Advertisement

Mesenchymal and Adipose Stem Cell Strategies for Peripheral Nerve Regeneration

Chapter
Part of the Stem Cell Biology and Regenerative Medicine book series (STEMCELL)

Abstract

Peripheral nerve injury (PNI) is a common sequela of soft tissue and bony trauma. The morbidity and loss of function secondary to PNI significantly limit patient quality of life. Strategies that restore or augment nerve regeneration and enable motor/sensory recovery after injury can help patients to return to functional/employable status while improving performance, morale, mobility, agility and capability. Suboptimal nerve regeneration after reconstructive transplantation remains one of the key obstacles to functional outcomes. Distal denervated muscles have impaired/no function and will undergo denervation atrophy if the nerves do not reach the motor end plates in time. Several drugs/biologics/growth factors (tacrolimus, chondroitinase, insulin-like growth factor-1, IGF1) as well as cellular therapies (Schwann cells (SC), mesenchymal stromal cells (MSC) of adipose, or bone marrow origin) have shown promise and potential in enhancing nerve regeneration via different mechanisms and distinct biochemical pathways. Combinations of these treatments may also provide an additive or even synergistic effect on the neuroregenerative process. Undifferentiated MSCs have inherent advantages over SCs or other cell types. These include higher yield, superior expansion characteristics and innate self-renewal, angiogeneic and immunomodulatory properties. Here in, we focus on the current experimental evidence for MSCs as promising potential therapies in accelerating or maximizing peripheral nerve regeneration and subsequent functional outcomes in reconstructive transplant indications.

Keywords

Adipose-derived stem cells Axon Functional outcome Gene transfection Mesenchymal stem cells Nerve conduit Nerve regeneration Peripheral nerve injury Schwann cells Wallerian degeneration 

References

  1. 1.
    Thorsen F, et al. Digital nerve injuries: epidemiology, results, costs, and impact on daily life. J Plast Surg H and Surg. 2012;46(3–4):184–90.Google Scholar
  2. 2.
    Taylor CA, et al. The incidence of peripheral nerve injury in extremity trauma. Am J Phys Med Rehabil. 2008;87(5):381–5.Google Scholar
  3. 3.
    Gaudet AD, Popovich PG, Ramer MS. Wallerian degeneration: gaining perspective on inflammatory events after peripheral nerve injury. J Neuroinflammation. 2011;8:110.Google Scholar
  4. 4.
    Rotshenker S. Wallerian degeneration: the innate-immune response to traumatic nerve injury. J Neuroinflammation. 2011;8:109.Google Scholar
  5. 5.
    Hoke A. Mechanisms of disease: what factors limit the success of peripheral nerve regeneration in humans? Nat Clin Pract Neurol. 2006;2(8):448–54.Google Scholar
  6. 6.
    Allodi I, Udina E, Navarro X. Navarro, Specificity of peripheral nerve regeneration: interactions at the axon level. Prog Neurobiol. 2012;98(1):16–37.Google Scholar
  7. 7.
    Bosse F. Extrinsic cellular and molecular mediators of peripheral axonal regeneration. Cell Tissue Res. 2012;349(1):5–14.Google Scholar
  8. 8.
    Keilhoff G, et al. Peripheral nerve tissue engineering: autologous Schwann cells vs. transdifferentiated mesenchymal stem cells. Tissue Eng. 2006;12(6):1451–65.Google Scholar
  9. 9.
    Kingham PJ, et al. Adipose-derived stem cells differentiate into a Schwann cell phenotype and promote neurite outgrowth in vitro. Exp Neurol. 2007;207(2):267–74.Google Scholar
  10. 10.
    di Summa PG, et al. Adipose-derived stem cells enhance peripheral nerve regeneration. J Plast Reconstr Aesthet Surg. 2010;63(9):1544–52.Google Scholar
  11. 11.
    Erba P, et al. Regeneration potential and survival of transplanted undifferentiated adipose tissue-derived stem cells in peripheral nerve conduits. J Plast Reconstr Aesthet Surg. 2010;63(12):e811–7.Google Scholar
  12. 12.
    Zheng L, Cui HF. Cui, Use of chitosan conduit combined with bone marrow mesenchymal stem cells for promoting peripheral nerve regeneration. J Mater Sci Mater Med. 2010;21(5):1713–20.Google Scholar
  13. 13.
    Sun F, et al. Repair of facial nerve defects with decellularized artery allografts containing autologous adipose-derived stem cells in a rat model. Neurosci Lett. 2011;499(2):104–8.Google Scholar
  14. 14.
    Yang Y, et al. Repair of rat sciatic nerve gap by a silk fibroin-based scaffold added with bone marrow mesenchymal stem cells. Tissue Eng Part A. 2011;17(17–18):2231–44.Google Scholar
  15. 15.
    Bain JR, et al. The peripheral nerve allograft: an assessment of regeneration across nerve allografts in rats immunosuppressed with cyclosporin A. Plast Reconstr Surg. 1988;82(6):1052–66.Google Scholar
  16. 16.
    Lukaszuk M, et al. Repair of the peripheral nerve gap with epineural sheath conduit to prevent muscle denervation atrophy in the diabetic rat model. Pol Przegl Chir. 2013;85(7):387–94.Google Scholar
  17. 17.
    Lin YC, Oh SJ, Marra KG. Synergistic lithium chloride and glial cell line-derived neurotrophic factor delivery for peripheral nerve repair in a rodent sciatic nerve injury model. Plast Reconstr Surg. 2013;132(2):251e–62e.Google Scholar
  18. 18.
    Wang S, et al. Acceleration effect of basic fibroblast growth factor on the regeneration of peripheral nerve through a 15-mm gap. J Biomed Mater Res A. 2003;66(3):522–31.Google Scholar
  19. 19.
    Ohta M, et al. Novel heparin/alginate gel combined with basic fibroblast growth factor promotes nerve regeneration in rat sciatic nerve. J Biomed Mater Res A. 2004;71(4):661–8.Google Scholar
  20. 20.
    Pierucci A, de Duek EA, de Oliveira AL. Peripheral nerve regeneration through biodegradable conduits prepared using solvent evaporation. Tissue Eng Part A. 2008;14(5):595–606.Google Scholar
  21. 21.
    Guenard V, Kleitman N, Morrissey TK, Bunge RP, Aebischer PJ. Syngeneic Schwann cells derived from adult nerves seeded in semipermeable guidance channels enhance peripheral nerve regeneration. Neurosci. 1992;12:3310–20Google Scholar
  22. 22.
    Mosahebi A, Woodward B, Wiberg M, Martin R, Terenghi G. Retroviral labeling of Schwann cells: in vitro characterization and in vivo transplantation to improve peripheral nerve regeneration. Glia. 2001;34:8–17.Google Scholar
  23. 23.
    Rodriguez FJ, Verdu E, Ceballos D, Navarro X. Nerve guides seeded with autologous schwann cells improve nerve regeneration. Exp Neurol. 2000;161:571–84.Google Scholar
  24. 24.
    Azizi SA, Stokes D, Augelli BJ, DiGirolamo C, Prockop DJ. Engraftment and migration of human bone marrow stromal cells implanted in the brains of albino rats–similarities to astrocyte grafts. Proc Natl Acad Sci U S A 1998;95:3908–13.Google Scholar
  25. 25.
    da Silva Meirelles L, Chagastelles PC, Nardi NB. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci. 2006;119(Pt 11):2204–13.Google Scholar
  26. 26.
    Strem BM, et al. Multipotential differentiation of adipose tissue-derived stem cells. Keio J Med. 2005;54(3):132–41.Google Scholar
  27. 27.
    Till JE, McCulloch EA. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Rad Res. 1961;14:213–22.Google Scholar
  28. 28.
    Loeffler M, Potten CS. Stem cells and cellular pedigrees: a conceptual introduction. In: Potten CS, editor. Stem Cells. London: Academic; 1997. pp. 1–27.Google Scholar
  29. 29.
    Marshak DR, Gottlieb D, Gardner RL. Introduction: stem cell biology. In: Marshak DR, Gardner RL, Gottlieb D, Editors. Stem Cell Biology. Cold Spring Harbor: Cold Spring Harbor Laboratory; 2001. pp. 1–16.Google Scholar
  30. 30.
    Thomas ED. Frontiers in bone marrow transplantation. Blood Cells. 1991;17:259–67.Google Scholar
  31. 31.
    Thompson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshal VS, Jones JM. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282:1145–47.Google Scholar
  32. 32.
    McLaren A. Ethical and social considerations of stem cell research. Nature. 2000;414:129–31.Google Scholar
  33. 33.
    Shapiro HT. Ethical dilemmas and stem cell research. Science. 1999;285:2065.Google Scholar
  34. 34.
    Toma JG, Akhaven M, Fernandes KJ. Isolation of multipotent adult stem cells from the dermis of mammalian skin. Nat Cell Biol. 2001;3:778–84.Google Scholar
  35. 35.
    Donovan PJ, Gearhart J. The end of the beginning for pluripotent stem cells. Nature. 2001;414:92–7.Google Scholar
  36. 36.
    Vogel G. Stem cell policy. Can adult stem cells suffice? Science. 2001;292:1820–22.Google Scholar
  37. 37.
    Sherley JL, Stadler PB, Johnson DR. Expression of the wild-type p53 antioncogene induces guanine nucleotide-dependent stem cell division kinetics. Proc Natl Acad Sci U S A. 1995:92(1):136–40.Google Scholar
  38. 38.
    Cheng T, Rodrigues N, Shen H. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science. 2000;287(5459):1804–8.Google Scholar
  39. 39.
    Potten CS, Loeffler M. Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt. Development. 1990;110:1001–20.Google Scholar
  40. 40.
    Fuchs E, Segre JA. Stem cells: a new lease on life. Cell. 2000;100:143–55.Google Scholar
  41. 41.
    Henderson ST, Gao D, Lambie EJ, Kimble J. lag-2 may encode a signaling ligand for the GLP-1 and LIN-12 receptors of C. elegans. Development. 1994;120(10):2913–24.Google Scholar
  42. 42.
    Kopan R, Nye JS, Weintraub H. The intracellular domain of mouse Notch: a constitutively activated repressor of myogenesis directed at the basic helix-loop-helix region of MyoD. Development. 1994;120(9):2385–96.Google Scholar
  43. 43.
    Reynolds BA, Weiss S. Clonal and population analyses demonstrate that an EGF-responsive mammalian embryonic CNS precursor is a stem cell. Dev Biol. 1996;175:1–13.Google Scholar
  44. 44.
    Gritti A, Parati EA, Cova L, Frolichsthal P, Galli R, Wanke E, Faravelli L, Morassutti DJ, Roisen F, Nickel DD, Vescovi AL. Multipotential stem cells from the adult mouse brain proliferate and self-renew in response to basic fibroblast growth factor. J Neurosci. 1996;16(3):1091–100.Google Scholar
  45. 45.
    Shah NM, Marchionni MA, Stroobant P, Anderson DJ. Glial growth factor restricts mammalian neural crest stem cells to a glial fate. Cell. 1994;77(3):349–60.Google Scholar
  46. 46.
    Shah NM, Groves A, Anderson DJ. Alternative neural crest cell fates are instructively promoted by TGFbeta superfamily members. Cell. 1996;85(3):331–43.Google Scholar
  47. 47.
    Quesenberry PJ, Becker PS. Stem cell homing: rolling, crawling, and nesting. Proc Natl Acad Sci U S A 1998;95(26):15155–157.Google Scholar
  48. 48.
    Jensen UB, Lowell S, Watt FM. The spatial relationship between stem cells and their progeny in the basal layer of human epidermis: a new view based on whole-mount labelling and lineage analysis. Development. 1999;126(11):2409–18.Google Scholar
  49. 49.
    Morrison SJ, Prowse KR, Ho P, Weissman IL. Telomerase activity in hematopoietic cells is associated with self-renewal potential. Immunity. 1996;5(3):207–16.Google Scholar
  50. 50.
    Seydoux G, Mello CC, Pettitt J, Wood WB, Priess JR, Fire A. Repression of gene expression in the embryonic germ lineage of C. Nature. 1996;382(6593):713–6.Google Scholar
  51. 51.
    Morrison SJ, Shah NM, Anderson DJ. Regulatory mechanisms in stem cell biology. Cell. 1997;88(3):287–98.Google Scholar
  52. 52.
    Sherley JL. Asymmetric cell kinetics genes: the key to expansion of adult stem cells in culture. Stem Cells. 2002;20:561–72.Google Scholar
  53. 53.
    Ikebuchi K, Clark SC, Ihle JN, Souza LM, Ogawa M. Granulocyte colony-stimulating factor enhances interleukin 3-dependent proliferation of multipotential hemopoietic progenitors. Proc Natl Acad Sci U S A 1988;85(10):3445–51.Google Scholar
  54. 54.
    Leary AG, Ikebuchi K, Hirai Y, Wong GG, Yang YC, Clark SC, Ogawa M. Synergism between interleukin-6 and interleukin-3 in supporting proliferation of human hematopoietic stem cells: comparison with interleukin-1 alpha. Blood. 1988;71(6):1759–65.Google Scholar
  55. 55.
    Verfaillie C, McGlave P. Leukemia inhibitory factor/human interleukin for DA cells: a growth factor that stimulates the in vitro development of multipotential human hematopoietic progenitors. Blood. 1991;77(2):263–70.Google Scholar
  56. 56.
    Szynkaruk M, Kemp SWP, Wood MMD, Gordon T, Borschel GH. Experimental and clinical evidence for use of decellularized nerve allografts in peripheral nerve gap reconstruction. Tissue Eng Part B: Rev. 2013;19(1):83–96.Google Scholar
  57. 57.
    Jia H, Wang Y, Tong X, Liu G, Li Q, Zhang L, Sun X. Sciatic nerve repair by acellular nerve xenografts implanted with BMSCs in rats xenograft combined with BMSCs. Synapse. 2012;66(3):256–69Google Scholar
  58. 58.
    Murakami T, Fujimoto Y, Yasunaga Y, et al. Transplanted neuronal progenitor cells in a peripheral nerve gap promote nerve repair. Brain Res. 2003;974(1–2):17–24.Google Scholar
  59. 59.
    Chen CJ, Ou YC, Liao SL, et al. Transplantation of bone marrow stromal cells for peripheral nerve repair. Exp Neurol. 2007;204(1):443–53.Google Scholar
  60. 60.
    Dezawa M, Takahashi I, Esaki M, et al. Sciatic nerve regeneration in rats induced by transplantation of in vitro differentiated bone-marrow stromal cells. Eur J Neurosci. 2001;14(11):1771–76.Google Scholar
  61. 61.
    Hu J, Zhu QT, Liu XL, et al. Repair of extended peripheral nerve lesions in rhesus monkeys using acellular allogenic nerve grafts implanted with autologous mesenchymal stem cells. Exp Neurol. 2007;204(2):658–66.Google Scholar
  62. 62.
    Keilhoff G, Stang F, Goihl A, et al. Transdifferentiated mesenchymal stem cells as alternative therapy in supporting nerve regeneration and myelination. Cell Mol Neurobiol. 2006;26(7– 8):1235–52.Google Scholar
  63. 63.
    Tohill M, Mantovani C, Wiberg M, et al. Rat bone marrow mesenchymal stem cells express glial markers and stimulate nerve regeneration. Neurosci Lett. 2004;362(3):200–3.Google Scholar
  64. 64.
    Vitry S, Bertrand JY, Cumano A, et al. Primordial hematopoietic stem cells generate microglia but not myelin-forming cells in a neural environment. J Neurosci. 2003;23(33):10724–31.Google Scholar
  65. 65.
    Hart AM, Brannstorm T, Wiberg M, Terenghi G. Primary sensory neurons and satellite cells after peripheral axotomy in the adult rat: timecourse of cell death and elimination. Exp Brain Res. 2002;142(3):308–18.Google Scholar
  66. 66.
    Le Douarin N. Glial cell lineages in the neural crest. Glia. 1991;4(2):175–84.Google Scholar
  67. 67.
    Murakami T, Fujimoto Y, Yasunaga Y, Ishida O, Tanaka N, Ikuta Y, Ochi M. Transplanted neuronal progenitor cells in a peripheral nerve gap promote nerve repair. Brain Res. 2003;974(1–2):17–24.Google Scholar
  68. 68.
    Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science. 1992;255(5052):1707–10.Google Scholar
  69. 69.
    Morrison SJ, White PM, Zock C, Anderson DJ. Cell. Prospective identification, isolation by flow cytometry, and in vivo self-renewal of multipotent mammalian neural crest stem cells. 1999;96(5):737–49.Google Scholar
  70. 70.
    Caplan AI. The mesengenic process. Clin Plastic Surg. 1994;21(3):429–35.Google Scholar
  71. 71.
    Verfaillie CM. Soluble factor(s) produced by human bone marrow stroma increase cytokine-induced proliferation and maturation of primitive hematopoietic progenitors while preventing their terminal differentiation. Blood. 1993;82(7):2045–53.Google Scholar
  72. 72.
    Bianco P, Riminucci M, Gronthos S, Gehron Robey P. Bone marrow stromal stem cells: nature, biology, and potential applications. Stem Cells. 2001;19(3):180–92.Google Scholar
  73. 73.
    Gronthos S, Simmons PJ. The growth factor requirements of STRO-1-positive human bone marrow stromal precursors under serum-deprived conditions in vitro. Blood. 1995;85(4):929–40.Google Scholar
  74. 74.
    Simmons PJ, Torok-Storb B. Identification of stromal cell precursors in human bone marrow by a novel monoclonal antibody, STRO-1. Blood. 1991;78(1):55–62.Google Scholar
  75. 75.
    Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143–7.Google Scholar
  76. 76.
    Muraglia A, Cancedda R, Quarto R. Clonal mesenchymal progenitors from human bone marrow differentiate in vitro according to a hierarchical model. J Cell Sci. 2000;113:1161–6.Google Scholar
  77. 77.
    Beresford JN, Bennett JH, Devlin C, Leboy PS, Owen ME. Evidence for an inverse relationship between the differentiation of adipocytic and osteogenic cells in rat marrow stromal cell cultures. J Cell Sci. 1992;102:341–51.Google Scholar
  78. 78.
    Gentili C, Bianco P, Neri M, Malpeli M, Campanile G, Castagnola P, Cancedda R, Cancedda FD. Cell proliferation, extracellular matrix mineralization, and ovotransferrin transient expression during in vitro differentiation of chick hypertrophic chondrocytes into osteoblast-like cells. J Cell Biol. 1993;122(3):703–12.Google Scholar
  79. 79.
    Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, Pickel J, McKay R, Nadal-Ginard B, Bodine BM, Leri A, Anversa P. Bone marrow cells regenerate infarcted myocardium. Nature. 2001;410(6829):701–5.Google Scholar
  80. 80.
    Lagasse E, Connors H, Al-Dhalimy M, Reitsma M, Dohse M, Osbourne L, Wang Z, Finegold M, Weissman IL, Grompe M. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nature. 2000;6(11):1229–34.Google Scholar
  81. 81.
    Ferrari G, Cusella-De Angelis G, Coletta M, Paolucci E, Storniuolo A, Cossu G, Mavilio F. Muscle regeneration by bone marrow-derived myogenic progenitors. Science. 1998;279(5356):1528–30.Google Scholar
  82. 82.
    Gojo S, Gojo N, Mori T, Abe H, Kyo S, Hata J, Umezawa A. In vivo cardiovasculogenesis by direct injection of isolated adult mesenchymal stem cells. Exp Cell Res. 2003;288(1):51–9.Google Scholar
  83. 83.
    Barbash IM, Chouraqui P, Baron J, Feinberg MS, Etzion S, Tessone A, Miller L, Guetta E, Zipori D, Kedes LH, Kloner RA, Leor J. Systemic delivery of bone marrow-derived mesenchymal stem cells to the infarcted myocardium: feasibility, cell migration, and body distribution. Circulation. 2003;108(7):863–8.Google Scholar
  84. 84.
    Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blakstad M, et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature. 2002;418(6893):41–9.Google Scholar
  85. 85.
    Kim BJ, Seo JH, Bubien JK, Young SO. Differentiation of adult bone marrow stem cells into neuroprogenitor cells in vitro. Neuroreport. 2002;13(9):1185–8.Google Scholar
  86. 86.
    Wislet-Gendebien S, Leprince P, Moonen G, Rogister B. Regulation of neural markers nestin and GFAP expression by cultivated bone marrow stromal cells. J Cell Sci. 2003;116(Pt 16): 3295–3302.Google Scholar
  87. 87.
    Dezawa M, Takahashi I, Esaki M, Takano M, Sawada H. Sciatic nerve regeneration in rats induced by transplantation of in vitro differentiated bone-marrow stromal cells. Eur J Neurosci. 2001;14(11):1771–6.Google Scholar
  88. 88.
    Kopen GC, Prockop DJ, Phinney DG.Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc Natl Acad Sci U S A 1999;96(19):10711–6.Google Scholar
  89. 89.
    Mezey E, Chandross KJ, Harta G, Maki RA, McKercher SR. Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science. 2000;290(5497):1779–82.Google Scholar
  90. 90.
    Akiyama Y, Radtke C, Honmou O, Kocsis JD. Remyelination of the spinal cord following intravenous delivery of bone marrow cells. Glia. 2002;39(3):229–36.Google Scholar
  91. 91.
    Hofstetter CP, Schwarz EJ, Hess D, Widenfalk J, El Manira A, Prockop DJ, Olson L. Marrow stromal cells form guiding strands in the injured spinal cord and promote recovery. Proc Natl Acad Sci U S A 2002;99(4):2199–2204.Google Scholar
  92. 92.
    Parekkadan B, Milwid JM. Mesenchymal stem cells as therapeutics. Annu Rev Biomed Eng. 2010;12:87–117.Google Scholar
  93. 93.
    Ugarte DA, et al. Differential expression of stem cell mobilization-associated molecules on multi-lineage cells from adipose tissue and bone marrow. Immunol Lett. 2003;89(2–3):267–70.Google Scholar
  94. 94.
    Ugarte DA, et al. Comparison of multi-lineage cells from human adipose tissue and bone marrow. Cells Tissues Organs. 2003;174(3):101–9.Google Scholar
  95. 95.
    Mantovani C, et al. Morphological, molecular and functional differences of adult bone marrow- and adipose-derived stem cells isolated from rats of different ages. Exp Cell Res. 2012;318(16):2034–48.Google Scholar
  96. 96.
    Im GI, Shin YW, Lee KB. Do adipose tissue-derived mesenchymal stem cells have the same osteogenic and chondrogenic potential as bone marrow-derived cells? Osteoarthritis Cartilage. 2005;13(10):845–53.Google Scholar
  97. 97.
    Boxall SA, Jones E. Markers for characterization of bone marrow multipotential stromal cells Stem Cells Int. 2012;2012:975871.Google Scholar
  98. 98.
    Caplan AI. Review: mesenchymal stem cells: cell-based reconstructive therapy in orthopedics. Review: Tissue Eng. 2005;11(7–8):1198–211.Google Scholar
  99. 99.
    Caplan AI, Correa D. The MSC: an injury drugstore. Cell stem cell. 2011;9(1):11–5.Google Scholar
  100. 100.
    Griffin MD, et al. Adult mesenchymal stromal cell therapy for inflammatory diseases: how well are we joining the dots? Stem Cells. 2013.Google Scholar
  101. 101.
    Min JY, et al. Significant improvement of heart function by cotransplantation of human mesenchymal stem cells and fetal cardiomyocytes in postinfarcted pigs. Ann Thorac Surg. 2002;74(5):1568–75.Google Scholar
  102. 102.
    Tateishi-Yuyama E, et al. Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet. 2002;360(9331):427–35.Google Scholar
  103. 103.
    Dabiri G, Heiner D, Falanga V. The emerging use of bone marrow-derived mesenchymal stem cells in the treatment of human chronic wounds. Expert Opin Emerg Drugs. 2013;18(4):405–19.Google Scholar
  104. 104.
    Caplan AI. Adult mesenchymal stem cells for tissue engineering versus regenerative medicine. J Cellular Physiol. 2007;213(2):341–7.Google Scholar
  105. 105.
    Kern S, et al. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells. 2006;24(5):1294–301.Google Scholar
  106. 106.
    Lee RH, et al. Characterization and expression analysis of mesenchymal stem cells from human bone marrow and adipose tissue. Cell Physiol Biochem. 2004;14(4–6):311–24.Google Scholar
  107. 107.
    James AW, et al. An abundant perivascular source of stem cells for bone tissue engineering. Stem Cells Transl Med. 2012;1(9):673–84.Google Scholar
  108. 108.
    Rombouts WJ, Ploemacher RE. Primary murine MSC show highly efficient homing to the bone marrow but lose homing ability following culture. Leukemia. 2003;17(1):160–70.Google Scholar
  109. 109.
    Dmitrieva RI, et al. Bone marrow- and subcutaneous adipose tissue-derived mesenchymal stem cells: differences and similarities. Cell Cycle. 2012;11(2):377–83.Google Scholar
  110. 110.
    Al-Nbaheen M, et al. Human stromal (mesenchymal) stem cells from bone marrow, adipose tissue and skin exhibit differences in molecular phenotype and differentiation potential. Stem Cell Rev. 2013;9(1):32–43.Google Scholar
  111. 111.
    Bayati V, et al. Expression of surface markers and myogenic potential of rat bone marrow- and adipose-derived stem cells: a comparative study. Anat Cell Biol. 2013;46(2):113–21.Google Scholar
  112. 112.
    De Ugarte DA, et al. Differential expression of stem cell mobilization-associated molecules on multi-lineage cells from adipose tissue and bone marrow. Immunol Lett. 2003;89(2–3):267–70.Google Scholar
  113. 113.
    Tohill M, et al. Rat bone marrow mesenchymal stem cells express glial markers and stimulate nerve regeneration. Neurosci Lett. 2004;362(3):200–3.Google Scholar
  114. 114.
    Dezawa M, et al. Sciatic nerve regeneration in rats induced by transplantation of in vitrodifferentiated bone-marrow stromal cells. Eur J Neurosci. 2001;14(11):1771–6.Google Scholar
  115. 115.
    Dezawa M, Takahashi I, Esaki M, Takano M, Sawada H. Sciatic nerve regeneration in ratsinduced by transplantation of in vitro differentiated bone-marrow stromal cells. Eur J Neurosci.2001;14(11):1771–6.Google Scholar
  116. 116.
    Cuevas P, Carceller F, Dujovny M, Garcia-Gomez I, Cuevas B, Gonzalez-Corrochan R,Diaz-Gonzalez D, Reimers D. Peripheral nerve regeneration by bone marrow stromal cells.Neurolog Res. 2002;24(7):634–8.Google Scholar
  117. 117.
    Mahanthappa NK, Anton ES, Matthew WD. Glial growth factor 2, a soluble neuregulin, directly increases Schwann cell motility and indirectly promotes neurite outgrowth. J Neurosci. 1996;16(15):4673–83.Google Scholar
  118. 118.
    Bartholomew A. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Haematol. 2002;30(1):42–8.Google Scholar
  119. 119.
    Saito T, Kuang JQ, Bittra B, Al-Khaldi A, Chin RC. Xenotransplant cardiac chimera: immune tolerance of adult stem cells. Ann Thorac Surg. 2002;74(1):19–24.Google Scholar
  120. 120.
    Deans RJ, Moseley AB. Mesenchymal stem cells: biology and potential clinical uses. Exp Haematol. 2000;28(8):875–84.Google Scholar
  121. 121.
    Tse WT, Pendleton D, Beyer W, D'Andrea A, Guinan EC. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation. 2003;75(3):389–97.Google Scholar
  122. 122.
    Hori J, Ng TF, Shatos M, Klassen H, Streilein JW, Young MJ. Neural progenitor cells lack immunogenicity and resist destruction as allografts. Stem Cells. 2003;21(4):405–16.Google Scholar
  123. 123.
    Rifle G, Mousson C. Donor-derived hematopoietic cells in organ transplantation: a major step toward allograft tolerance? Transplantation. 2003;75(9 Suppl):3S–7S.Google Scholar
  124. 124.
    Wekerle T, Blaha P, Koporc Z, Bigenzahn S, Pusch M, Muehlbacher F. Mechanisms of tolerance induction through the transplantation of donor hematopoietic stem cells: central versus peripheral tolerance. Transplantation. 2003;75(9 Suppl):21S–5S.Google Scholar
  125. 125.
    Bartholomew A, Patil S, Mackay A, Nelson M, Buyaner D, Hardy W, Mosca J, Sturgeon C, Siatska M, Mahmud N, et al. Baboon mesenchymal stem cells can be genetically modified to secrete human erythropoietin in vivo. Hum Gene Ther. 2001;12(12):1527–41.Google Scholar
  126. 126.
    Studeny M, Marini FC, Champlin RE, Zompetta C, Fidler IJ, Andreeff M. Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors. Cancer Res. 2002;62(13):3603–8.Google Scholar
  127. 127.
    Kokai LE, Ghaznavi AM, Marra KG. Incorporation of double-walled microspheres into polymer nerve guides for the sustained delivery of glial cell line-derived neurotrophic factor. Biomaterials. 2010;31(8):2313–22.Google Scholar
  128. 128.
    Kokai LE, Bourbeau D, Weber D, McAtee J, Marra KG. Sustained growth factor delivery promotes axonal regeneration in long gap peripheral nerve repair. Tissue Eng Part A. 2011;17(9–10):1263–75.Google Scholar
  129. 129.
    Ward MS, Khoobehi A, Lavik EB, Langer R, Young MJ. Neuroprotection of retinal ganglion cells in DBA/2J mice with GDNF-loaded biodegradable microspheres. J Pharm Sci. 2007;96(3):558–68.Google Scholar
  130. 130.
    Checa-Casalengua P, Jiang C, Bravo-Osuna I, Tucker BA, Molina-Martinez IT, Young MJ, Herrero-Vanrell R. Retinal ganglion cells survival in a glaucoma model by GDNF/Vit E PLGA microspheres prepared according to a novel microencapsulation procedure. J Control Release. 2011;156(1):92–100.Google Scholar
  131. 131.
    Schmeer C, Straten G, Kugler S, Gravel C, Bahr M, Isenmann S. Dose-dependent rescue of axotomized rat retinal ganglion cells by adenovirus-mediated expression of glial cell-line derived neurotrophic factor in vivo. Eur J Neurosci. 2002;15(4):637–43.Google Scholar
  132. 132.
    Wu WC, Lai CC, Chen SL, Sun MH, Xiao X, Chen TL, Tsai RJ, Kuo SW, Tsao YP. GDNF gene therapy attenuates retinal ischemic injuries in rats. Mol Vis. 2004;10:93–102.Google Scholar
  133. 133.
    Miyoshi H TM, Gage FH, Verma IM. Stable and efficient gene transfer into the retina using an HIV-based lentiviral vector. Proc Natl Acad Sci U S A. 1997;94(19):10319–23.Google Scholar
  134. 134.
    Hermens WT, Verhaagen J. Viral vectors, tools for gene transfer in the nervous system. Prog Neurobiol. 1998;55(4):399–432.Google Scholar
  135. 135.
    Bainbridge JW, Stephens C, Parsley K, Demaison C, Halfyard A, Thrasher AJ, Ali RR. In vivo gene transfer to the mouse eye using an HIV-based lentiviral vector; efficient long-term transduction of corneal endothelium and retinal pigment epithelium. Gene Ther. 2001;8(21):1665–8.Google Scholar
  136. 136.
    Liu Y, et al. A new method for Schwann-like cell differentiation of adipose derived stem cells. Neurosci Lett. 2013;551:79–83.Google Scholar
  137. 137.
    Caddick J, et al. Phenotypic and functional characteristics of mesenchymal stem cells differentiated along a Schwann cell lineage. Glia. 2006;54(8):840–9.Google Scholar
  138. 138.
    Dadon-Nachum M, et al. Differentiated mesenchymal stem cells for sciatic nerve injury. Stem Cell Rev. 2011;7(3):664–71.Google Scholar
  139. 139.
    Wei Y, et al. Schwann-like cell differentiation of rat adipose-derived stem cells by indirect co-culture with Schwann cells in vitro. Cell Prolif. 2010;43(6):606–16.Google Scholar
  140. 140.
    Kalbermatten DF, et al. Neurotrophic activity of human adipose stem cells isolated from deep and superficial layers of abdominal fat. Cell Tissue Res. 2011;344(2):251–60.Google Scholar
  141. 141.
    Kaewkhaw R, Scutt AM, Haycock JW. Haycock, Anatomical site influences the differentiation of adipose-derived stem cells for Schwann-cell phenotype and function. Glia. 2011;59(5):734–49.Google Scholar
  142. 142.
    Sowa Y, et al. Adipose-derived stem cells produce factors enhancing peripheral nerve regeneration: influence of age and anatomic site of origin. Stem Cells Dev. 2012;21(11):1852–62.Google Scholar
  143. 143.
    Marconi S, et al. Human adipose-derived mesenchymal stem cells systemically injected promote peripheral nerve regeneration in the mouse model of sciatic crush. Tissue Eng Part A. 2012;18(11–12):1264–72.Google Scholar
  144. 144.
    Schlosser S, et al. Paracrine effects of mesenchymal stem cells enhance vascular regeneration in ischemic murine skin. Microvascular. 2012Google Scholar
  145. 145.
    Omori Y, et al. Optimization of a therapeutic protocol for intravenous injection of human mesenchymal stem cells after cerebral ischemia in adult rats. Brain Res. 2008;1236:30–8.Google Scholar
  146. 146.
    Assis AC, et al. Time-dependent migration of systemically delivered bone marrow mesenchymal stem cells to the infarcted heart. Cell Transplant. 2010;19(2):219–30.Google Scholar
  147. 147.
    Gao J, et al. The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion. Cells Tissues Organs. 2001;169(1):12–20.Google Scholar
  148. 148.
    Eggenhofer E, et al. Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion. Front Immunol. 2012;3:297.Google Scholar
  149. 149.
    Karp JM, Teo GS. Teo, Mesenchymal stem cell homing: the devil is in the details. Stem Cell. 2009;4(3):206–16.Google Scholar
  150. 150.
    Lee RH, et al. Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Stem Cell. 2009;5(1):54–63.Google Scholar
  151. 151.
    McGrath AM, et al. Fibrin conduit supplemented with human mesenchymal stem cells and immunosuppressive treatment enhances regeneration after peripheral nerve injury. Neurosci Lett. 2012;516(2):171–6.Google Scholar
  152. 152.
    Carriel V, et al. Combination of fibrin-agarose hydrogels and adipose-derived mesenchymal stem cells for peripheral nerve regeneration. J Neural Eng. 2013;10(2):026022.Google Scholar
  153. 153.
    Cuevas P, et al. Peripheral nerve regeneration by bone marrow stromal cells. Neurol Res. 2002;24(7):634–8.Google Scholar
  154. 154.
    Santiago LY, et al. Delivery of adipose-derived precursor cells for peripheral nerve repair. Cell Transplant. 2009;18(2):145–58.Google Scholar
  155. 155.
    Liu BS, Yang YC, Shen CC. Regenerative effect of adipose tissue-derived stem cells transplantation using nerve conduit therapy on sciatic nerve injury in rats. J Tissue Eng Regen Med. 2012;8(5):337–50.Google Scholar
  156. 156.
    Chen X, et al. Study of in vivo differentiation of rat bone marrow stromal cells into schwann cell-like cells. Microsurgery. 2006;26(2):111–5.Google Scholar
  157. 157.
    Keilhoff G, et al. Transdifferentiated mesenchymal stem cells as alternative therapy in supporting nerve regeneration and myelination. Cell Mol Neurobiol. 2006;26(7–8):1235–52.Google Scholar
  158. 158.
    Mimura T, et al. Peripheral nerve regeneration by transplantation of bone marrow stromal cell-derived Schwann cells in adult rats. J Neurosurg. 2004;101(5):806–12.Google Scholar
  159. 159.
    Hu N, et al. Long-term outcome of the repair of 50 mm long median nerve defects in rhesus monkeys with marrow mesenchymal stem cells-containing, chitosan-based tissue engineered nerve grafts. Biomaterials. 2013;34(1):100–11.Google Scholar
  160. 160.
    Orbay H, et al. Differentiated and undifferentiated adipose-derived stem cells improve function in rats with peripheral nerve gaps. J Plast Reconstr Aesthet Surg. 2012;65(5):657–64.Google Scholar
  161. 161.
    Hu J, et al. Repair of extended peripheral nerve lesions in rhesus monkeys using acellular allogenic nerve grafts implanted with autologous mesenchymal stem cells. Exp Neurol. 2007;204(2):658–66.Google Scholar
  162. 162.
    Ding F, et al. Use of tissue-engineered nerve grafts consisting of a chitosan/poly(lactic-co-glycolic acid)-based scaffold included with bone marrow mesenchymal cells for bridging 50-mm dog sciatic nerve gaps. Tissue Eng Part A. 2010;16(12):3779–90.Google Scholar
  163. 163.
    Wakao S, et al. Long-term observation of auto-cell transplantation in non-human primate reveals safety and efficiency of bone marrow stromal cell-derived Schwann cells in peripheral nerve regeneration. Exp Neurol. 2010;223(2):537–47.Google Scholar
  164. 164.
    Xue C, et al. Joint use of a chitosan/PLGA scaffold and MSCs to bridge an extra large gap in dog sciatic nerve. Neurorehabil Neural Repair. 2012;26(1):96–106.Google Scholar
  165. 165.
    Fischer UM, et al. Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev. 2009;18(5):683–92.Google Scholar
  166. 166.
    Ball LM, et al. Multiple infusions of mesenchymal stromal cells induce sustained remission in children with steroid-refractory, grade III-IV acute graft-versus-host disease. Br J Haematol. 2013;163:501–9.Google Scholar
  167. 167.
    Forbes GM, et al. A phase 2 study of allogeneic mesenchymal stromal cells for luminal Crohn’s disease refractory to biologic therapy. Clin Gastroenterol Hepatol. 2014;12(1):64–71.Google Scholar
  168. 168.
    Hao H, et al. Multiple intravenous infusions of bone marrow mesenchymal stem cells reverse hyperglycemia in experimental type 2 diabetes rats. Biochem Biophys Res Commun. 2013;436(3):418–23.Google Scholar
  169. 169.
    Wang H, et al. Hematopoietic stem cell transplantation with umbilical cord multipotent stromal cell infusion for the treatment of aplastic anemia-a single-center experience. Cytotherapy. 2013;15(9):1118–25.Google Scholar
  170. 170.
    Pereira Lopes FR, et al. Bone marrow stromal cells and resorbable collagen guidance tubes enhance sciatic nerve regeneration in mice. Exp Neurol. 2006;198(2):457–68.Google Scholar
  171. 171.
    Zhang P, et al. Bridging small-gap peripheral nerve defects using biodegradable chitin conduits with cultured schwann and bone marrow stromal cells in rats. J Reconstr Microsurg. 2005;21(8):565–71.Google Scholar
  172. 172.
    Zheng L, Cui HF. Enhancement of nerve regeneration along a chitosan conduit combined with bone marrow mesenchymal stem cells. J Mater Sci Mater Med. 2012;23(9):2291–302.Google Scholar
  173. 173.
    Ao Q, et al. The regeneration of transected sciatic nerves of adult rats using chitosan nerve conduits seeded with bone marrow stromal cell-derived Schwann cells. Biomaterials. 2011;32(3):787–96.Google Scholar
  174. 174.
    Zhao Z, et al. Repair of nerve defect with acellular nerve graft supplemented by bone marrow stromal cells in mice. Microsurgery. 2011;31(5):388–94.Google Scholar
  175. 175.
    Oliveira JT, et al. Mesenchymal stem cells in a polycaprolactone conduit enhance median-nerve regeneration, prevent decrease of creatine phosphokinase levels in muscle, and improve functional recovery in mice. Neuroscience. 2010;170(4):1295–303.Google Scholar
  176. 176.
    Pereira Lopes FR, et al. Transplantation of bone-marrow-derived cells into a nerve guide resulted in transdifferentiation into Schwann cells and effective regeneration of transected mouse sciatic nerve. Micron. 2010;41(7):783–90.Google Scholar
  177. 177.
    Shimizu S, et al. Peripheral nerve regeneration by the in vitro differentiated-human bone marrow stromal cells with Schwann cell property. Biochem Biophys Res Commun. 2007;359(4):915–20.Google Scholar
  178. 178.
    Frattini F, et al. Mesenchymal stem cells in a polycaprolactone conduit promote sciatic nerve regeneration and sensory neuron survival after nerve injury. Tissue Eng Part A. 2012;18(19–20):2030–9.Google Scholar
  179. 179.
    Ladak A, et al. Differentiation of mesenchymal stem cells to support peripheral nerve regeneration in a rat model. Exp Neurol. 2011;228(2):242–52.Google Scholar
  180. 180.
    Wang J, et al. Bone marrow mesenchymal stem cells promote cell proliferation and neurotrophic function of Schwann cells in vitro and in vivo. Brain Res. 2009;1262:7–15.Google Scholar
  181. 181.
    Liu G, et al. Transplantation of adipose-derived stem cells for peripheral nerve repair. Int J Mol Med. 2011;28(4):565–72.Google Scholar
  182. 182.
    Liu GB, et al. Adipose-derived stem cells promote peripheral nerve repair. Arch Med Sci. 2011;7(4):592–6.Google Scholar
  183. 183.
    Chen CJ, et al. Transplantation of bone marrow stromal cells for peripheral nerve repair. Exp Neurol. 2007;204(1):443–53.Google Scholar
  184. 184.
    Wang Y, et al. Recellularized nerve allografts with differentiated mesenchymal stem cells promote peripheral nerve regeneration. Neurosci Lett. 2012;514(1):96–101.Google Scholar
  185. 185.
    Costa HJ, et al. Mesenchymal bone marrow stem cells within polyglycolic acid tube observed in vivo after six weeks enhance facial nerve regeneration. Brain Res. 2013;1510:10–21.Google Scholar
  186. 186.
    Zarbakhsh S, et al. The effects of schwann and bone marrow stromal stem cells on sciatic nerve injury in rat: a comparison of functional recovery. Cell J. 2012;14(1):39–46.Google Scholar
  187. 187.
    Shen CC, Yang YC, Liu BS. Peripheral nerve repair of transplanted undifferentiated adipose tissue-derived stem cells in a biodegradable reinforced nerve conduit. J Biomed Mater Res A. 2012;100(1):48–63.Google Scholar
  188. 188.
    Wang D, et al. Repairing large radial nerve defects by acellular nerve allografts seeded with autologous bone marrow stromal cells in a monkey model. J Neurotrauma. 2010;27(10):1935–43.Google Scholar
  189. 189.
    Lopatina T, et al. Adipose-derived stem cells stimulate regeneration of peripheral nerves: BDNF secreted by these cells promotes nerve healing and axon growth de novo. PLoS One. 2011;6(3):e17899.Google Scholar
  190. 190.
    Hou SY, et al. Tissue-engineered peripheral nerve grafting by differentiated bone marrow stromal cells. Neuroscience. 2006;140(1):101–10.Google Scholar
  191. 191.
    Reid AJ, et al. Nerve repair with adipose-derived stem cells protects dorsal root ganglia neurons from apoptosis. Neuroscience. 2011;199:515–22.Google Scholar
  192. 192.
    Wang D, et al. Bridging small-gap peripheral nerve defects using acellular nerve allograft implanted with autologous bone marrow stromal cells in primates. Brain Res. 2008;1188:44–53.Google Scholar
  193. 193.
    Ghoreishian M, et al. Facial nerve repair with Gore-Tex tube and adipose-derived stem cells: an animal study in dogs. J Oral Maxillofac Surg. 2013;71(3):577–87.Google Scholar
  194. 194.
    Choi BH, et al. Transplantation of cultured bone marrow stromal cells to improve peripheral nerve regeneration. Int J Oral Maxillofac Surg. 2005;34(5):537–42.Google Scholar
  195. 195.
    Wang X, et al. Schwann-like mesenchymal stem cells within vein graft facilitate facial nerve regeneration and remyelination. Brain Res. 2011;1383:71–80.Google Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Vascularized Composite Allotransplantation (VCA) Laboratory, Department of Plastic SurgeryUniversity of PittsburghPittsburghUSA
  2. 2.Adipose Stem Cell Center, Department of Plastic SurgeryUniversity of PittsburghPittsburghUSA
  3. 3.Department of Plastic and Hand SurgeryUniversity Hospital ZurichZurichSwitzerland
  4. 4.Department of Plastic SurgeryUniversity of Pittsburgh Medical CenterPittsburghUSA

Personalised recommendations