/10.1016/B978-0-12-410499-0.00002-2
Gonzalez-Perez F, Cobianchi S, Heimann C, Phillips JB, Udina E, Navarro X (2017) Stabilization, rolling, and addition of other extracellular matrix proteins to collagen hydrogels improve regeneration in chitosan guides for long peripheral nerve gaps in rats. Neurosurgery 80(3):465–474. https://doi.org/10.1093/neuros/nyw068
Gordon T (2020) Peripheral nerve regeneration and muscle reinnervation. Int J Mol Sci 21(22):8652. https://doi.org/10.3390/ijms21228652
Grinsell D, Keating CP (2014) Peripheral nerve reconstruction after injury: a review of clinical and experimental therapies. Biomed Res Int. https://doi.org/10.1155/2014/698256
Gu X, Ding F, Yang Y, Liu J (2011) Construction of tissue engineered nerve grafts and their application in peripheral nerve regeneration. Prog Neurobiol 93:204–230
Gu X, Ding F, Williams DF (2014) Neural tissue engineering options for peripheral nerve regeneration. Biomaterials 35:6143–6156. https://doi.org/10.1016/j.biomaterials.2014.04.064
Hao J, Ma A, Wang L et al (2020) General requirements for stem cells. Cell Prolif 53(12):e12926. https://doi.org/10.1111/cpr.12926
Herberts CA, Kwa MSG, Hermsen HPH (2011) Risk factors in the development of stem cell therapy. J Transl Med 9:1–14. https://doi.org/10.1186/1479-5876-9-29
Hong Hei W, Almansoori AA, Sung MA et al (2017) Adenovirus vector-mediated ex vivo gene transfer of brain-derived neurotrophic factor (BDNF) tohuman umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) promotescrush-injured rat sciatic nerve regeneration. Neurosci Lett 643:111–120. https://doi.org/10.1016/j.neulet.2017.02.030
Hong P, Yang H, Wu Y, Li K, Tang Z (2019) The functions and clinical application potential of exosomes derived from adipose mesenchymal stem cells: a comprehensive review. Stem Cell Res Ther 10(1):242. https://doi.org/10.1186/s13287-019-1358-y
Hopf A, Schaefer DJ, Kalbermatten DF, Guzman R, Madduri S (2020) Schwann cell-like cells: origin and usability for repair and regeneration of the peripheral and central nervous system. Cells 9(9):1990. https://doi.org/10.3390/cells9091990
Huang CW, Hsueh YY, Huang WC, Patel S, Li S (2019) Multipotent vascular stem cells contribute to neurovascular regeneration of peripheral nerve. Stem Cell Res Ther 10(1):234. https://doi.org/10.1186/s13287-019-1317-7
Hussin HM, Lawi MM, Haflah NHM, Kassim AYM, Idrus RBH, Lokanathan Y (2020) Centella asiatica (L.)-neurodifferentiated mesenchymal stem cells promote the regeneration of peripheral nerve. Tissue Eng Regen Med 17(2):237–251. https://doi.org/10.1007/s13770-019-00235-6
Hyun I (2010) The bioethics of stem cell research and therapy. J Clin Invest 120:71–75. https://doi.org/10.1172/JCI40435
Ikeda M, Uemura T, Takamatsu K et al (2014) Acceleration of peripheral nerve regeneration using nerve conduits in combination with induced pluripotent stem cell technology and a basic fibroblast growth factor drug delivery system. J Biomed Mater Res Part A 102:1370–1378. https://doi.org/10.1002/jbm.a.34816
Jessen KR, Mirsky R (2019) The success and failure of the Schwann cell response to nerve injury. Front Cell Neurosci 13:33. https://doi.org/10.3389/fncel.2019.00033
Jiang L, Jones S, Jia X (2017) Stem cell transplantation for peripheral nerve regeneration: current options and opportunities. Int J Mol Sci 18:1–17. https://doi.org/10.3390/ijms18010094
Jones S, Eisenberg HM, Jia X (2016) Advances and future applications of augmented peripheral nerve regeneration. Int J Mol Sci 17:1–17
Kehoe S, Zhang XF, Boyd D (2012) FDA approved guidance conduits and wraps for peripheral nerve injury: a review of materials and efficacy. Injury 43:553–572. https://doi.org/10.1016/j.injury.2010.12.030
Kimura H, Ouchi T, Shibata S et al (2018) Stem cells purified from human induced pluripotent stem cell-derived neural crest-like cells promote peripheral nerve regeneration. Sci Rep 8:10071. https://doi.org/10.1038/s41598-018-27952-7
Kingham PJ, Kolar MK, Novikova LN et al (2014) Stimulating the neurotrophic and angiogenic properties of human adipose-derived stem cells enhances nerve repair. Stem Cells Dev 23:741–754. https://doi.org/10.1089/scd.2013.0396
Kolar MK, Itte VN, Kingham PJ et al (2017) The neurotrophic effects of different human dental mesenchymal stem cells. Sci Rep 7:1–12. https://doi.org/10.1038/s41598-017-12969-1
Lasso JM, Pérez Cano R, Castro Y et al (2015) Xenotransplantation of human adipose-derived stem cells in the regeneration of a rabbit peripheral nerve. J Plast Reconstr Aesthetic Surg 68:e189–e197. https://doi.org/10.1016/j.bjps.2015.07.005
Lavorato A, Raimondo S, Boido M et al (2021) Mesenchymal stem cell treatment perspectives in peripheral nerve regeneration: systematic review. Int J Mol Sci 22(2):572. https://doi.org/10.3390/ijms22020572
Lee AC, Yu VM, Lowe JB et al (2003) Controlled release of nerve growth factor enhances sciatic nerve regeneration. Exp Neurol 184:295–303. https://doi.org/10.1016/S0014-4886(03)00258-9
Lehmann HC, Höke A (2016) Use of engineered Schwann cells in peripheral neuropathy: hopes and hazards. Brain Res 1638:97–104
Levi AD, Burks SS, Anderson KD et al (2016) The use of autologous schwann cells to supplement sciatic nerve repair with a large gap: first in human experience. Cell Transplant 25:1395–1403. https://doi.org/10.3727/096368915X690198
Li R, Liu Z, Pan Y et al (2014) Peripheral nerve injuries treatment: a systematic review. Cell Biochem Biophys 68:449–4547
Lin YJ, Lee YW, Chang CW, Huang CC (2020) 3D spheroids of umbilical cord blood msc-derived schwann cells promote peripheral nerve regeneration. Front Cell Dev Biol 8:604946. https://doi.org/10.3389/fcell.2020.604946
Lundborg G, Rosén B, Dahlin L et al (2004) Tubular repair of the median or ulnar nerve in the human forearm: a 5 - year follow up. J Hand Surg Am 29:100–107. https://doi.org/10.1016/j.jhsb.2003.09.018
Ma Y, Dong L, Zhou D et al (2019) Extracellular vesicles from human umbilical cord mesenchymal stem cells improve nerve regeneration after sciatic nerve transection in rats. J Cell Mol Med 23(4):2822–2835. https://doi.org/10.1111/jcmm.14190
Madduri S, Feldman K, Tervoort T et al (2010) Collagen nerve conduits releasing the neurotrophic factors GDNF and NGF. J Control Release 143:168–174. https://doi.org/10.1016/j.jconrel.2009.12.017
Masgutov R, Masgutova G, Mukhametova L et al (2018) Allogenic adipose derived stem cells transplantation improved sciatic nerve regeneration in rats: autologous nerve graft model. Front Pharmacol 9:86. https://doi.org/10.3389/fphar.2018.00086
Muheremu A, Ao Q (2015) Past, Present, and future of nerve conduits in the treatment of peripheral nerve injury. Biomed Res Int 2015:1–7. https://doi.org/10.1155/2015/237507
Muheremu A, Chen L, Wang X et al (2017) Chitosan nerve conduits seeded with autologous bone marrow mononuclear cells for 30 mm goat peroneal nerve defect. Sci Rep 7:1–12. https://doi.org/10.1038/srep44002
Pabari A, Lloyd-Hughes H, Seifalian AM, Mosahebi A (2014) Nerve conduits for peripheral nerve surgery. Plast Reconstr Surg 133:1420–1430. https://doi.org/10.1097/PRS.0000000000000226
Pitta MC, Wolford LM, Mehra P, Hopkin J (2001) Use of Gore-Tex tubing as a conduit for inferior alveolar and lingual nerve repair: experience with 6 cases. J Oral Maxillofac Surg 59:493–496. https://doi.org/10.1053/joms.2001.22671
Rao F, Wang Y, Zhang D et al (2020) Aligned chitosan nanofiber hydrogel grafted with peptides mimicking bioactive brain-derived neurotrophic factor and vascular endothelial growth factor repair long-distance sciatic nerve defects in rats. Theranostics 10(4):1590–1603. https://doi.org/10.7150/thno.36272
Ribeiro-Resende VT, Carrier-Ruiz A, Lemes R, RM, et al (2012) Bone marrow-derived fibroblast growth factor-2 induces glial cell proliferation in the regenerating peripheral nervous system. Mol Neurodegener 7:34. https://doi.org/10.1186/1750-1326-7-34
Robinton DA, Daley GQ (2012) The promise of induced pluripotent stem cells in research and therapy. Nature 481:295–305. https://doi.org/10.1038/nature10761
Rodríguez-Sánchez DN, Pinto GBA, Cartarozzi LP et al (2021) 3D-printed nerve guidance conduits multi-functionalized with canine multipotent mesenchymal stromal cells promote neuroregeneration after sciatic nerve injury in rats. Stem Cell Res Ther 12(1):303. https://doi.org/10.1186/s13287-021-02315-8
Saez DM, Sasaki RT, Martins DO, Chacur M, Kerkis I, da Silva MCP (2019) Rat facial nerve regeneration with human immature dental pulp stem cells. Cell Transplant 28(12):1573–1584. https://doi.org/10.1177/0963689719854446
Sameem M, Wood TJ, Bain JR (2011) A systematic review on the use of fibrin glue for peripheral nerve repair. Plast Reconstr Surg 127:2381–2390
Schmidt CE, Leach JB (2003) Neural tissue engineering: strategies for repair and regeneration. Annu Rev Biomed Eng 5:293–347. https://doi.org/10.1146/annurev.bioeng.5.011303.120731
Schuh CMAP, Day AGE, Redl H, Phillips J (2018) An optimized collagen-fibrin blend engineered neural tissue promotes peripheral nerve repair. Tissue Eng Part A 24(17–18):1332–1340. https://doi.org/10.1089/ten.TEA.2017.0457
Seddon HJ (1942) A classification of nerve injuries. Br Med J 2:237. https://doi.org/10.1136/bmj.2.4260.237
Sensharma P, Madhumathi G, Jayant RD, Jaiswal AK (2017) Biomaterials and cells for neural tissue engineering: Current choices. Mater Sci Eng C 77:1302–1315
Sugimura-Wakayama Y, Katagiri W, Osugi M et al (2015) Peripheral nerve regeneration by secretomes of stem cells from human exfoliated deciduous teeth. Stem Cells Dev 24:2687–2699. https://doi.org/10.1089/scd.2015.0104
Sunderland SS (1990) The anatomy and physiology of nerve injury. Muscle Nerve 13:771–784. https://doi.org/10.1002/mus.880130903
Takahashi K, Tanabe K, Ohnuki M et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872. https://doi.org/10.1016/j.cell.2007.11.019
Tamaki T, Hirata M, Nakajima N et al (2016) A Long-gap peripheral nerve injury therapy using human skeletal muscle-derived stem cells (Sk-SCs): an achievement of significant morphological. Numerical and Functional Recovery Plos One 11:e0166639. https://doi.org/10.1371/journal.pone.0166639
Taylor CA, Braza D, Rice JB, Dillingham T (2008) The incidence of peripheral nerve injury in extremity trauma. Am J Phys Med Rehabil 87:381–385. https://doi.org/10.1097/PHM.0b013e31815e6370
Tezcan AH (2017) Peripheral nerve injury and current treatment strategies. In: Maurício AC (ed) Peripheral nerve regeneration - from surgery to new therapeutic approaches including biomaterials and cell-based therapies development. InTech, pp 3–31
Tomita K, Madura T, Sakai Y et al (2013) Glial differentiation of human adipose-derived stem cells: implications for cell-based transplantation therapy. Neuroscience 236:55–65. https://doi.org/10.1016/j.neuroscience.2012.12.066
Tremp M, Sprenger L, Degrugillier L et al (2018) Regeneration of nerve crush injury using adipose-derived stem cells: a multimodal comparison. Muscle Nerve 58(4):566–572. https://doi.org/10.1002/mus.26188
Wang J, Ding F, Gu Y et al (2009) Bone marrow mesenchymal stem cells promote cell proliferation and neurotrophic function of Schwann cells in vitro and in vivo. Brain Res 1262:7–15. https://doi.org/10.1016/j.brainres.2009.01.056
Wang S, Ghezzi CE, White JD, Kaplan DL (2015) Coculture of dorsal root ganglion neurons and differentiated human corneal stromal stem cells on silk-based scaffolds. J Biomed Mater Res Part A 103:3339–3348. https://doi.org/10.1002/jbm.a.35465
Williams DF (2006) To engineer is to create: The link between engineering and regeneration. Trends Biotechnol 24:4–8. https://doi.org/10.1016/j.tibtech.2005.10.006
Williams D (2014) Essential biomaterials science. Cambridge University Press
Yamamoto T, Osako Y, Ito M et al (2016) Trophic effects of dental pulp stem cells on Schwann cells in peripheral nerve regeneration. Cell Transplant 25:183–193. https://doi.org/10.3727/096368915X688074
Yi S, Xu L, Gu X (2019) Scaffolds for peripheral nerve repair and reconstruction. Exp. Neurol. 319:112761
Yi S, Zhang Y, Gu X, Huang L, Zhang K, Qian T (2020) Application of stem cells in peripheral nerve regeneration. Burns Trauma. 8:tkaa002. https://doi.org/10.1093/burnst/tkaa002
Yurie H, Ikeguchi R, Aoyama T et al (2020) Bio 3D conduits derived from bone marrow stromal cells promote peripheral nerve regeneration. Cell Transplant 29:963689720951551. https://doi.org/10.1177/0963689720951551
Zakrzewski W, Dobrzyński M, Szymonowicz M, Rybak Z (2019) Stem cells: past, present, and future. Stem Cell Res Ther. 10(1):68. https://doi.org/10.1186/s13287-019-1165-5
Zheng C, Yang Z, Chen S et al (2021) Nanofibrous nerve guidance conduits decorated with decellularized matrix hydrogel facilitate peripheral nerve injury repair. Theranostics 11(6):2917–2931. https://doi.org/10.7150/thno.50825
Zhou LN, Wang JC, Zilundu PLM et al (2020) A comparison of the use of adipose-derived and bone marrow-derived stem cells for peripheral nerve regeneration in vitro and in vivo. Stem Cell Res Ther 11(1):153. https://doi.org/10.1186/s13287-020-01661-3
Ziegler L, Grigoryan S, Yang IH et al (2011) Efficient generation of schwann cells from human embryonic stem cell-derived neurospheres. Stem Cell Rev Reports 7:394–403. https://doi.org/10.1007/s12015-010-9198-2
Acknowledgements
Consejo Nacional de Ciencia y Tecnologia (CONACYT) is thankfully acknowledged for partially supporting this work under Sistema Nacional de Investigadores (SNI) program awarded to Hafiz M.N. Iqbal (CVU: 735340). The authors thankfully acknowledge the literature access provided by their respective institutions/organizations.
Funding
This article received no funding.
Author information
Authors and Affiliations
Contributions
All listed authors equally contributed from conceptualization to compilation.
Corresponding authors
Ethics declarations
Conflict of Interest
The listed author(s) declare no competing interests.
Ethical Approval
Not applicable.
Consent to Participate
Not applicable.
Consent for Publication
All listed authors have read and agreed with this submission and give their consent to publish in Molecular Neurobiology.
Animals Rights
Not applicable.
Informed Consent
Not applicable.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
de Assis, A.C.C., Reis, A.L.S., Nunes, L.V. et al. Stem Cells and Tissue Engineering-Based Therapeutic Interventions: Promising Strategies to Improve Peripheral Nerve Regeneration. Cell Mol Neurobiol 43, 433–454 (2023). https://doi.org/10.1007/s10571-022-01199-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10571-022-01199-3