Abstract
Although there is a considerable regenerative potential in the peripheral nervous system, recovery after traumatic nerve injuries, especially in the case of severe lesions, is incomplete. Despite the recent improvements in microsurgical techniques and the development of new nerve conduits that have widened the availability of tools to achieve more successful reinnervation of the peripheral targets, the clinical outcome is often still not satisfactory. The availability of autologous Schwann cells as donor cell types is very limited and their use from allogeneic sources raises a number of questions. Therefore the use of the regeneration-promoting effect of stem cells in peripheral nerve regeneration following injuries appears to be crucial. Multi- or pluripotent stem cells with a self-renewing capacity may be taken from several sources for preclinical applications and their use proved to be very promising to induce improved morphological and functional recovery in the injured peripheral nervous system.
The future opportunities along with the pros and cons of stem cell–based therapies to improve peripheral nerve regeneration are discussed in this chapter.
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References
Abdallah BM, Kassem M (2008) Human mesenchymal stem cells: from basic biology to clinical applications. Gene Ther 15:109–116. https://doi.org/10.1038/sj.gt.3303067
Al-Zer H, Kalbouneh H (2015) Dental pulp stem cells-derived Schwann cells for peripheral nerve injury regeneration. Neural Regen Res 10:1945–1946. https://doi.org/10.4103/1673-5374.172309
Al-Zer H et al (2015) Enrichment and Schwann cell differentiation of neural crest-derived dental pulp stem cells. In Vivo 29:319–326
Amoh Y et al (2005) Implanted hair follicle stem cells form Schwann cells that support repair of severed peripheral nerves. Proc Natl Acad Sci USA 102:17734–17738. https://doi.org/10.1073/pnas.0508440102
Amoh Y et al (2009a) Human hair follicle pluripotent stem (hfPS) cells promote regeneration of peripheral-nerve injury: an advantageous alternative to ES and iPS cells. J Cell Biochem 107:1016–1020. https://doi.org/10.1002/jcb.22204
Amoh Y et al (2009b) Human and mouse hair follicles contain both multipotent and monopotent stem cells. Cell Cycle 8:176–177. https://doi.org/10.4161/Cc.8.1.7342
Amoh Y et al (2012) Nestin-positive hair follicle pluripotent stem cells can promote regeneration of impinged peripheral nerve injury. J Dermatol 39:33–38. https://doi.org/10.1111/j.1346-8138.2011.01413.x
Arthur A, Rychkov G, Shi S, Koblar SA, Gronthos S (2008) Adult human dental pulp stem cells differentiate toward functionally active neurons under appropriate environmental cues. Stem Cells 26:1787–1795. https://doi.org/10.1634/stemcells.2007-0979
Beane OS, Fonseca VC, Cooper LL, Koren G, Darling EM (2014) Impact of aging on the regenerative properties of bone marrow-, muscle-, and adipose-derived mesenchymal stem/stromal cells. PLoS One 9:ARTN e115963. https://doi.org/10.1371/journal.pone.0115963
Bhangra KS, Busuttil F, Phillips JB, Rahim AA (2016, 2016) Using stem cells to grow artificial tissue for peripheral nerve repair. Stem Cells Int:Artn 7502178. https://doi.org/10.1155/2016/7502178
Bianco P, Robey PG (2015) Skeletal stem cells. Development 142:1023–1027. https://doi.org/10.1242/dev.102210
Bourin P et al (2013) Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal/stem cells: a joint statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT). Cytotherapy 15:641–648. https://doi.org/10.1016/j.jcyt.2013.02.006
Carnevale G et al (2018) Human dental pulp stem cells expressing STRO-1, c-kit and CD34 markers in peripheral nerve regeneration. J Tissue Eng Regen Med 12:E774–E785. https://doi.org/10.1002/term.2468
Caseiro AR, Pereira T, Ivanova G, Luis AL, Mauricio AC (2016, 2016) Neuromuscular regeneration: perspective on the application of mesenchymal stem cells and their secretion products. Stem Cells Int:Artn 9756973. https://doi.org/10.1155/2016/9756973
Chen CJ et al (2007) Transplantation of bone marrow stromal cells for peripheral nerve repair. Exp Neurol 204:443–453. https://doi.org/10.1016/j.expneurol.2006.12.004
Crisan M et al (2008) A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3:301–313. https://doi.org/10.1016/j.stem.2008.07.003
de Luca AC, Faroni A, Downes S, Terenghi G (2016) Differentiated adipose-derived stem cells act synergistically with RGD-modified surfaces to improve neurite outgrowth in a co-culture model. J Tissue Eng Regen Med 10:647–655. https://doi.org/10.1002/term.1804
Deng WW, Obrocka M, Fischer I, Prockop DJ (2001) In vitro differentiation of human marrow stromal cells into early progenitors of neural cells by conditions that increase intracellular cyclic AMP. Biochem Bioph Res Co 282:148–152. https://doi.org/10.1006/bbrc.2001.4570
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 et al (2010) Adipose-derived stem cells enhance peripheral nerve regeneration. J Plast Reconstr Aes 63:1544–1552. https://doi.org/10.1016/j.bjps.2009.09.012
di Summa PG, Kingham PJ, Campisi CC, Raffoul W, Kalbermatten DF (2014) Collagen (NeuraGen (R)) nerve conduits and stem cells for peripheral nerve gap repair. Neurosci Lett 572:26–31. https://doi.org/10.1016/j.neulet.2014.04.029
Eglitis MA, Mezey E (1997) Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice. Proc Natl Acad Sci USA 94:4080–4085. https://doi.org/10.1073/pnas.94.8.4080
Fairbairn NG, Meppelink AM, Ng-Glazier J, Randolph MA, Winograd JM (2015) Augmenting peripheral nerve regeneration using stem cells: a review of current opinion. World J Stem Cells 7:11–26. https://doi.org/10.4252/wjsc.v7.i1.11
Faroni A et al (2011) Schwann-like adult stem cells derived from bone marrow and adipose tissue express gamma-aminobutyric acid type B receptors. J Neurosci Res 89:1351–1362. https://doi.org/10.1002/jnr.22652
Faroni A, Terenghi G, Magnaghi V (2012) Expression of functional gamma-aminobutyric acid type a receptors in Schwann-like adult stem cells. J Mol Neurosci 47:619–630. https://doi.org/10.1007/s12031-011-9698-9
Faroni A, Calabrese F, Riva MA, Terenghi G, Magnaghi V (2013a) Baclofen modulates the expression and release of neurotrophins in Schwann-like adipose stem cells. J Mol Neurosci 49:233–243. https://doi.org/10.1007/s12031-012-9813-6
Faroni A, Terenghi G, Reid AJ (2013b) Adipose-derived stem cells and nerve regeneration: promises and pitfalls. Int Rev Neurobiol 108:121. https://doi.org/10.1016/B978-0-12-410499-0.00005-8
Fu XM et al (2019) The combination of adipose-derived Schwann-like cells and acellular nerve allografts promotes sciatic nerve regeneration and repair through the JAK2/STAT3 signaling pathway in rats. Neuroscience 422:134–145. https://doi.org/10.1016/j.neuroscience.2019.10.018
Fusaki N, Ban H, Nishiyama A, Saeki K, Hasegawa M (2009) Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome. Proc Jpn Acad B-Phys 85:348–362. https://doi.org/10.2183/pjab.85.348
Grochmal J, Dhaliwal S, Stys PK, van Minnen J, Midha R (2014) Skin-derived precursor Schwann cell myelination capacity in focal tibial demyelination. Muscle Nerve 50:262–272. https://doi.org/10.1002/mus.24136
Gronthos S, Mankani M, Brahim J, Robey PG, Shi S (2000) Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci USA 97:13625–13630. https://doi.org/10.1073/pnas.240309797
Gronthos S et al (2002) Stem cell properties of human dental pulp stem cells. J Dent Res 81:531–535. https://doi.org/10.1177/154405910208100806
Hanna J et al (2007) Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 318:1920–1923. https://doi.org/10.1126/science.1152092
Hu J, Zhu QT, Liu XL, Xu YB, Zhu JK (2007) Repair of extended peripheral nerve lesions in rhesus monkeys using acellular allogenic nerve grafts implanted with autologous mesenchymal stem cells. Exp Neurol 204:658–666. https://doi.org/10.1016/j.expneurol.2006.11.018
Huang GTJ, Gronthos S, Shi S (2009) Mesenchymal stem cells derived from dental tissues vs. those from other sources: their biology and role in regenerative medicine. J Dent Res 88:792–806. https://doi.org/10.1177/0022034509340867
Iohara K et al (2006) Side population cells isolated from porcine dental pulp tissue with self-renewal and multipotency for dentinogenesis, chondrogenesis, adipogenesis, and neurogenesis. Stem Cells 24:2493–2503. https://doi.org/10.1634/stemcells.2006-0161
Ishkitiev N et al (2010) Deciduous and permanent dental pulp mesenchymal cells acquire hepatic morphologic and functional features in vitro. J Endod 36:469–474. https://doi.org/10.1016/j.joen.2009.12.022
Kim D et al (2009) Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 4:472–476. https://doi.org/10.1016/j.stem.2009.05.005
Kingham PJ et al (2007) Adipose-derived stem cells differentiate into a Schwann cell phenotype and promote neurite outgrowth in vitro. Exp Neurol 207:267–274. https://doi.org/10.1016/j.expneurol.2007.06.029
Lin HY et al (2009) Pluripotent hair follicle neural crest stem-cell-derived neurons and Schwann cells functionally repair sciatic nerves in rats. Mol Neurobiol 40:216–223. https://doi.org/10.1007/s12035-009-8082-z
Liu QY et al (2012) Human neural crest stem cells derived from human ESCs and induced pluripotent stem cells: induction, maintenance, and differentiation into functional Schwann cells. Stem Cells Transl Med 1:266–278. https://doi.org/10.5966/sctm.2011-0042
Ma MS, Boddeke E, Copray S (2015) Pluripotent stem cells for Schwann cell engineering. Stem Cell Rev Rep 11:205–218. https://doi.org/10.1007/s12015-014-9577-1
Maherali N et al (2008) A high-efficiency system for the generation and study of human induced pluripotent stem cells. Cell Stem Cell 3:340–345. https://doi.org/10.1016/j.stem.2008.08.003
Mantovani C et al (2010) Bone marrow- and adipose-derived stem cells show expression of myelin mRNAs and proteins. Regen Med 5:403–410. https://doi.org/10.2217/Rme.10.15
Marconi S et al (2012) Human adipose-derived mesenchymal stem cells systemically injected promote peripheral nerve regeneration in the mouse model of sciatic crush. Tissue Eng Pt A 18:1264–1272. https://doi.org/10.1089/ten.tea.2011.0491
Martens W et al (2014) Human dental pulp stem cells can differentiate into Schwann cells and promote and guide neurite outgrowth in an aligned tissue-engineered collagen construct in vitro. FASEB J 28:1634–1643. https://doi.org/10.1096/fj.13-243980
Mead B, Logan A, Berry M, Leadbeater W, Scheven BA (2013) Intravitreally transplanted dental pulp stem cells promote neuroprotection and axon regeneration of retinal ganglion cells after optic nerve injury. Invest Ophthalmol Vis Sci 54:7544–7556. https://doi.org/10.1167/iovs.13-13045
Mead B, Logan A, Berry M, Leadbeater W, Scheven BA (2017) Concise review: dental pulp stem cells: a novel cell therapy for retinal and central nervous system repair. Stem Cells 35:61–67. https://doi.org/10.1002/stem.2398
Morsczeck C (2019) Cellular senescence in dental pulp stem cells. Arch Oral Biol 99:150–155. https://doi.org/10.1016/j.archoralbio.2019.01.012
Narazaki G et al (2008) Directed and systematic differentiation of cardiovascular cells from mouse induced pluripotent stem cells. Circulation 118:498–506. https://doi.org/10.1161/Circulationaha.108.769562
Okita K, Ichisaka T, Yamanaka S (2007) Generation of germline-competent induced pluripotent stem cells. Nature 448:313–317. https://doi.org/10.1038/nature05934
Pepper JP, Wang TV, Hennes V, Sun SY, Ichida JK (2017) Human induced pluripotent stem cell-derived motor neuron transplant for neuromuscular atrophy in a mouse model of sciatic nerve injury. JAMA Facial Plast Surg 19:197–205. https://doi.org/10.1001/jamafacial.2016.1544
Polak JM, Bishop AE (2006) Stem cells and tissue engineering: past, present, and future. Ann N Y Acad Sci 1068:352–366. https://doi.org/10.1196/annals.1346.001
Reid AJ et al (2011) Nerve repair with adipose-derived stem cells protects dorsal root ganglia neurons from apoptosis. Neuroscience 199:515–522. https://doi.org/10.1016/j.neuroscience.2011.09.064
Reynolds AJ, Jahoda CAB (2004) Cultured human and rat tooth papilla cells induce hair follicle regeneration and fiber growth. Differentiation 72:566–575. https://doi.org/10.1111/j.1432-0436.2004.07209010.x
Rodrigues MCO, Rodrigues AA, Glover LE, Voltarelli J, Borlongan CV (2012) Peripheral nerve repair with cultured Schwann cells: getting closer to the clinics. Sci World J:Artn 413091. https://doi.org/10.1100/2012/413091
Santiago LY, Clavijo-Alvarez J, Brayfield C, Rubin JP, Marra KG (2009) Delivery of adipose-derived precursor cells for peripheral nerve repair. Cell Transplant 18:145–158. https://doi.org/10.3727/096368909788341289
Sieber-Blum M, Grim M, Hu YF, Szeder V (2004) Pluripotent neural crest stem cells in the adult hair follicle. Dev Dyn 231:258–269. https://doi.org/10.1002/dvdy.20129
Si-Tayeb K et al (2010) Generation of human induced pluripotent stem cells by simple transient transfection of plasmid DNA encoding reprogramming factors. BMC Dev Biol 10:Artn 81. https://doi.org/10.1186/1471-213x-10-81
Somers A et al (2010) Generation of transgene-free lung disease-specific human induced pluripotent stem cells using a single excisable lentiviral stem cell cassette. Stem Cells 28:1728–1740. https://doi.org/10.1002/stem.495
Sowa Y et al (2016) Adipose-derived stem cells promote peripheral nerve regeneration in vivo without differentiation into Schwann-Like lineage. Plast Reconstr Surg 137:318e–330e. https://doi.org/10.1097/01.prs.0000475762.86580.36
Spagnuolo G et al (2018) Commitment of oral-derived stem cells in dental and maxillofacial applications. Dent J (Basel) 6. https://doi.org/10.3390/dj6040072
Stadtfeld M, Brennand K, Hochedlinger K (2008a) Reprogramming of pancreatic beta cells into induced pluripotent stem cells. Curr Biol 18:890–894. https://doi.org/10.1016/j.cub.2008.05.010
Stadtfeld M, Nagaya M, Utikal J, Weir G, Hochedlinger K (2008b) Induced pluripotent stem cells generated without viral integration. Science 322:945–949. https://doi.org/10.1126/science.1162494
Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676. https://doi.org/10.1016/j.cell.2006.07.024
Takahashi K 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
Tse KH, Novikov LN, Wiberg M, Kingham PJ (2015) Intrinsic mechanisms underlying the neurotrophic activity of adipose derived stem cells. Exp Cell Res 331:142–151. https://doi.org/10.1016/j.yexcr.2014.08.034
Tsuji O et al (2010) Therapeutic potential of appropriately evaluated safe-induced pluripotent stem cells for spinal cord injury. Proc Natl Acad Sci USA 107:12704–12709. https://doi.org/10.1073/pnas.0910106107
Uemura T et al (2012) Transplantation of induced pluripotent stem cell-derived neurospheres for peripheral nerve repair. Biochem Bioph Res Co 419:130–135. https://doi.org/10.1016/j.bbrc.2012.01.154
Ullah I et al (2016) In vitro comparative analysis of human dental stem cells from a single donor and its neuronal differentiation potential evaluated by electrophysiology. Life Sci 154:39–51. https://doi.org/10.1016/j.lfs.2016.04.026
Wang AJ et al (2011) Induced pluripotent stem cells for neural tissue engineering. Biomaterials 32:5023–5032. https://doi.org/10.1016/j.biomaterials.2011.03.070
Wang Y, Li ZW, Luo M, Li YJ, Zhang KQ (2015) Biological conduits combining bone marrow mesenchymal stem cells and extracellular matrix to treat long-segment sciatic nerve defects. Neural Regen Res 10:965–971. https://doi.org/10.4103/1673-5374.158362
Woo DH, Hwang HS, Shim JH (2016) Comparison of adult stem cells derived from multiple stem cell niches. Biotechnol Lett 38:751–759. https://doi.org/10.1007/s10529-016-2050-2
Woodbury D, Schwarz EJ, Prockop DJ, Black IB (2000) Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res 61:364–370. https://doi.org/10.1002/1097-4547(20000815)61:4<364::Aid-Jnr2>3.0.Co;2-C
Xu HY et al (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112:1821–1830. https://doi.org/10.1172/Jci200319451
Xu YF et al (2008) Myelin-forming ability of Schwann cell-like cells induced from rat adipose-derived stem cells in vitro. Brain Res 1239:49–55. https://doi.org/10.1016/j.brainres.2008.08.088
Xu D et al (2009) Phenotypic correction of murine hemophilia A using an iPS cell-based therapy. Proc Natl Acad Sci USA 106:808–813. https://doi.org/10.1073/pnas.0812090106
Yamanaka S (2020) Pluripotent stem cell-based cell therapy-promise and challenges. Cell Stem Cell 27:523–531. https://doi.org/10.1016/j.stem.2020.09.014
Yamazaki A et al (2017) Implanted hair-follicle-associated pluripotent (HAP) stem cells encapsulated in polyvinylidene fluoride membrane cylinders promote effective recovery of peripheral nerve injury. Cell Cycle 16:1927–1932. https://doi.org/10.1080/15384101.2017.1363941
Yashiro M et al (2015) From hair to heart: nestin-expressing hair-follicle-associated pluripotent (HAP) stem cells differentiate to beating cardiac muscle cells. Cell Cycle 14:2362–2366. https://doi.org/10.1080/15384101.2015.1042633
Yoshida Y, Yamanaka S (2010) Recent stem cell advances: induced pluripotent stem cells for disease modeling and stem cell-based regeneration. Circulation 122:80–87. https://doi.org/10.1161/Circulationaha.109.881433
Yu JY et al (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917–1920. https://doi.org/10.1126/science.1151526
Zarbakhsh S et al (2012) The effects of Schwann and bone marrow stromal stem cells on sciatic nerve injury in rat: a comparison of functional recovery. Cell J 14:39–46
Zhou WB, Freed CR (2009) Adenoviral gene delivery can reprogram human fibroblasts to induced pluripotent stem cells. Stem Cells 27:2667–2674. https://doi.org/10.1002/stem.201
Zhou HY et al (2009) Generation of induced pluripotent stem cells using recombinant proteins (vol 4, pg 381, 2009). Cell Stem Cell 4:581–581. https://doi.org/10.1016/j.stem.2009.05.014
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This study was written based partly on works supported by the research program GINOP-2.3.2-15-2016-00036 (granted to A.N).
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Pajer, K., Nógrádi, A. (2021). Therapeutic Cells and Stem Cells for Nerve Regeneration. In: Phillips, J., Hercher, D., Hausner, T. (eds) Peripheral Nerve Tissue Engineering and Regeneration. Reference Series in Biomedical Engineering(). Springer, Cham. https://doi.org/10.1007/978-3-030-06217-0_7-1
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