Peripheral nerve injury is a relatively commonly occurring trauma which seriously compromises the quality of life for many individuals. There is a major need to devise new treatment strategies, and one possible approach is to develop cellular therapies to bioengineer new nerve tissue and/or modulate the endogenous regenerative mechanisms within the peripheral nervous system. In this short review we describe how stem cells isolated from adipose tissue could be a suitable element of this approach. We describe the possible mechanisms through which the stem cells might exert a positive influence on peripheral nerve regeneration. These include their ability to differentiate into cells resembling Schwann cells and their secretion of a plethora of neurotrophic growth factors. We also review the literature describing the effects of these cells when tested using in vivo peripheral nerve injury models.

1.
Bell, J.H., J.W. Haycock (2012) Next generation nerve guides: materials, fabrication, growth factors, and cell delivery. Tissue Eng Part B Rev 18: 116-128.
2.
Bosse, F. (2012) Extrinsic cellular and molecular mediators of peripheral axonal regeneration. Cell Tissue Res 349: 5-14.
3.
Carlson, K.B., P. Singh, M.M. Feaster, A. Ramnarain, C. Pavlides, Z.L. Chen, W.M. Yu, M.L. Feltri, S. Strickland (2011) Mesenchymal stem cells facilitate axon sorting, myelination, and functional recovery in paralyzed mice deficient in Schwann cell-derived laminin. Glia 59: 267-277.
4.
Craff, M.N., J.L. Zeballos, T.S. Johnson, M.P. Ranka, R. Howard, P. Motarjem, M.A. Randolph, J.M. Winograd (2007) Embryonic stem cell-derived motor neurons preserve muscle after peripheral nerve injury. Plast Reconstr Surg 119: 235-245.
5.
Cui, L., J. Jiang, L. Wei, X. Zhou, J.L. Fraser, B.J. Snider, S.P. Yu (2008) Transplantation of embryonic stem cells improves nerve repair and functional recovery after severe sciatic nerve axotomy in rats. Stem Cells 26: 1356-1365.
6.
Dai, L.G., G.S. Huang, S.H. Hsu (2013) Sciatic nerve regeneration by cocultured Schwann cells and stem cells on microporous nerve conduits. Cell Transplant 22: 2029-2039.
7.
de Luca, A.C., A. Faroni, S. Downes, G. Terenghi (2013) 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, Epub ahead of print.
8.
di Summa, P.G., D.F. Kalbermatten, E. Pralong, W. Raffoul, P.J. Kingham, G. Terenghi (2011) Long-term in vivo regeneration of peripheral nerves through bioengineered nerve grafts. Neuroscience 181: 278-291.
9.
di Summa, P.G., D.F. Kalbermatten, W. Raffoul, G. Terenghi, P.J. Kingham (2013) Extracellular matrix molecules enhance the neurotrophic effect of Schwann cell-like differentiated adipose-derived stem cells and increase cell survival under stress conditions. Tissue Eng Part A 19: 368-379.
10.
di Summa, P.G., P.J. Kingham, W. Raffoul, M. Wiberg, G. Terenghi, D.F. Kalbermatten (2010) Adipose-derived stem cells enhance peripheral nerve regeneration. J Plast Reconstr Aesthet Surg 63: 1544-1552.
11.
Erba, P., C. Mantovani, D.F. Kalbermatten, G. Pierer, G. Terenghi, P.J. Kingham (2010a) Regeneration potential and survival of transplanted undifferentiated adipose tissue-derived stem cells in peripheral nerve conduits. J Plast Reconstr Aesthet Surg 63: e811-e817.
12.
Erba, P., G. Terenghi, P.J. Kingham (2010b) Neural differentiation and therapeutic potential of adipose tissue derived stem cells. Curr Stem Cell Res Ther 5: 153-160.
13.
Faroni, A., F. Calabrese, M.A. Riva, G. Terenghi, V. Magnaghi (2013a) Baclofen modulates the expression and release of neurotrophins in Schwann-like adipose stem cells. J Mol Neurosci 49: 233-243.
14.
Faroni, A., S.W. Rothwell, A.A. Grolla, G. Terenghi, V. Magnaghi, A. Verkhratsky (2013b) Differentiation of adipose-derived stem cells into Schwann cell phenotype induces expression of P2X receptors that control cell death. Cell Death Dis 4: e743.
15.
Fu, S.Y., T. Gordon (1995) Contributing factors to poor functional recovery after delayed nerve repair: prolonged axotomy. J Neurosci 15: 3876-3885.
16.
Gimble, J.M., B.A. Bunnell, T. Frazier, B. Rowan, F. Shah, C. Thomas-Porch, X. Wu (2013) Adipose-derived stromal/stem cells: a primer. Organogenesis 9: 3-10.
17.
Gordon, T., N. Tyreman, M.A. Raji (2011) The basis for diminished functional recovery after delayed peripheral nerve repair. J Neurosci 31: 5325-5334.
18.
Gu, J.H., Y.H. Ji, E.S. Dhong, D.H. Kim, E.S. Yoon (2012) Transplantation of adipose derived stem cells for peripheral nerve regeneration in sciatic nerve defects of the rat. Curr Stem Cell Res Ther 7: 347-355.
19.
Hobson, M.I., C.J. Green, G. Terenghi (2000) VEGF enhances intraneural angiogenesis and improves nerve regeneration after axotomy. J Anat 197: 591-605.
20.
Hsiao, S.T., A. Asgari, Z. Lokmic, R. Sinclair, G.J. Dusting, S.Y. Lim, R.J. Dilley (2012) Comparative analysis of paracrine factor expression in human adult mesenchymal stem cells derived from bone marrow, adipose, and dermal tissue. Stem Cells Dev 21: 2189-2203.
21.
Hsueh, Y.Y., Y.J. Chang, T.C. Huang, S.C. Fan, D.H. Wang, J.J. Chen, C.C. Wu, S.C. Lin (2014) Functional recoveries of sciatic nerve regeneration by combining chitosan-coated conduit and neurosphere cells induced from adipose-derived stem cells. Biomaterials 35: 2234-2244.
22.
Hundepool, C.A., T.H. Nijhuis, B. Mohseny, R.W. Selles, S.E. Hovius (2014) The effect of stem cells in bridging peripheral nerve defects: a meta-analysis. J Neurosurg 121: 195-209.
23.
Jiang, L., J.K. Zhu, X.L. Liu, P. Xiang, J. Hu, W.H. Yu (2008) Differentiation of rat adipose tissue-derived stem cells into Schwann-like cells in vitro. Neuroreport 19: 1015-1019.
24.
Jonsson, S., R. Wiberg, A.M. McGrath, L.N. Novikov, M. Wiberg, L.N. Novikova, P.J. Kingham (2013) Effect of delayed peripheral nerve repair on nerve regeneration, Schwann cell function and target muscle recovery. PLoS One 8: e56484.
25.
Kaewkhaw, R., A.M. Scutt, J.W. Haycock (2011) Anatomical site influences the differentiation of adipose-derived stem cells for Schwann-cell phenotype and function. Glia 59: 734-749.
26.
Kalbermatten, D.F., D. Schaakxs, P.J. Kingham, M. Wiberg (2011) Neurotrophic activity of human adipose stem cells isolated from deep and superficial layers of abdominal fat. Cell Tissue Res 344: 251-260.
27.
Kapur, S.K., A.J. Katz (2013) Review of the adipose derived stem cell secretome. Biochimie 95: 2222-2228.
28.
Kingham, P.J., D.F. Kalbermatten, D. Mahay, S.J. Armstrong, M. Wiberg, G. Terenghi (2007) Adipose-derived stem cells differentiate into a Schwann cell phenotype and promote neurite outgrowth in vitro. Exp Neurol 207: 267-274.
29.
Kingham, P.J., M.K. Kolar, L.N. Novikova, L.N. Novikov, M. Wiberg (2014) Stimulating the neurotrophic and angiogenic properties of human adipose-derived stem cells enhances nerve repair. Stem Cells Dev 23: 741-754.
30.
Kosacka, J., M. Nowicki, J. Kacza, J. Borlak, J. Engele, K. Spanel-Borowski (2006) Adipocyte-derived angiopoietin-1 supports neurite outgrowth and synaptogenesis of sensory neurons. J Neurosci Res 83: 1160-1169.
31.
Lattanzi, W., M.C. Geloso, N. Saulnier, S. Giannetti, M.A. Puglisi, V. Corvino, A. Gasbarrini, F. Michetti (2011) Neurotrophic features of human adipose tissue-derived stromal cells: in vitro and in vivo studies. J Biomed Biotechnol 2011: 468705.
32.
Liao, D., P. Gong, X. Li, Z. Tan, Q. Yuan (2010) Co-culture with Schwann cells is an effective way for adipose-derived stem cells neural transdifferentiation. Arch Med Sci 6: 145-151.
33.
Liu, Y., Z. Zhang, Y. Qin, H. Wu, Q. Lv, X. Chen, W. Deng (2013) A new method for Schwann-like cell differentiation of adipose derived stem cells. Neurosci Lett 551: 79-83.
34.
Lopatina, T., S. Bruno, C. Tetta, N. Kalinina, M. Porta, G. Camussi (2014) Platelet-derived growth factor regulates the secretion of extracellular vesicles by adipose mesenchymal stem cells and enhances their angiogenic potential. Cell Commun Signal 12: 26.
35.
Lopatina, T., N. Kalinina, M. Karagyaur, D. Stambolsky, K. Rubina, A. Revischin, G. Pavlova, Y. Parfyonova, V. Tkachuk (2011) Adipose-derived stem cells stimulate regeneration of peripheral nerves: BDNF secreted by these cells promotes nerve healing and axon growth de novo. PLoS One 6: e17899.
36.
Lu, S., C. Lu, Q. Han, J. Li, Z. Du, L. Liao, R.C. Zhao (2011) Adipose-derived mesenchymal stem cells protect PC12 cells from glutamate excitotoxicity-induced apoptosis by upregulation of XIAP through PI3-K/Akt activation. Toxicology 279: 189-195.
37.
Mantovani, C., D. Mahay, P.J. Kingham, G. Terenghi, S.G. Shawcross, M. Wiberg (2010) Bone marrow- and adipose-derived stem cells show expression of myelin mRNAs and proteins. Regen Med 5: 403-410.
38.
Marconi, S., G. Castiglione, E. Turano, G. Bissolotti, S. Angiari, A. Farinazzo, G. Constantin, G. Bedogni, A. Bedogni, B. Bonetti (2012) Human adipose-derived mesenchymal stem cells systemically injected promote peripheral nerve regeneration in the mouse model of sciatic crush. Tissue Eng Part A 18: 1264-1272.
39.
Mohammadi, R., S. Azizi, K. Amini (2013) Effects of undifferentiated cultured omental adipose-derived stem cells on peripheral nerve regeneration. J Surg Res 180: e91-e97.
40.
Mohammadi, R., S. Azizi, N. Delirezh, R. Hobbenaghi, K. Amini (2011) Comparison of beneficial effects of undifferentiated cultured bone marrow stromal cells and omental adipose-derived nucleated cell fractions on sciatic nerve regeneration. Muscle Nerve 43: 157-163.
41.
Moriyama, M., H. Moriyama, A. Ueda, Y. Nishibata, H. Okura, A. Ichinose, A. Matsuyama, T. Hayakawa (2012) Human adipose tissue-derived multilineage progenitor cells exposed to oxidative stress induce neurite outgrowth in PC12 cells through p38 MAPK signaling. BMC Cell Biol 13: 21.
42.
Oliveira, J.T., K. Mostacada, S. de Lima, A.M. Martinez (2013) Bone marrow mesenchymal stem cell transplantation for improving nerve regeneration. Int Rev Neurobiol 108: 59-77.
43.
Radtke, C., B. Schmitz, M. Spies, J.D. Kocsis, P.M. Vogt (2009) Peripheral glial cell differentiation from neurospheres derived from adipose mesenchymal stem cells. Int J Dev Neurosci 27: 817-823.
44.
Raisi, A., S. Azizi, N. Delirezh, B. Heshmatian, A.A. Farshid, K. Amini (2014) The mesenchymal stem cell-derived microvesicles enhance sciatic nerve regeneration in rat: a novel approach in peripheral nerve cell therapy. J Trauma Acute Care Surg 76: 991-997.
45.
Razavi, S., M. Mardani, M. Kazemi, E. Esfandiari, M. Narimani, A. Esmaeili, N. Ahmadi (2013) Effect of leukemia inhibitory factor on the myelinogenic ability of Schwann-like cells induced from human adipose-derived stem cells. Cell Mol Neurobiol 33: 283-289.
46.
Reid, A.J., M. Sun, M. Wiberg, S. Downes, G. Terenghi, P.J. Kingham (2011) Nerve repair with adipose-derived stem cells protects dorsal root ganglia neurons from apoptosis. Neuroscience 199: 515-522.
47.
Ribeiro, C.A., J.S. Fraga, M. Graos, N.M. Neves, R.L. Reis, J.M. Gimble, N. Sousa, A.J. Salgado (2012) The secretome of stem cells isolated from the adipose tissue and Wharton jelly acts differently on central nervous system derived cell populations. Stem Cell Res Ther 3: 18.
48.
Rodrigues, M.C., A.A. Rodrigues Jr., L.E. Glover, J. Voltarelli, C.V. Borlongan (2012) Peripheral nerve repair with cultured Schwann cells: getting closer to the clinics. ScientificWorldJournal 2012: 413091.
49.
Scheib, J., A. Höke (2013) Advances in peripheral nerve regeneration. Nat Rev Neurol 9: 668-676.
50.
Scholz, T., A. Sumarto, A. Krichevsky, G.R. Evans (2011) Neuronal differentiation of human adipose tissue-derived stem cells for peripheral nerve regeneration in vivo. Arch Surg 146: 666-674.
51.
Strem, B.M., K.C. Hicok, M. Zhu, I. Wulur, Z. Alfonso, R.E. Schreiber, J.K. Fraser, M.H. Hedrick (2005) Multipotential differentiation of adipose tissue-derived stem cells. Keio J Med 54: 132-141.
52.
Sun, F., K. Zhou, W.J. Mi, J.H. Qiu (2011) Combined use of decellularized allogeneic artery conduits with autologous transdifferentiated adipose-derived stem cells for facial nerve regeneration in rats. Biomaterials 32: 8118-8128.
53.
Sun, D., X. Zhuang, S. Zhang, Z.B. Deng, W. Grizzle, D. Miller, H.G. Zhang (2013) Exosomes are endogenous nanoparticles that can deliver biological information between cells. Adv Drug Deliv Rev 65: 342-347.
54.
Tan, B., Z. Luan, X. Wei, Y. He, G. Wei, B.H. Johnstone, M. Farlow, Y. Du (2011) AMP-activated kinase mediates adipose stem cell-stimulated neuritogenesis of PC12 cells. Neuroscience 181: 40-47.
55.
Terenghi, G., A. Hart, M. Wiberg (2011) The nerve injury and the dying neurons: diagnosis and prevention. J. Hand Surg Eur Vol 36: 730-734.
56.
Tomita, K., T. Madura, C. Mantovani, G. Terenghi (2012) Differentiated adipose-derived stem cells promote myelination and enhance functional recovery in a rat model of chronic denervation. J Neurosci Res 90: 1392-1402.
57.
Tomita, K., T. Madura, Y. Sakai, K. Yano, G. Terenghi, K. Hosokawa (2013) Glial differentiation of human adipose-derived stem cells: implications for cell-based transplantation therapy. Neuroscience 236: 55-65.
58.
Tremp, M., S.M. Meyer Zu Schwabedissen, E.A. Kappos, P.E. Engels, A. Fischmann, A. Scherberich, D.J. Schaefer, D.F. Kalbermatten (2013) The regeneration potential after human and autologous stem cell transplantation in a rat sciatic nerve injury model can be monitored by MRI. Cell Transplant, Epub ahead of print.
59.
Tse, K.H., M. Sun, C. Mantovani, G. Terenghi, S. Downes, P.J. Kingham (2010) In vitro evaluation of polyester-based scaffolds seeded with adipose derived stem cells for peripheral nerve regeneration. J Biomed Mater Res A 95: 701-708.
60.
Wang, Y., Z. Zhao, Z. Ren, B. Zhao, L. Zhang, J. Chen, W. Xu, S. Lu, Q. Zhao, J. Peng (2012) Recellularized nerve allografts with differentiated mesenchymal stem cells promote peripheral nerve regeneration. Neurosci Lett 514: 96-101.
61.
Wei, Y., K. Gong, Z. Zheng, L. Liu, A. Wang, L. Zhang, Q. Ao, Y. Gong, X. Zhang (2010) Schwann-like cell differentiation of rat adipose-derived stem cells by indirect co-culture with Schwann cells in vitro. Cell Prolif 43: 606-616.
62.
Welin, D., L.N. Novikova, M. Wiberg, J.O. Kellerth, L.N. Novikov (2008) Survival and regeneration of cutaneous and muscular afferent neurons after peripheral nerve injury in adult rats. Exp Brain Res 186: 315-323.
63.
Xu, W., C.S. Cox, Y. Li (2011) Induced pluripotent stem cells for peripheral nerve regeneration. J Stem Cells 6: 39-49.
64.
Xu, Y., L. Liu, Y. Li, C. Zhou, F. Xiong, Z. Liu, R. Gu, X. Hou, C. Zhang (2008a) Myelin-forming ability of Schwann cell-like cells induced from rat adipose-derived stem cells in vitro. Brain Res 1239: 49-55.
65.
Xu, Y., Z. Liu, L. Liu, C. Zhao, F. Xiong, C. Zhou, Y. Li, Y. Shan, F. Peng, C. Zhang (2008b) Neurospheres from rat adipose-derived stem cells could be induced into functional Schwann cell-like cells in vitro. BMC Neurosci 9: 21.
66.
Zavan, B., L. Michelotto, L. Lancerotto, P.A. Della, D. D'Avella, G. Abatangelo, V. Vindigni, R. Cortivo (2010) Neural potential of a stem cell population in the adipose and cutaneous tissues. Neurol Res 32: 47-54.
67.
Zhang, H., R. Yang, Z. Wang, G. Lin, T.F. Lue, C.S. Lin (2011) Adipose tissue-derived stem cells secrete CXCL5 cytokine with neurotrophic effects on cavernous nerve regeneration. J Sex Med 8: 437-446.
68.
Zhang, Y., H. Luo, Z. Zhang, Y. Lu, X. Huang, L. Yang, J. Xu, W. Yang, X. Fan, B. Du, P. Gao, G. Hu, Y. Jin (2010) A nerve graft constructed with xenogeneic acellular nerve matrix and autologous adipose-derived mesenchymal stem cells. Biomaterials 31: 5312-5324.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.