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Adult Stem Cell-Based Strategies for Peripheral Nerve Regeneration

  • Metzere Bierlein De la Rosa
  • Emily M. Kozik
  • Donald S. SakaguchiEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1119)

Abstract

Peripheral nerve injuries (PNI) occur as the result of sudden trauma and can lead to life-long disability, reduced quality of life, and heavy economic and social burdens. Although the peripheral nervous system (PNS) has the intrinsic capacity to regenerate and regrow axons to a certain extent, current treatments frequently show incomplete recovery with poor functional outcomes, particularly for large PNI. Many surgical procedures are available to halt the propagation of nerve damage, and the choice of a procedure depends on the extent of the injury. In particular, recovery from large PNI gaps is difficult to achieve without any therapeutic intervention or some form of tissue/cell-based therapy. Autologous nerve grafting, considered the “gold standard” is often implemented for treatment of gap formation type PNI. Although these surgical procedures provide many benefits, there are still considerable limitations associated with such procedures as donor site morbidity, neuroma formation, fascicle mismatch, and scarring. To overcome such restrictions, researchers have explored various avenues to improve post-surgical outcomes. The most commonly studied methods include: cell transplantation, growth factor delivery to stimulate regenerating axons and implanting nerve guidance conduits containing replacement cells at the site of injury. Replacement cells which offer maximum benefits for the treatment of PNI, are Schwann cells (SCs), which are the peripheral glial cells and in part responsible for clearing out debris from the site of injury. Additionally, they release growth factors to stimulate myelination and axonal regeneration. Both primary SCs and genetically modified SCs enhance nerve regeneration in animal models; however, there is no good source for extracting SCs and the only method to obtain SCs is by sacrificing a healthy nerve. To overcome such challenges, various cell types have been investigated and reported to enhance nerve regeneration.

In this review, we have focused on cell-based strategies aimed to enhance peripheral nerve regeneration, in particular the use of mesenchymal stem cells (MSCs). Mesenchymal stem cells are preferred due to benefits such as autologous transplantation, routine isolation procedures, and paracrine and immunomodulatory properties. Mesenchymal stem cells have been transplanted at the site of injury either directly in their native form (undifferentiated) or in a SC-like form (transdifferentiated) and have been shown to significantly enhance nerve regeneration. In addition to transdifferentiated MSCs, some studies have also transplanted ex-vivo genetically modified MSCs that hypersecrete growth factors to improve neuroregeneration.

Keywords

Peripheral nerve regeneration Neuroregeneration Neuroprotection Mesenchymal stem cells Schwann cells Genetic modification Transplantation Transdifferentiation Brain-derived neurotrophic factor Clinical trials 

Abbreviations

AMD

age-related macular degeneration

BDNF

brain-derived neurotrophic factor

bFGF

basic fibroblast growth factor

BMMC

bone marrow mononuclear cell

CNTF

ciliary neurotrophic factor

CNV

choroidal neovascularization

CREB

cAMP-response-element-binding protein

DRG

dorsal root ganglia

ELISA

enzyme linked immunosorbent assay

GDNF

glial cell line-derived neurotrophic factor

GFP

green fluorescent protein

iPSC

induced pluripotent stem cell

MBP

myelin basic protein

MRI

magnetic resonance imaging

MSC

mesenchymal stem cell

NGF

nerve growth factor

NT-3

neurtrophin 3

NT-4/5

neurotrophins 4 and 5

PDGF

platelet-derived growth factor

PNI

peripheral nerve injury

PNS

peripheral nervous system

RGC

retinal ganglion cell

SC

Schwann cell

TDM

transdifferentiation media

TENG

tissue engineered nerve graft

Trk

tropomyosin receptor kinases

tMSC

transdifferentiated mesenchymal stem cell

uMSC

undifferentiated mesenchymal stem cell

VEGF

vascular endothelial growth factor

Notes

Acknowledgements

This work was supported by the Stem Cell Biology Research Fund.

Conflict of Interest

The authors declare no conflict of interest.

References

  1. Acquistapace A, Bru T, Lesault PF, Figeac F, Coudert AE, le Coz O, Christov C, Baudin X, Auber F, Yiou R, Dubois-Rande JL, Rodriguez AM (2011) Human mesenchymal stem cells reprogram adult cardiomyocytes toward a progenitor-like state through partial cell fusion and mitochondria transfer. Stem Cells 29(5):812–824PubMedPubMedCentralGoogle Scholar
  2. Aggarwal S, Pittenger MF (2005) Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105(4):1815–1822PubMedGoogle Scholar
  3. Amoh Y, Li L, Campillo R, Kawahara K, Katsuoka K, Penman S, Hoffman RM (2005) Implanted hair follicle stem cells form Schwann cells that support repair of severed peripheral nerves. Proc Natl Acad Sci U S A 102(49):17734–17738PubMedPubMedCentralGoogle Scholar
  4. Anderson KD, Guest JD, Dietrich WD, Bunge MB, Curiel R, Dididze M, Green BA, Khan A, Pearse DD, Saraf-Lavi E (2017) Safety of autologous human schwann cell transplantation in subacute thoracic spinal cord injury. J Neurotrauma 34:2950–2963PubMedGoogle Scholar
  5. Bathina S, Das UN (2015) Brain-derived neurotrophic factor and its clinical implications. Arch Med Sci 11(6):1164–1178PubMedPubMedCentralGoogle Scholar
  6. Bauer G, Dao MA, Case SS, Meyerrose T, Wirthlin L, Zhou P, Wang X, Herrbrich P, Arevalo J, Csik S, Skelton DC, Walker J, Pepper K, Kohn DB, Nolta JA (2008) In vivo biosafety model to assess the risk of adverse events from retroviral and lentiviral vectors. Mol Ther 16(7):1308–1315PubMedPubMedCentralGoogle Scholar
  7. Bjorklund LM, Sanchez-Pernaute R, Chung S, Andersson T, Chen IY, McNaught KS, Brownell AL, Jenkins BG, Wahlestedt C, Kim KS, Isacson O (2002) Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc Natl Acad Sci U S A 99(4):2344–2349PubMedPubMedCentralGoogle Scholar
  8. Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME (1999) Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 286(5443):1358–1362PubMedGoogle Scholar
  9. Boyd JG, Gordon T (2002) A dose-dependent facilitation and inhibition of peripheral nerve regeneration by brain-derived neurotrophic factor. Eur J Neurosci 15(4):613–626PubMedGoogle Scholar
  10. Boyd JG, Gordon T (2003) Neurotrophic factors and their receptors in axonal regeneration and functional recovery after peripheral nerve injury. Mol Neurobiol 27(3):277–324PubMedGoogle Scholar
  11. Braga-Silva J, Gehlen D, Padoin A, Machado D, Garicochea B, Costa da Costa J (2008) Can local supply of bone marrow mononuclear cells improve the outcome from late tubular repair of human median and ulnar nerves? J Hand Surg Eur Vol 33(4):488–493PubMedGoogle Scholar
  12. Bredesen DE, Rabizadeh S (1997) p75NTR and apoptosis: Trk-dependent and Trk-independent effects. Trends Neurosci 20(7):287–290PubMedGoogle Scholar
  13. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96(6):857–868PubMedGoogle Scholar
  14. Bunge MB, Monje PV, Khan A, Wood PM (2017) From transplanting Schwann cells in experimental rat spinal cord injury to their transplantation into human injured spinal cord in clinical trials. Prog Brain Res 231:107–133PubMedGoogle Scholar
  15. Burnett MG, Zager EL (2004) Pathophysiology of peripheral nerve injury: a brief review. Neurosurg Focus 16(5):E1PubMedGoogle Scholar
  16. Campbell WW (2008) Evaluation and management of peripheral nerve injury. Clin Neurophysiol 119(9):1951–1965PubMedGoogle Scholar
  17. Chan JR, Cosgaya JM, Wu YJ, Shooter EM (2001) Neurotrophins are key mediators of the myelination program in the peripheral nervous system. Proc Natl Acad Sci U S A 98(25):14661–14668PubMedPubMedCentralGoogle Scholar
  18. Chao MV, Bothwell MA, Ross AH, Koprowski H, Lanahan AA, Buck CR, Sehgal A (1986) Gene transfer and molecular cloning of the human NGF receptor. Science 232(4749):518–521PubMedGoogle Scholar
  19. Chen J, Li Y, Wang L, Lu M, Zhang X, Chopp M (2001) Therapeutic benefit of intracerebral transplantation of bone marrow stromal cells after cerebral ischemia in rats. J Neurol Sci 189(1-2):49–57PubMedGoogle Scholar
  20. Chen J, Zhang ZG, Li Y, Wang L, Xu YX, Gautam SC, Lu M, Zhu Z, Chopp M (2003) Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats. Circ Res 92(6):692–699PubMedGoogle Scholar
  21. Chen CJ, Ou YC, Liao SL, Chen WY, Chen SY, Wu CW, Wang CC, Wang WY, Huang YS, Hsu SH (2007) Transplantation of bone marrow stromal cells for peripheral nerve repair. Exp Neurol 204(1):443–453PubMedGoogle Scholar
  22. Chiu DT (1999) Autogenous venous nerve conduits. A review. Hand Clin 15(4):667–671 ixPubMedGoogle Scholar
  23. Chiu DT, Strauch B (1990) A prospective clinical evaluation of autogenous vein grafts used as a nerve conduit for distal sensory nerve defects of 3 cm or less. Plast Reconstr Surg 86(5):928–934PubMedGoogle Scholar
  24. Cuevas P, Carceller F, Dujovny M, Garcia-Gomez I, Cuevas B, Gonzalez-Corrochano R, Diaz-Gonzalez D, Reimers D (2002) Peripheral nerve regeneration by bone marrow stromal cells. Neurol Res 24(7):634–638PubMedGoogle Scholar
  25. Dadon-Nachum M, Sadan O, Srugo I, Melamed E, Offen D (2011) Differentiated mesenchymal stem cells for sciatic nerve injury. Stem Cell Rev 7(3):664–671PubMedGoogle Scholar
  26. Das SR, Uz M, Ding S, Lentner MT, Hondred JA, Cargill AA, Sakaguchi DS, Mallapragada S, Claussen JC (2017) Electrical differentiation of mesenchymal stem cells into Schwann-cell-like phenotypes using inkjet-printed graphene circuits. Adv Healthc Mater 6(7)Google Scholar
  27. De la Rosa MB, Sharma AD, Mallapragada SK, Sakaguchi DS (2017) Transdifferentiation of brain-derived neurotrophic factor (BDNF)-secreting mesenchymal stem cells significantly enhance BDNF secretion and Schwann cell marker proteins. J Biosci Bioeng 124(5):572–582Google Scholar
  28. Dey ND, Bombard MC, Roland BP, Davidson S, Lu M, Rossignol J, Sandstrom MI, Skeel RL, Lescaudron L, Dunbar GL (2010) Genetically engineered mesenchymal stem cells reduce behavioral deficits in the YAC 128 mouse model of Huntington’s disease. Behav Brain Res 214(2):193–200PubMedGoogle Scholar
  29. 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(11):1771–1776PubMedGoogle Scholar
  30. Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, Grisanti S, Gianni AM (2002) Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 99(10):3838–3843PubMedGoogle Scholar
  31. Dodd J, Jessell TM (1988) Axon guidance and the patterning of neuronal projections in vertebrates. Science 242(4879):692–699PubMedGoogle Scholar
  32. Drake DB (1996) Nerve injuries: operative results for major nerve injuries, entrapments and tumors. Plast Reconstr Surg 98(4):749Google Scholar
  33. Eriksson NP, Lindsay RM, Aldskogius H (1994) BDNF and NT-3 rescue sensory but not motoneurones following axotomy in the neonate. Neuroreport 5(12):1445–1448PubMedGoogle Scholar
  34. Ernfors P, Rosario CM, Merlio JP, Grant G, Aldskogius H, Persson H (1993) Expression of mRNAs for neurotrophin receptors in the dorsal root ganglion and spinal cord during development and following peripheral or central axotomy. Brain Res Mol Brain Res 17(3-4):217–226PubMedGoogle Scholar
  35. Fields RD, Ellisman MH (1986) Axons regenerated through silicone tube splices. I. Conduction properties. Exp Neurol 92(1):48–60PubMedGoogle Scholar
  36. Friedman DS, Wolfs R, O’Colmain BJ, Klein BE, Taylor HR, West S, Leske MC, Mitchell P, Congdon N, Kempen J (2004) Prevalence of open-angle glaucoma among adults in the United States. Arch Ophthalmol 122:532–538PubMedGoogle Scholar
  37. Fu SY, Gordon T (1997) The cellular and molecular basis of peripheral nerve regeneration. Mol Neurobiol 14(1-2):67–116PubMedGoogle Scholar
  38. Funakoshi H, Frisen J, Barbany G, Timmusk T, Zachrisson O, Verge VM, Persson H (1993) Differential expression of mRNAs for neurotrophins and their receptors after axotomy of the sciatic nerve. J Cell Biol 123(2):455–465PubMedGoogle Scholar
  39. Gao M, Lu P, Lynam D, Bednark B, Campana WM, Sakamoto J, Tuszynski M (2016) BDNF gene delivery within and beyond templated agarose multi-channel guidance scaffolds enhances peripheral nerve regeneration. J Neural Eng 13(6):066011PubMedGoogle Scholar
  40. Gao F, Chiu S, Motan D, Zhang Z, Chen L, Ji H, Tse H, Fu Q-L, Lian Q (2017) Mesenchymal stem cells and immunomodulation: current status and future prospects. Cell Death Dis 7(1):e2062Google Scholar
  41. Gargano N, Levi A, Alema S (1997) Modulation of nerve growth factor internalization by direct interaction between p75 and TrkA receptors. J Neurosci Res 50(1):1–12PubMedGoogle Scholar
  42. Gaudet AD, Popovich PG, Ramer MS (2011) Wallerian degeneration: gaining perspective on inflammatory events after peripheral nerve injury. J Neuroinflammation 8:110PubMedPubMedCentralGoogle Scholar
  43. Geuna S, Raimondo S, Ronchi G, Di Scipio F, Tos P, Czaja K, Fornaro M (2009) Chapter 3: histology of the peripheral nerve and changes occurring during nerve regeneration. Int Rev Neurobiol 87:27–46PubMedGoogle Scholar
  44. Geuna S, Gnavi S, Perroteau I, Tos P, Battiston B (2013) Tissue engineering and peripheral nerve reconstruction: an overview. Int Rev Neurobiol 108:35–57PubMedGoogle Scholar
  45. Gordon T (2009) The role of neurotrophic factors in nerve regeneration. Neurosurg Focus 26(2):E3PubMedGoogle Scholar
  46. Goto E, Mukozawa M, Mori H, Hara M (2010) A rolled sheet of collagen gel with cultured Schwann cells: model of nerve conduit to enhance neurite growth. J Biosci Bioeng 109(5):512–518PubMedGoogle Scholar
  47. Gu Y, Wang J, Ding F, Hu N, Wang Y, Gu X (2010) Neurotrophic actions of bone marrow stromal cells on primary culture of dorsal root ganglion tissues and neurons. J Mol Neurosci 40(3):332–341PubMedGoogle Scholar
  48. Guertin AD, Zhang DP, Mak KS, Alberta JA, Kim HA (2005) Microanatomy of axon/glial signaling during Wallerian degeneration. J Neurosci 25(13):3478–3487PubMedGoogle Scholar
  49. Gundersen RW, Barrett JN (1980) Characterization of the turning response of dorsal root neurites toward nerve growth factor. J Cell Biol 87(3 Pt 1):546–554PubMedGoogle Scholar
  50. Hadlock T, Sundback C, Hunter D, Cheney M, Vacanti JP (2000) A polymer foam conduit seeded with Schwann cells promotes guided peripheral nerve regeneration. Tissue Eng 6(2):119–127PubMedGoogle Scholar
  51. Hall S (2001) Nerve repair: a neurobiologist’s view. J Hand Surg Br 26(2):129–136PubMedGoogle Scholar
  52. Harper MM, Grozdanic SD, Blits B, Kuehn MH, Zamzow D, Buss JE, Kardon RH, Sakaguchi DS (2011) Transplantation of BDNF-secreting mesenchymal stem cells provides neuroprotection in chronically hypertensive rat eyes. Invest Ophthalmol Vis Sci 52(7):4506–4515PubMedPubMedCentralGoogle Scholar
  53. Harrop JS, Hashimoto R, Norvell D, Raich A, Aarabi B, Grossman RG, Guest JD, Tator CH, Chapman J, Fehlings MG (2012) Evaluation of clinical experience using cell-based therapies in patients with spinal cord injury: a systematic review. J Neurosurg Spine 17(1 Suppl):230–246PubMedGoogle Scholar
  54. Hei WH, Almansoori AA, Sung MA, Ju KW, Seo N, Lee SH, Kim BJ, Kim SM, Jahng JW, He H, Lee JH (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 643:111–120PubMedGoogle Scholar
  55. Hirasawa Y, Sakakida K (1983) Sports and peripheral nerve injury. Am J Sports Med 11(6):420–426PubMedGoogle Scholar
  56. Horita Y, Honmou O, Harada K, Houkin K, Hamada H, Kocsis JD (2006) Intravenous administration of glial cell line-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in the adult rat. J Neurosci Res 84(7):1495–1504PubMedPubMedCentralGoogle Scholar
  57. Hou H-Y, Liang H-L, Wang Y-S, Zhang Z-X, Wang B-R, Shi Y-Y, Dong X, Cai Y (2010) A therapeutic strategy for choroidal neovascularization based on recruitment of mesenchymal stem cells to the sites of lesions. Mol Ther 18(10):1837–1845PubMedPubMedCentralGoogle Scholar
  58. Hu N, Wu H, Xue C, Gong Y, Wu J, Xiao Z, Yang Y, Ding F, Gu X (2013) 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 34(1):100–111PubMedGoogle Scholar
  59. Huang JK, Phillips GR, Roth AD, Pedraza L, Shan W, Belkaid W, Mi S, Fex-Svenningsen A, Florens L, Yates JR 3rd, Colman DR (2005) Glial membranes at the node of Ranvier prevent neurite outgrowth. Science 310(5755):1813–1817PubMedGoogle Scholar
  60. Huang J, Ye Z, Hu X, Lu L, Luo Z (2010) Electrical stimulation induces calcium-dependent release of NGF from cultured Schwann cells. Glia 58(5):622–631PubMedGoogle Scholar
  61. Iihoshi S, Honmou O, Houkin K, Hashi K, Kocsis JD (2004) A therapeutic window for intravenous administration of autologous bone marrow after cerebral ischemia in adult rats. Brain Res 1007(1-2):1–9PubMedGoogle Scholar
  62. Ishikawa N, Suzuki Y, Dezawa M, Kataoka K, Ohta M, Cho H, Ide C (2009) Peripheral nerve regeneration by transplantation of BMSC-derived Schwann cells as chitosan gel sponge scaffolds. J Biomed Mater Res A 89((4):1118–1124Google Scholar
  63. Islam MN, Das SR, Emin MT, Wei M, Sun L, Westphalen K, Rowlands DJ, Quadri SK, Bhattacharya S, Bhattacharya J (2012) Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med 18(5):759–765PubMedPubMedCentralGoogle Scholar
  64. Jaquet JB, Luijsterburg AJ, Kalmijn S, Kuypers PD, Hofman A, Hovius SE (2001) Median, ulnar, and combined median-ulnar nerve injuries: functional outcome and return to productivity. J Trauma 51(4):687–692PubMedGoogle Scholar
  65. Jiang XX, Zhang Y, Liu B, Zhang SX, Wu Y, Yu XD, Mao N (2005) Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood 105(10):4120–4126PubMedGoogle Scholar
  66. Kamada T, Koda M, Dezawa M, Anahara R, Toyama Y, Yoshinaga K, Hashimoto M, Koshizuka S, Nishio Y, Mannoji C, Okawa A, Yamazaki M (2011) Transplantation of human bone marrow stromal cell-derived Schwann cells reduces cystic cavity and promotes functional recovery after contusion injury of adult rat spinal cord. Neuropathology 31(1):48–58PubMedGoogle Scholar
  67. Karanth S, Yang G, Yeh J, Richardson PM (2006) Nature of signals that initiate the immune response during Wallerian degeneration of peripheral nerves. Exp Neurol 202(1):161–166PubMedGoogle Scholar
  68. Keilhoff G, Fansa H (2011) Mesenchymal stem cells for peripheral nerve regeneration--a real hope or just an empty promise? Exp Neurol 232(2):110–113PubMedGoogle Scholar
  69. Keilhoff G, Goihl A, Langnase K, Fansa H, Wolf G (2006) Transdifferentiation of mesenchymal stem cells into Schwann cell-like myelinating cells. Eur J Cell Biol 85(1):11–24PubMedGoogle Scholar
  70. Kerrebijn JD, Freeman JL (1998) Facial nerve reconstruction: outcome and failures. J Otolaryngol 27(4):183–186PubMedGoogle Scholar
  71. Kim BJ, Seo JH, Bubien JK, Oh YS (2002) Differentiation of adult bone marrow stem cells into neuroprogenitor cells in vitro. Neuroreport 13(9):1185–1188PubMedGoogle Scholar
  72. Kingham PJ, Kalbermatten DF, Mahay D, Armstrong SJ, Wiberg M, Terenghi G (2007) Adipose-derived stem cells differentiate into a Schwann cell phenotype and promote neurite outgrowth in vitro. Exp Neurol 207(2):267–274PubMedGoogle Scholar
  73. Kishino A, Ishige Y, Tatsuno T, Nakayama C, Noguchi H (1997) BDNF prevents and reverses adult rat motor neuron degeneration and induces axonal outgrowth. Exp Neurol 144(2):273–286PubMedGoogle Scholar
  74. Klimaschewski L, Hausott B, Angelov DN (2013) The pros and cons of growth factors and cytokines in peripheral axon regeneration. Int Rev Neurobiol 108:137–171PubMedGoogle Scholar
  75. Kobayashi NR, Bedard AM, Hincke MT, Tetzlaff W (1996) Increased expression of BDNF and trkB mRNA in rat facial motoneurons after axotomy. Eur J Neurosci 8(5):1018–1029PubMedGoogle Scholar
  76. Koppes AN, Seggio AM, Thompson DM (2011) Neurite outgrowth is significantly increased by the simultaneous presentation of Schwann cells and moderate exogenous electric fields. J Neural Eng 8(4):046023PubMedGoogle Scholar
  77. Koppes AN, Nordberg AL, Paolillo GM, Goodsell NM, Darwish HA, Zhang L, Thompson DM (2014) Electrical stimulation of schwann cells promotes sustained increases in neurite outgrowth. Tissue Eng Part A 20(3-4):494–506PubMedGoogle Scholar
  78. Kouyoumdjian JA (2006) Peripheral nerve injuries: a retrospective survey of 456 cases. Muscle Nerve 34(6):785–788PubMedGoogle Scholar
  79. Kreutzberg GW (1995) Reaction of the neuronal cell body to axonal damage. In: Waxman SG, Kocsis JD, Stys PK (eds) The axon: structure, function and pathophysiology. Oxford University Press, Oxford, pp 355–374Google Scholar
  80. Kurozumi K, Nakamura K, Tamiya T, Kawano Y, Kobune M, Hirai S, Uchida H, Sasaki K, Ito Y, Kato K, Honmou O, Houkin K, Date I, Hamada H (2004) BDNF gene-modified mesenchymal stem cells promote functional recovery and reduce infarct size in the rat middle cerebral artery occlusion model. Mol Ther 9(2):189–197PubMedGoogle Scholar
  81. Kurozumi K, Nakamura K, Tamiya T, Kawano Y, Ishii K, Kobune M, Hirai S, Uchida H, Sasaki K, Ito Y, Kato K, Honmou O, Houkin K, Date I, Hamada H (2005) Mesenchymal stem cells that produce neurotrophic factors reduce ischemic damage in the rat middle cerebral artery occlusion model. Mol Ther 11(1):96–104PubMedGoogle Scholar
  82. Latif MJ, Afthinos JN, Connery CP, Perin N, Bhora FY, Chwajol M, Todd GJ, Belsley SJ (2008) Robotic intercostal nerve graft for reversal of thoracic sympathectomy: a large animal feasibility model. Int J Med Robot 4(3):258–262PubMedGoogle Scholar
  83. Lee H, Jo EK, Choi SY, Oh SB, Park K, Kim JS, Lee SJ (2006) Necrotic neuronal cells induce inflammatory Schwann cell activation via TLR2 and TLR3: implication in Wallerian degeneration. Biochem Biophys Res Commun 350(3):742–747PubMedGoogle Scholar
  84. Levkovitch-Verbin H, Sadan O, Vander S, Rosner M, Barhum Y, Melamed E, Offen D, Melamed S (2010) Intravitreal injections of neurotrophic factors secreting mesenchymal stem cells are neuroprotective in rat eyes following optic nerve transection. Invest Ophthalmol Vis Sci 51(12):6394–6400PubMedGoogle Scholar
  85. Lewin GR, Barde YA (1996) Physiology of the neurotrophins. Annu Rev Neurosci 19:289–317PubMedGoogle Scholar
  86. Lewin SL, Utley DS, Cheng ET, Verity AN, Terris DJ (1997) Simultaneous treatment with BDNF and CNTF after peripheral nerve transection and repair enhances rate of functional recovery compared with BDNF treatment alone. Laryngoscope 107(7):992–999PubMedGoogle Scholar
  87. Lewis EB (1992) The 1991 Albert Lasker Medical Awards. Clusters of master control genes regulate the development of higher organisms. JAMA 267(11):1524–1531PubMedGoogle Scholar
  88. Li Y, Chen J, Wang L, Lu M, Chopp M (2001) Treatment of stroke in rat with intracarotid administration of marrow stromal cells. Neurology 56(12):1666–1672PubMedGoogle Scholar
  89. Li Y, McIntosh K, Chen J, Zhang C, Gao Q, Borneman J, Raginski K, Mitchell J, Shen L, Zhang J, Lu D, Chopp M (2006) Allogeneic bone marrow stromal cells promote glial-axonal remodeling without immunologic sensitization after stroke in rats. Exp Neurol 198(2):313–325PubMedGoogle Scholar
  90. Li LY, Li JT, Wu QY, Li J, Feng ZT, Liu S, Wang TH (2008) Transplantation of NGF-gene-modified bone marrow stromal cells into a rat model of Alzheimer’ disease. J Mol Neurosci 34(2):157–163PubMedGoogle Scholar
  91. Li X-Y, Zheng Z-H, Li X-Y, Guo J, Zhang Y, Li H, Wang Y-W, Ren J, Wu Z-B (2013) Treatment of foot disease in patients with type 2 diabetes mellitus using human umbilical cord blood mesenchymal stem cells: response and correction of immunological anomalies. Curr Pharm Des 19(27):4893–4899PubMedGoogle Scholar
  92. Li X, Zhang Y, Yeung SC, Liang Y, Liang X, Ding Y, Ip MS, Tse HF, Mak JC, Lian Q (2014) Mitochondrial transfer of induced pluripotent stem cell-derived mesenchymal stem cells to airway epithelial cells attenuates cigarette smoke-induced damage. Am J Respir Cell Mol Biol 51(3):455–465PubMedGoogle Scholar
  93. Lieberman AR (1971) The axon reaction: a review of the principal features of perikaryal responses to axon injury. Int Rev Neurobiol 14:49–124PubMedGoogle Scholar
  94. Lin CH, Forscher P (1993) Cytoskeletal remodeling during growth cone-target interactions. J Cell Biol 121(6):1369–1383PubMedGoogle Scholar
  95. Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F (1993) GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 260(5111):1130–1132Google Scholar
  96. López-León M, Outeiro TF, Goya RG (2017) Cell reprogramming: therapeutic potential and the promise of rejuvenation for the aging brain. Ageing Res Rev 40:168–181PubMedGoogle Scholar
  97. Lu D, Mahmood A, Wang L, Li Y, Lu M, Chopp M (2001) Adult bone marrow stromal cells administered intravenously to rats after traumatic brain injury migrate into brain and improve neurological outcome. Neuroreport 12(3):559–563PubMedGoogle Scholar
  98. Lu P, Jones LL, Tuszynski MH (2005) BDNF-expressing marrow stromal cells support extensive axonal growth at sites of spinal cord injury. Exp Neurol 191(2):344–360PubMedGoogle Scholar
  99. Lundborg G (2000) A 25-year perspective of peripheral nerve surgery: evolving neuroscientific concepts and clinical significance. J Hand Surg 25(3):391–414Google Scholar
  100. Machalińska A, Kawa M, Pius-Sadowska E, Stępniewski J, Nowak W, Rogińska D, Kaczyńska K, Baumert B, Wiszniewska B, Józkowicz A (2013) Long-Term Neuroprotective Effects of NT-4–Engineered Mesenchymal Stem Cells Injected Intravitreally in a Mouse Model of Acute Retinal Injury. Invest Ophthalmol Vis Sci 54(13):8292–8305PubMedGoogle Scholar
  101. Mahay D, Terenghi G, Shawcross SG (2008) Schwann cell mediated trophic effects by differentiated mesenchymal stem cells. Exp Cell Res 314(14):2692–2701PubMedGoogle Scholar
  102. Maricevic A, Erceg M (1997) War injuries to the extremities. Mil Med 162(12):808–811PubMedGoogle Scholar
  103. Mazzoni A, Bronte V, Visintin A, Spitzer JH, Apolloni E, Serafini P, Zanovello P, Segal DM (2002) Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism. J Immunol 168(2):689–695PubMedGoogle Scholar
  104. McMahon SB, Armanini MP, Ling LH, Phillips HS (1994) Expression and coexpression of Trk receptors in subpopulations of adult primary sensory neurons projecting to identified peripheral targets. Neuron 12(5):1161–1171PubMedGoogle Scholar
  105. Meek MF, Coert JH (2002) Clinical use of nerve conduits in peripheral-nerve repair: review of the literature. J Reconstr Microsurg 18(2):97–109PubMedGoogle Scholar
  106. Millesi H (1981) Interfascicular nerve grafting. Orthop Clin North Am 12(2): 287–301PubMedGoogle Scholar
  107. Mimura T, Dezawa M, Kanno H, Sawada H, Yamamoto I (2004) Peripheral nerve regeneration by transplantation of bone marrow stromal cell-derived Schwann cells in adult rats. J Neurosurg 101(5):806–812PubMedGoogle Scholar
  108. Mimura T, Dezawa M, Kanno H, Yamamoto I (2005) Behavioral and histological evaluation of a focal cerebral infarction rat model transplanted with neurons induced from bone marrow stromal cells. J Neuropathol Exp Neurol 64(12):1108–1117PubMedGoogle Scholar
  109. Moloney TC, Rooney GE, Barry FP, Howard L, Dowd E (2010) Potential of rat bone marrow-derived mesenchymal stem cells as vehicles for delivery of neurotrophins to the Parkinsonian rat brain. Brain Res 1359:33–43PubMedGoogle Scholar
  110. Moreno-Flores MT, Bradbury EJ, Martin-Bermejo MJ, Agudo M, Lim F, Pastrana E, Avila J, Diaz-Nido J, McMahon SB, Wandosell F (2006) A clonal cell line from immortalized olfactory ensheathing glia promotes functional recovery in the injured spinal cord. Mol Ther 13(3):598–608PubMedGoogle Scholar
  111. Mosahebi A, Woodward B, Wiberg M, Martin R, Terenghi G (2001) Retroviral labeling of Schwann cells: in vitro characterization and in vivo transplantation to improve peripheral nerve regeneration. Glia 34(1):8–17PubMedGoogle Scholar
  112. Muraglia A, Cancedda R, Quarto R (2000) Clonal mesenchymal progenitors from human bone marrow differentiate in vitro according to a hierarchical model. J Cell Sci 113. ( Pt 7:1161–1166PubMedGoogle Scholar
  113. Nakajima H, Uchida K, Guerrero AR, Watanabe S, Sugita D, Takeura N, Yoshida A, Long G, Wright KT, Johnson WE, Baba H (2012) Transplantation of mesenchymal stem cells promotes an alternative pathway of macrophage activation and functional recovery after spinal cord injury. J Neurotrauma 29(8):1614–1625PubMedPubMedCentralGoogle Scholar
  114. Nectoux E, Taleb C, Liverneaux P (2009) Nerve repair in telemicrosurgery: an experimental study. J Reconstr Microsurg 25(4):261–265PubMedGoogle Scholar
  115. Ni WF, Yin LH, Lu J, Xu HZ, Chi YL, Wu JB, Zhang N (2010) In vitro neural differentiation of bone marrow stromal cells induced by cocultured olfactory ensheathing cells. Neurosci Lett 475(2):99–103PubMedGoogle Scholar
  116. Nizzardo M, Simone C, Falcone M, Riboldi G, Comi GP, Bresolin N, Corti S (2013) Direct reprogramming of adult somatic cells into other lineages: past evidence and future perspectives. Cell Transplant 22(6):921–944PubMedGoogle Scholar
  117. Noble J, Munro CA, Prasad VS, Midha R (1998) Analysis of upper and lower extremity peripheral nerve injuries in a population of patients with multiple injuries. J Trauma 45(1):116–122PubMedGoogle Scholar
  118. Nomura T, Honmou O, Harada K, Houkin K, Hamada H, Kocsis JD (2005) I.V. infusion of brain-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat. Neuroscience 136(1):161–169PubMedPubMedCentralGoogle Scholar
  119. Novikov L, Novikova L, Kellerth JO (1995) Brain-derived neurotrophic factor promotes survival and blocks nitric oxide synthase expression in adult rat spinal motoneurons after ventral root avulsion. Neurosci Lett 200(1):45–48PubMedGoogle Scholar
  120. Oliveira JT, Almeida FM, Biancalana A, Baptista AF, Tomaz MA, Melo PA, Martinez AM (2010) 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 170(4):1295–1303PubMedGoogle Scholar
  121. Oliveira JT, Mostacada K, de Lima S, Martinez AM (2013) Bone marrow mesenchymal stem cell transplantation for improving nerve regeneration. Int Rev Neurobiol 108:59–77PubMedGoogle Scholar
  122. Oppenheim RW (1991) Cell death during development of the nervous system. Annu Rev Neurosci 14:453–501PubMedGoogle Scholar
  123. Oppenheim RW, Yin QW, Prevette D, Yan Q (1992) Brain-derived neurotrophic factor rescues developing avian motoneurons from cell death. Nature 360(6406):755–757PubMedGoogle Scholar
  124. Pan HC, Cheng FC, Chen CJ, Lai SZ, Lee CW, Yang DY, Chang MH, Ho SP (2007) Post-injury regeneration in rat sciatic nerve facilitated by neurotrophic factors secreted by amniotic fluid mesenchymal stem cells. J Clin Neurosci 14(11):1089–1098PubMedGoogle Scholar
  125. Park H-YL, Kim JH, Kim HS, Park CK (2012) Stem cell-based delivery of brain-derived neurotrophic factor gene in the rat retina. Brain Res 1469:10–23PubMedGoogle Scholar
  126. Pereira Lopes FR, Camargo de Moura Campos L, Dias Correa J Jr, Balduino A, Lora S, Langone F, Borojevic R, Blanco Martinez AM (2006) Bone marrow stromal cells and resorbable collagen guidance tubes enhance sciatic nerve regeneration in mice. Exp Neurol 198(2):457–468PubMedGoogle Scholar
  127. Pereira JH, Bowden RE, Gattuso JM, Norris RW (1991) Comparison of results of repair of digital nerves by denatured muscle grafts and end-to-end sutures. J Hand Surg Br 16(5):519–523PubMedGoogle Scholar
  128. Pereira JH, Bowden RE, Narayanakumar TS, Gschmeissner SE (1996) Peripheral nerve reconstruction using denatured muscle autografts for restoring protective sensation in hands and feet of leprosy patients. Indian J Lepr 68(1):83–91PubMedGoogle Scholar
  129. Plotnikov EY, Khryapenkova TG, Vasileva AK, Marey MV, Galkina SI, Isaev NK, Sheval EV, Polyakov VY, Sukhikh GT, Zorov DB (2008) Cell-to-cell cross-talk between mesenchymal stem cells and cardiomyocytes in co-culture. J Cell Mol Med 12(5A):1622–1631PubMedGoogle Scholar
  130. Pollock K, Dahlenburg H, Nelson H, Fink KD, Cary W, Hendrix K, Annett G, Torrest A, Deng P, Gutierrez J, Nacey C, Pepper K, Kalomoiris S, J DA, McGee J, Gruenloh W, Fury B, Bauer G, Duffy A, Tempkin T, Wheelock V, Nolta JA (2016) Human Mesenchymal Stem Cells Genetically Engineered to Overexpress Brain-derived Neurotrophic Factor Improve Outcomes in Huntington’s Disease Mouse Models. Mol Ther 24(5):965–977PubMedPubMedCentralGoogle Scholar
  131. Prasad A, Manivannan J, Loong DT, Chua SM, Gharibani PM, All AH (2016) A review of induced pluripotent stem cell, direct conversion by trans-differentiation, direct reprogramming and oligodendrocyte differentiation. Regen Med 11(2):181–191PubMedGoogle Scholar
  132. Purves D (1986) The trophic theory of neural concentrations. Trends Neurosci 9:486–489Google Scholar
  133. Rath EM (2002) Skeletal muscle autograft for repair of the human inferior alveolar nerve: a case report. J Oral Maxillofac Surg 60(3):330–334PubMedGoogle Scholar
  134. Ren Z, Wang J, Wang S, Zou C, Li X, Guan Y, Chen Z, Zhang YA (2013) Autologous transplantation of GDNF-expressing mesenchymal stem cells protects against MPTP-induced damage in cynomolgus monkeys. Sci Rep 3:2786PubMedPubMedCentralGoogle Scholar
  135. Ribeiro-Resende VT, Pimentel-Coelho PM, Mesentier-Louro LA, Mendez RM, Mello-Silva JP, Cabral-da-Silva MC, de Mello FG, de Melo Reis RA, Mendez-Otero R (2009) Trophic activity derived from bone marrow mononuclear cells increases peripheral nerve regeneration by acting on both neuronal and glial cell populations. Neuroscience 159(2):540–549PubMedGoogle Scholar
  136. Robinson LR (2000) Traumatic injury to peripheral nerves. Muscle Nerve 23(6):863–873PubMedGoogle Scholar
  137. Robinson LR (2004) traumatic injury to peripheral nerves. Suppl Clin Neurophysiol 57:173–186PubMedGoogle Scholar
  138. Rosberg HE, Carlsson KS, Dahlin LB (2005) Prospective study of patients with injuries to the hand and forearm: costs, function, and general health. Scand J Plast Reconstr Surg Hand Surg 39(6):360–369PubMedGoogle Scholar
  139. Sakaguchi DS (2017) Regenerative and repair strategies for the central nervous system. In: Neuroimmune pharmacology. Springer, Cham, pp 799–818Google Scholar
  140. Salzer JL, Bunge RP (1980) Studies of Schwann cell proliferation. I. An analysis in tissue culture of proliferation during development, Wallerian degeneration, and direct injury. J Cell Biol 84(3):739–752PubMedGoogle Scholar
  141. Sameem M, Wood TJ, Bain JR (2011) A systematic review on the use of fibrin glue for peripheral nerve repair. Plast Reconstr Surg 127(6):2381–2390PubMedGoogle Scholar
  142. Sandquist EJ, Uz M, Sharma AD, Patel BB, Mallapragada SK, Sakaguchi DS (2016) Stem cells, bioengineering and 3-D scaffolds for nervous system repair and regeneration. In: Zhang LG, Kaplan D (eds) Neural engineering: from advanced biomaterials to 3D fabrication techniques. Springer, New YorkGoogle Scholar
  143. Sasaki M, Radtke C, Tan AM, Zhao P, Hamada H, Houkin K, Honmou O, Kocsis JD (2009) BDNF-hypersecreting human mesenchymal stem cells promote functional recovery, axonal sprouting, and protection of corticospinal neurons after spinal cord injury. J Neurosci 29(47):14932–14941PubMedPubMedCentralGoogle Scholar
  144. Schlosshauer B, Muller E, Schroder B, Planck H, Muller HW (2003) Rat Schwann cells in bioresorbable nerve guides to promote and accelerate axonal regeneration. Brain Res 963(1-2):321–326PubMedGoogle Scholar
  145. Seddon HJ, Medawar PB, Smith H (1943) Rate of regeneration of peripheral nerves in man. J Physiol 102(2):191–215PubMedPubMedCentralGoogle Scholar
  146. Sharma AD, Brodskiy PA, Petersen EM, Dagdeviren M, Ye EA, Mallapragada SK, Sakaguchi DS (2015) High throughput characterization of adult stem cells engineered for delivery of therapeutic factors for neuroprotective strategies. J Vis Exp (95)Google Scholar
  147. Sharma AD, Wiederin J, Uz M, Ciborowski P, Mallapragada SK, Gendelman HE, Sakaguchi DS (2017) Proteomic analysis of mesenchymal to Schwann cell transdifferentiation. J Proteomics 165:93–101PubMedGoogle Scholar
  148. Shibata T, Naruse K, Kamiya H, Kozakae M, Kondo M, Yasuda Y, Nakamura N, Ota K, Tosaki T, Matsuki T (2008) Transplantation of bone marrow–derived mesenchymal stem cells improves diabetic polyneuropathy in rats. Diabetes 57(11):3099–3107PubMedPubMedCentralGoogle Scholar
  149. Shimizu S, Kitada M, Ishikawa H, Itokazu Y, Wakao S, Dezawa M (2007) Peripheral nerve regeneration by the in vitro differentiated-human bone marrow stromal cells with Schwann cell property. Biochem Biophys Res Commun 359(4):915–920PubMedGoogle Scholar
  150. Shirley DM, Williams SA, Santos PM (1996) Brain-derived neurotrophic factor and peripheral nerve regeneration: a functional evaluation. Laryngoscope 106(5 Pt 1):629–632PubMedGoogle Scholar
  151. Siemionow M, Brzezicki G (2009) Chapter 8: Current techniques and concepts in peripheral nerve repair. Int Rev Neurobiol 87:141–172PubMedGoogle Scholar
  152. Siniscalco D, Giordano C, Galderisi U, Luongo L, de Novellis V, Rossi F, Maione S (2011) Long-lasting effects of human mesenchymal stem cell systemic administration on pain-like behaviors, cellular, and biomolecular modifications in neuropathic mice. Front Integr Neurosci 5:79PubMedPubMedCentralGoogle Scholar
  153. Someya Y, Koda M, Dezawa M, Kadota T, Hashimoto M, Kamada T, Nishio Y, Kadota R, Mannoji C, Miyashita T, Okawa A, Yoshinaga K, Yamazaki M (2008) Reduction of cystic cavity, promotion of axonal regeneration and sparing, and functional recovery with transplanted bone marrow stromal cell-derived Schwann cells after contusion injury to the adult rat spinal cord. J Neurosurg Spine 9(6):600–610PubMedGoogle Scholar
  154. Song HJ, Poo MM (1999) Signal transduction underlying growth cone guidance by diffusible factors. Curr Opin Neurobiol 9(3):355–363PubMedGoogle Scholar
  155. Spees JL, Olson SD, Whitney MJ, Prockop DJ (2006) Mitochondrial transfer between cells can rescue aerobic respiration. Proc Natl Acad Sci U S A 103(5):1283–1288PubMedPubMedCentralGoogle Scholar
  156. Squillaro T, Peluso G, Galderisi U (2016) Clinical trials with mesenchymal stem cells: an update. Cell Transplant 25(5):829–848PubMedGoogle Scholar
  157. Stanec S, Tonkovic I, Stanec Z, Tonkovic D, Dzepina I (1997) Treatment of upper limb nerve war injuries associated with vascular trauma. Injury 28(7):463–468PubMedGoogle Scholar
  158. Stoll G, Griffin JW, Li CY, Trapp BD (1989) Wallerian degeneration in the peripheral nervous system: participation of both Schwann cells and macrophages in myelin degradation. J Neurocytol 18(5):671–683PubMedGoogle Scholar
  159. Stoll G, Jander S, Myers RR (2002) Degeneration and regeneration of the peripheral nervous system: from Augustus Waller’s observations to neuroinflammation. J Peripher Nerv Syst 7(1):13–27PubMedGoogle Scholar
  160. Strauch B, Rodriguez DM, Diaz J, Yu HL, Kaplan G, Weinstein DE (2001) Autologous Schwann cells drive regeneration through a 6-cm autogenous venous nerve conduit. J Reconstr Microsurg 17(8):589–595 discussion 596-587PubMedGoogle Scholar
  161. Streppel M, Azzolin N, Dohm S, Guntinas-Lichius O, Haas C, Grothe C, Wevers A, Neiss WF, Angelov DN (2002) Focal application of neutralizing antibodies to soluble neurotrophic factors reduces collateral axonal branching after peripheral nerve lesion. Eur J Neurosci 15(8):1327–1342PubMedGoogle Scholar
  162. Sunderland S, Williams HB (1992) Nerve injuries and their repair: a critical appraisal. LWWGoogle Scholar
  163. Takemura Y, Imai S, Kojima H, Katagi M, Yamakawa I, Kasahara T, Urabe H, Terashima T, Yasuda H, Chan L, Kimura H, Matsusue Y (2012) Brain-derived neurotrophic factor from bone marrow-derived cells promotes post-injury repair of peripheral nerve. PLoS One 7(9):e44592PubMedPubMedCentralGoogle Scholar
  164. Terenghi G (1999) Peripheral nerve regeneration and neurotrophic factors. J Anat 194. ( Pt 1:1–14PubMedPubMedCentralGoogle Scholar
  165. Terness P, Bauer TM, Röse L, Dufter C, Watzlik A, Simon H, Opelz G (2002) Inhibition of allogeneic T cell proliferation by indoleamine 2, 3-dioxygenase–expressing dendritic cells: mediation of suppression by tryptophan metabolites. J Exp Med 196(4):447–457PubMedPubMedCentralGoogle Scholar
  166. Tetzlaff W (1982) Tight junction contact events and temporary gap junctions in the sciatic nerve fibres of the chicken during Wallerian degeneration and subsequent regeneration. J Neurocytol 11(5):839–858PubMedGoogle Scholar
  167. Thoma EC, Merkl C, Heckel T, Haab R, Knoflach F, Nowaczyk C, Flint N, Jagasia R, Jensen Zoffmann S, Truong HH, Petitjean P, Jessberger S, Graf M, Iacone R (2014) Chemical conversion of human fibroblasts into functional Schwann cells. Stem Cell Rep 3(4):539–547Google Scholar
  168. Tofaris GK, Patterson PH, Jessen KR, Mirsky R (2002) Denervated Schwann cells attract macrophages by secretion of leukemia inhibitory factor (LIF) and monocyte chemoattractant protein-1 in a process regulated by interleukin-6 and LIF. J Neurosci 22(15):6696–6703PubMedGoogle Scholar
  169. Tseng TC, Hsu SH (2014) Substrate-mediated nanoparticle/gene delivery to MSC spheroids and their applications in peripheral nerve regeneration. Biomaterials 35(9):2630–2641Google Scholar
  170. Tung TH, Mackinnon SE (2010) Nerve transfers: indications, techniques, and outcomes. J Hand Surg [Am] 35(2):332–341Google Scholar
  171. Uz M, Büyüköz M, Sharma AD, Sakaguchi DS, Altinkaya SA, Mallapragada SK (2017) Gelatin-based 3D conduits for transdifferentiation of mesenchymal stem cells into Schwann cell-like phenotypes. Acta Biomater 53:293–306PubMedGoogle Scholar
  172. Uz M, Das SR, Ding S, Sakaguchi DS, Claussen JC, Mallapragada SK (2018) Advances in controlling differentiation of adult stem cells for peripheral nerve regeneration. Adv Healthc Mater:1701046Google Scholar
  173. Vallabhaneni KC, Haller H, Dumler I (2012) Vascular smooth muscle cells initiate proliferation of mesenchymal stem cells by mitochondrial transfer via tunneling nanotubes. Stem Cells Dev 21(17):3104–3113PubMedPubMedCentralGoogle Scholar
  174. van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ (2009) Regeneration of the ischemic brain by engineered stem cells: fuelling endogenous repair processes. Brain Res Rev 61(1):1–13PubMedGoogle Scholar
  175. Verge VM, Merlio JP, Grondin J, Ernfors P, Persson H, Riopelle RJ, Hokfelt T, Richardson PM (1992) Colocalization of NGF binding sites, trk mRNA, and low-affinity NGF receptor mRNA in primary sensory neurons: responses to injury and infusion of NGF. J Neurosci 12(10):4011–4022PubMedGoogle Scholar
  176. Verge VM, Richardson PM, Wiesenfeld-Hallin Z, Hokfelt T (1995) Differential influence of nerve growth factor on neuropeptide expression in vivo: a novel role in peptide suppression in adult sensory neurons. J Neurosci 15(3 Pt 1):2081–2096PubMedGoogle Scholar
  177. Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Sudhof TC, Wernig M (2010) Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463(7284):1035–1041PubMedPubMedCentralGoogle Scholar
  178. Wakao S, Hayashi T, Kitada M, Kohama M, Matsue D, Teramoto N, Ose T, Itokazu Y, Koshino K, Watabe H, Iida H, Takamoto T, Tabata Y, Dezawa M (2010) 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 223(2):537–547PubMedGoogle Scholar
  179. Wang J, Ding F, Gu Y, Liu J, Gu X (2009) Bone marrow mesenchymal stem cells promote cell proliferation and neurotrophic function of Schwann cells in vitro and in vivo. Brain Res 1262:7–15PubMedGoogle Scholar
  180. Wang X, Luo E, Li Y, Hu J (2011) Schwann-like mesenchymal stem cells within vein graft facilitate facial nerve regeneration and remyelination. Brain Res 1383:71–80PubMedGoogle Scholar
  181. Wang Y, Chen X, Cao W, Shi Y (2014) Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Nat Immunol 15(11):1009PubMedGoogle Scholar
  182. Watson WE (1974) The binding of actinomycin D to the nuclei of axotomised neurones. Brain Res 65(2):317–322PubMedGoogle Scholar
  183. Weimann JM, Johansson CB, Trejo A, Blau HM (2003) Stable reprogrammed heterokaryons form spontaneously in Purkinje neurons after bone marrow transplant. Nat Cell Biol 5(11):959–966PubMedGoogle Scholar
  184. Weintraub H, Davis R, Tapscott S, Thayer M, Krause M, Benezra R, Blackwell TK, Turner D, Rupp R, Hollenberg S et al (1991) The myoD gene family: nodal point during specification of the muscle cell lineage. Science 251(4995):761–766PubMedGoogle Scholar
  185. Whitlock EL, Kasukurthi R, Yan Y, Tung TH, Hunter DA, Mackinnon SE (2010) Fibrin glue mitigates the learning curve of microneurosurgical repair. Microsurgery 30(3):218–222PubMedGoogle Scholar
  186. Woodbury D, Schwarz EJ, Prockop DJ, Black IB (2000) Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res 61(4):364–370PubMedGoogle Scholar
  187. Wright DE, Snider WD (1995) Neurotrophin receptor mRNA expression defines distinct populations of neurons in rat dorsal root ganglia. J Comp Neurol 351(3):329–338PubMedGoogle Scholar
  188. Wu J, Yu W, Chen Y, Su Y, Ding Z, Ren H, Jiang Y, Wang J (2010) Intrastriatal transplantation of GDNF-engineered BMSCs and its neuroprotection in lactacystin-induced Parkinsonian rat model. Neurochem Res 35(3):495–502PubMedGoogle Scholar
  189. Wyse RD, Dunbar GL, Rossignol J (2014) Use of genetically modified mesenchymal stem cells to treat neurodegenerative diseases. Int J Mol Sci 15(2):1719–1745PubMedPubMedCentralGoogle Scholar
  190. Xue C, Hu N, Gu Y, Yang Y, Liu Y, Liu J, Ding F, Gu X (2012) Joint use of a chitosan/PLGA scaffold and MSCs to bridge an extra large gap in dog sciatic nerve. Neurorehabil Neural Repair 26(1):96–106PubMedGoogle Scholar
  191. Yan Q, Elliott J, Snider WD (1992) Brain-derived neurotrophic factor rescues spinal motor neurons from axotomy-induced cell death. Nature 360(6406):753–755PubMedGoogle Scholar
  192. Yan Q, Matheson C, Lopez OT, Miller JA (1994) The biological responses of axotomized adult motoneurons to brain-derived neurotrophic factor. J Neurosci 14(9):5281–5291PubMedGoogle Scholar
  193. Yang J, Lou Q, Huang R, Shen L, Chen Z (2008) Dorsal root ganglion neurons induce transdifferentiation of mesenchymal stem cells along a Schwann cell lineage. Neurosci Lett 445(3):246–251PubMedGoogle Scholar
  194. Yang Y, Yuan X, Ding F, Yao D, Gu Y, Liu J, Gu X (2011) Repair of rat sciatic nerve gap by a silk fibroin-based scaffold added with bone marrow mesenchymal stem cells. Tissue Eng Part A 17(17-18):2231–2244PubMedGoogle Scholar
  195. Ye E-A, Chawla SS, Khan MZ, Sakaguchi DS (2016) Bone marrow-derived mesenchymal stem cells (MSCs) stimulate neurite outgrowth from differentiating adult hippocampal progenitor cells. Stem Cell Biol Res 3(1):3Google Scholar
  196. Yin Q, Kemp GJ, Frostick SP (1998) Neurotrophins, neurones and peripheral nerve regeneration. J Hand Surg Br 23(4):433–437PubMedGoogle Scholar
  197. Zhang CG, Gu YD (2011) Contralateral C7 nerve transfer – our experiences over past 25 years. J Brachial Plex Peripher Nerve Inj 6(1):10PubMedPubMedCentralGoogle Scholar
  198. Zhang JY, Luo XG, Xian CJ, Liu ZH, Zhou XF (2000) Endogenous BDNF is required for myelination and regeneration of injured sciatic nerve in rodents. Eur J Neurosci 12(12):4171–4180PubMedGoogle Scholar
  199. Zhang F, Blain B, Beck J, Zhang J, Chen Z, Chen ZW, Lineaweaver WC (2002) Autogenous venous graft with one-stage prepared Schwann cells as a conduit for repair of long segmental nerve defects. J Reconstr Microsurg 18(4):295–300PubMedGoogle Scholar
  200. Zheng M, Kuffler DP (2000) Guidance of regenerating motor axons in vivo by gradients of diffusible peripheral nerve-derived factors. J Neurobiol 42(2):212–219PubMedGoogle Scholar
  201. Zheng J, Sun J, Lu X, Zhao P, Li K, Li L (2016) BDNF promotes the axonal regrowth after sciatic nerve crush through intrinsic neuronal capability upregulation and distal portion protection. Neurosci Lett 621:1–8PubMedGoogle Scholar
  202. Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, Conti L, MacDonald ME, Friedlander RM, Silani V, Hayden MR (2001) Loss of huntingtin-mediated BDNF gene transcription in Huntington’s disease. Science 293(5529):493–498PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Metzere Bierlein De la Rosa
    • 1
    • 2
  • Emily M. Kozik
    • 3
    • 4
  • Donald S. Sakaguchi
    • 1
    • 3
    • 4
    • 5
    Email author
  1. 1.Department of Biomedical SciencesCollege of Veterinary Medicine, Iowa State UniversityAmesUSA
  2. 2.Veterinary Specialty CenterBuffalo GroveUSA
  3. 3.Biology Program, Department of Genetics, Development and Cell BiologyIowa State UniversityAmesUSA
  4. 4.Department of Genetics, Development and Cell BiologyIowa State UniversityAmesUSA
  5. 5.Neuroscience ProgramIowa State UniversityAmesUSA

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