Skip to main content

Advertisement

SpringerLink
Log in

Stem Cell-Based Approaches to Improve Nerve Regeneration: Potential Implications for Reconstructive Transplantation?

  • Review
  • Published:
Archivum Immunologiae et Therapiae Experimentalis Aims and scope

Abstract

Reconstructive transplantation has become a viable option to restore form and function after devastating tissue loss. Functional recovery is a key determinant of overall success and critically depends on the quality and pace of nerve regeneration. Several molecular and cell-based therapies have been postulated and tested in pre-clinical animal models to enhance nerve regeneration. Schwann cells remain the mainstay of research focus providing neurotrophic support and signaling cues for regenerating axons. Alternative cell sources such as mesenchymal stem cells and adipose-derived stromal cells have also been tested in pre-clinical animal models and in clinical trials due to their relative ease of harvest, rapid expansion in vitro, minimal immunogenicity, and capacity to integrate and survive within host tissues, thereby overcoming many of the challenges faced by culturing of human Schwann cells and nerve allografting. Induced pluripotent stem cell-derived Schwann cells are of particular interest since they can provide abundant, patient-specific autologous Schwann cells. The majority of experimental evidence on cell-based therapies, however, has been generated using stem cell-seeded nerve guides that were developed to enhance nerve regeneration across “gaps” in neural repair. Although primary end-to-end repair is the preferred method of neurorrhaphy in reconstructive transplantation, mechanistic studies elucidating the principles of cell-based therapies from nerve guidance conduits will form the foundation of further research employing stem cells in end-to-end repair of donor and recipient nerves. This review presents key components of nerve regeneration in reconstructive transplantation and highlights the pre-clinical studies that utilize stem cells to enhance nerve regeneration.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Aggarwal S, Pittenger MF (2005) Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105:1815–1822

    CAS  PubMed  Google Scholar 

  • Amariglio N, Hirshberg A, Scheithauer BW et al (2009) Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Med 6:e1000029

    PubMed Central  PubMed  Google Scholar 

  • Ansselin AD, Fink T, Davey DF (1997) Peripheral nerve regeneration through nerve guides seeded with adult Schwann cells. Neuropathol Appl Neurobiol 23:387–398

    CAS  PubMed  Google Scholar 

  • Ao Q, Fung C-K, Tsui AY et al (2011) The regeneration of transected sciatic nerves of adult rats using chitosan nerve conduits seeded with bone marrow stromal cell-derived Schwann cells. Biomaterials 32:787–796

    CAS  PubMed  Google Scholar 

  • Argyros O, Wong SP, Niceta M et al (2008) Persistent episomal transgene expression in liver following delivery of a scaffold/matrix attachment region containing non-viral vector. Gene Ther 15:1593–1605

    CAS  PubMed  Google Scholar 

  • Asteria Biotherapeutics (2010) Safety Study of GRNOPC1 in Spinal Cord Injury (2010) http://clinicaltrials.gov/ct2/show/NCT01217008?term=GRNOPC1&rank=1 (Identification No. NCT01217008)

  • Bainbridge J, Dhillon B (2011) Safety and tolerability of sub-retinal transplantation of human embryonic stem cell derived retinal pigmented epithelial (hESC-RPE) cells in patients with Stargardt’s macular dystrophy (SMD) In: ClinicalTrials.gov [Internet]. National Library of Medicine (US), Bethesda. http://clinicaltrials.gov/ct2/show/NCT01469832 (Cited 27 Jun 2014)

  • Berrocal YA, Almeida VW, Gupta R et al (2013) Transplantation of Schwann cells in a collagen tube for the repair of large, segmental peripheral nerve defects in rats. J Neurosurg 119:720–732

    PubMed  Google Scholar 

  • Bhatheja K, Field J (2006) Schwann cells: origins and role in axonal maintenance and regeneration. Int J Biochem Cell Biol 38:1995–1999

    CAS  PubMed  Google Scholar 

  • Bigbee JW, Yoshino JE, DeVries GH (1987) Morphological and proliferative responses of cultured Schwann cells following rapid phagocytosis of a myelin-enriched fraction. J Neurocytol 16:487–496

    CAS  PubMed  Google Scholar 

  • Bonab MM, Alimoghaddam K, Talebian F et al (2006) Aging of mesenchymal stem cell in vitro. BMC Cell Biol 7:14

    PubMed Central  PubMed  Google Scholar 

  • Boyd JG, Gordon T (2003) Glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor sustain the axonal regeneration of chronically axotomized motoneurons in vivo. Exp Neurol 183:610–619

    CAS  PubMed  Google Scholar 

  • Brown RE, Erdmann D, Lyons SF et al (1996) The use of cultured Schwann cells in nerve repair in a rabbit hind-limb model. J Reconstr Microsurg 12:149–152

    CAS  PubMed  Google Scholar 

  • Brushart TM (1988) Preferential reinnervation of motor nerves by regenerating motor axons. J Neurosci 8:1026–1031

    CAS  PubMed  Google Scholar 

  • Bunge RP (1994) The role of the Schwann cell in trophic support and regeneration. J Neurol 242:S19–S21

    CAS  PubMed  Google Scholar 

  • Caddick J, Kingham PJ, Gardiner NJ et al (2006) Phenotypic and functional characteristics of mesenchymal stem cells differentiated along a Schwann cell lineage. Glia 54:840–849

    PubMed  Google Scholar 

  • Cajal R (1928) Degeneration and regeneration of the nervous system. Oxford University Press, London

    Google Scholar 

  • Chabas JF, Alluin O, Rao G et al (2008) Vitamin D2 potentiates axon regeneration. J Neurotrauma 25:1247–1256

    PubMed  Google Scholar 

  • Chen CJ, Ou YC, Liao SL et al (2007) Transplantation of bone marrow stromal cells for peripheral nerve repair. Exp Neurol 204:443–453

    CAS  PubMed  Google Scholar 

  • Chew SY, Mi R, Hoke A et al (2008) The effect of the alignment of electrospun fibrous scaffolds on Schwann cell maturation. Biomaterials 29:653–661

    CAS  PubMed Central  PubMed  Google Scholar 

  • Csete M (2010) Translational prospects for human induced pluripotent stem cells. Regen Med 5:509–519

    PubMed  Google Scholar 

  • Cuevas P, Carceller F, Garcia-Gomez I et al (2004) Bone marrow stromal cell implantation for peripheral nerve repair. Neurol Res 26:230–232

    PubMed  Google Scholar 

  • Cui L, Yin S, Liu W et al (2007) Expanded adipose-derived stem cells suppress mixed lymphocyte reaction by secretion of prostaglandin E2. Tissue Eng 13:1185–1195

    CAS  PubMed  Google Scholar 

  • Dedkov EI, Kostrominova TY, Borisov AB et al (2002) Survival of Schwann cells in chronically denervated skeletal muscles. Acta Neuropathol 103:565–574

    CAS  PubMed  Google Scholar 

  • DelaRosa O, Lombardo E, Beraza A et al (2009) Requirement of IFN-gamma-mediated indoleamine 2,3-dioxygenase expression in the modulation of lymphocyte proliferation by human adipose-derived stem cells. Tissue Eng Part A 15:2795–2806

    CAS  PubMed  Google Scholar 

  • Deng LX, Deng P, Ruan Y et al (2013) A novel growth-promoting pathway formed by GDNF-overexpressing Schwann cells promotes propriospinal axonal regeneration, synapse formation, and partial recovery of function after spinal cord injury. J Neurosci 33:5655–5667

    CAS  PubMed Central  PubMed  Google Scholar 

  • Dezawa M, Takahashi I, Esaki M et al (2001) Sciatic nerve regeneration in rats induced by transplantation of in vitro differentiated bone-marrow stromal cells. Eur J Neurosci 14:1771–1776

    CAS  PubMed  Google Scholar 

  • Di Summa PG, Kingham PJ, Raffoul W et al (2010) Adipose-derived stem cells enhance peripheral nerve regeneration. J Plast Reconstr Aesthet Surg 63:1544–1552

    PubMed  Google Scholar 

  • Dimos JT, Rodolfa KT, Niakan KK et al (2008) Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321:1218–1221

    CAS  PubMed  Google Scholar 

  • Dominici M, Le Blanc K, Mueller I et al (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8:315–317

    CAS  PubMed  Google Scholar 

  • Dorronsoro A, Fernández-Rueda J, Fechter K et al (2013) Human mesenchymal stromal cell-mediated immunoregulation: mechanisms of action and clinical applications. Bone Marrow Res 2013:203643

    PubMed Central  PubMed  Google Scholar 

  • Dumont CE, Bolin LM, Hentz VR (1996) A composite nerve graft system: extracted rat peripheral nerve injected with cultured Schwann cells. Muscle Nerve 19:97–99

    CAS  PubMed  Google Scholar 

  • Ebert AD, Yu J, Rose FF et al (2009) Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 457:277–280

    CAS  PubMed Central  PubMed  Google Scholar 

  • Erba P, Mantovani C, Kalbermatten DF et al (2010) Regeneration potential and survival of transplanted undifferentiated adipose tissue-derived stem cells in peripheral nerve conduits. J Plast Reconstr Aesthet Surg 63:e811–e817

    CAS  PubMed  Google Scholar 

  • Evans GRD, Brandt K, Katz S et al (2002) Bioactive poly(L-lactic acid) conduits seeded with Schwann cells for peripheral nerve regeneration. Biomaterials 23:841–848

    CAS  PubMed  Google Scholar 

  • Fang B, Song Y, Liao L et al (2007a) Favorable response to human adipose tissue-derived mesenchymal stem cells in steroid-refractory acute graft-versus-host disease. Transplant Proc 39:3358–3362

    CAS  PubMed  Google Scholar 

  • Fang B, Song Y, Lin Q et al (2007b) Human adipose tissue-derived mesenchymal stromal cells as salvage therapy for treatment of severe refractory acute graft-vs.-host disease in two children. Pediatr Transplant 11:814–817

    CAS  PubMed  Google Scholar 

  • Fang B, Song Y, Li N et al (2009) Mesenchymal stem cells for the treatment of refractory pure red cell aplasia after major ABO-incompatible hematopoietic stem cell transplantation. Ann Hematol 88:261–266

    PubMed  Google Scholar 

  • Fang Y, Mo X, Guo W et al (2010) A new type of Schwann cell graft transplantation to promote optic nerve regeneration in adult rats. J Tissue Eng Regen Med 4:581–589

    CAS  PubMed  Google Scholar 

  • Fansa H, Keilhoff G, Plogmeier K et al (1999) Successful implantation of Schwann cells in acellular muscles. J Reconstr Microsurg 15:61–65

    CAS  PubMed  Google Scholar 

  • Fornaro M, Tos P, Geuna S et al (2001) Confocal imaging of Schwann-cell migration along muscle-vein combined grafts used to bridge nerve defects in the rat. Microsurgery 21:153–155

    CAS  PubMed  Google Scholar 

  • Fu SY, Gordon T (1997) The cellular and molecular basis of peripheral nerve regeneration. Mol Neurobiol 14:67–116

    CAS  PubMed  Google Scholar 

  • Fu J, Wang YK, Yang MT et al (2010) Mechanical regulation of cell function with geometrically modulated elastomeric substrates. Nat Methods 7:733–736

    CAS  PubMed Central  PubMed  Google Scholar 

  • Fukaya K, Hasegawa M, Mashitani T et al (2003) Oxidized galectin-1 stimulates the migration of Schwann cells from both proximal and distal stumps of transected nerves and promotes axonal regeneration after peripheral nerve injury. J Neuropathol Exp Neurol 62:162–172

    CAS  PubMed  Google Scholar 

  • Funakoshi H, Frisen J, Barbany G et al (1993) Differential expression of mRNAs for neurotrophins and their receptors after axotomy of the sciatic nerve. J Cell Biol 123:455–465

    CAS  PubMed  Google Scholar 

  • Furey MJ, Midha R, Xu QG et al (2007) Prolonged target deprivation reduces the capacity of injured motoneurons to regenerate. Neurosurgery 60:723–732 (discussion 732–733)

    PubMed  Google Scholar 

  • Geuna S, Raimondo S, Ronchi G et al (2009) Histology of the peripheral nerve and changes occurring during nerve regeneration. Int Rev Neurobiol 87:27–46

    PubMed  Google Scholar 

  • Gimble JM, Katz AJ, Bunnell BA (2007) Adipose-derived stem cells for regenerative medicine. Circ Res 100:1249–1260

    CAS  PubMed  Google Scholar 

  • Glaus SW, Johnson PJ, Mackinnon SE (2011) Clinical strategies to enhance nerve regeneration in composite tissue allotransplantation. Hand Clin 27:495–509

    PubMed Central  PubMed  Google Scholar 

  • Gonzalez-Rey E, Anderson P, Gonzalez MA et al (2009) Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis. Gut 58:929–939

    CAS  PubMed  Google Scholar 

  • Gonzalez-Rey E, Gonzalez MA, Varela N et al (2010) Human adipose-derived mesenchymal stem cells reduce inflammatory and T cell responses and induce regulatory T cells in vitro in rheumatoid arthritis. Ann Rheum Dis 69:241–248

    CAS  PubMed  Google Scholar 

  • Gordon T (2009) The role of neurotrophic factors in nerve regeneration. Neurosurg Focus 26:E3

    PubMed  Google Scholar 

  • Gordon T, Chan KM, Sulaiman OA et al (2009) Accelerating axon growth to overcome limitations in functional recovery after peripheral nerve injury. Neurosurgery 65(4 Suppl):A132–A144

    PubMed  Google Scholar 

  • Gronthos S, Franklin DM, Leddy HA et al (2001) Surface protein characterization of human adipose tissue-derived stromal cells. J Cell Physiol 189:54–63

    CAS  PubMed  Google Scholar 

  • Guenard V, Kleitman N, Morrissey T et al (1992) Syngeneic Schwann cells derived from adult nerves seeded in semipermeable guidance channels enhance peripheral nerve regeneration. J Neurosci 12:3310–3320

    CAS  PubMed  Google Scholar 

  • Gulati AK, Cole GP (1990) Nerve graft immunogenicity as a factor determining axonal regeneration in the rat. J Neurosurg 72:114–122

    CAS  PubMed  Google Scholar 

  • Gulati AK, Rai DR, Ali AM (1995) The influence of cultured Schwann cells on regeneration through acellular basal lamina grafts. Brain Res 705:118–124

    CAS  PubMed  Google Scholar 

  • Hayashi A, Koob JW, Liu DZ et al (2007) A double-transgenic mouse used to track migrating Schwann cells and regenerating axons following engraftment of injured nerves. Exp Neurol 207:128–138

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hermanns S, Wunderlich G, Rosenbaum C et al (1997) Lack of immune responses to immediate or delayed implanted allogeneic and xenogeneic Schwann cell suspensions. Glia 21:299–314

    CAS  PubMed  Google Scholar 

  • Hess JR, Brenner MJ, Fox IK et al (2007) Use of cold-preserved allografts seeded with autologous Schwann cells in the treatment of a long-gap peripheral nerve injury. Plast Reconstr Surg 119:246–259

    CAS  PubMed  Google Scholar 

  • Heumann R (1987) Regulation of the synthesis of nerve growth factor. J Exp Biol 132:133–150

    CAS  PubMed  Google Scholar 

  • Höke A, Gordon T, Zochodne DW et al (2002) A decline in glial cell-line-derived neurotrophic factor expression is associated with impaired regeneration after long-term Schwann cell denervation. Exp Neurol 173:77–85

    PubMed  Google Scholar 

  • Hong SJ, Traktuev DO, March KL (2010) Therapeutic potential of adipose-derived stem cells in vascular growth and tissue repair. Curr Opin Organ Transplant 15:86–91

    PubMed  Google Scholar 

  • Hood B, Levene HB, Levi AD (2009) Transplantation of autologous Schwann cells for the repair of segmental peripheral nerve defects. Neurosurg Focus 26:E4

    PubMed  Google Scholar 

  • Hou SY, Zhang HY, Quan DP et al (2006) Tissue-engineered peripheral nerve grafting by differentiated bone marrow stromal cells. Neuroscience 140:101–110

    CAS  PubMed  Google Scholar 

  • Hu X, Huang J, Ye Z et al (2009) A novel scaffold with longitudinally oriented microchannels promotes peripheral nerve regeneration. Tissue Eng Part A 15:3297–3308

    CAS  PubMed  Google Scholar 

  • Huebsch N, Arany PR, Mao AS et al (2010) Harnessing traction-mediated manipulation of the cell/matrix interface to control stem-cell fate. Nat Mater 9:518–526

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ide C (1996) Peripheral nerve regeneration. Neurosci Res 25:101–121

    CAS  PubMed  Google Scholar 

  • Jokinen J, Dadu E, Nykvist P et al (2004) Integrin-mediated cell adhesion to type I collagen fibrils. J Biol Chem 279:31956–31963

    CAS  PubMed  Google Scholar 

  • Jung Y, Bauer G, Nolta JA (2012) Concise review: Induced pluripotent stem cell-derived mesenchymal stem cells: progress toward safe clinical products. Stem Cells 30:42–47

    CAS  PubMed Central  PubMed  Google Scholar 

  • Keilhoff G, Fansa H (2011) Mesenchymal stem cells for peripheral nerve regeneration–a real hope or just an empty promise? Exp Neurol 232:110–113

    PubMed  Google Scholar 

  • Keilhoff G, Goihl A, Langnase K et al (2006a) Transdifferentiation of mesenchymal stem cells into Schwann cell-like myelinating cells. Eur J Cell Biol 85:11–24

    CAS  PubMed  Google Scholar 

  • Keilhoff G, Stang F, Goihl A et al (2006b) Transdifferentiated mesenchymal stem cells as alternative therapy in supporting nerve regeneration and myelination. Cell Mol Neurobiol 26:1235–1252

    PubMed  Google Scholar 

  • Kingham PJ, Kalbermatten DF, Mahay D et al (2007) Adipose-derived stem cells differentiate into a Schwann cell phenotype and promote neurite outgrowth in vitro. Exp Neurol 207:267–274

    CAS  PubMed  Google Scholar 

  • Koshimune M, Takamatsu K, Nakatsuka H et al (2003) Creating bioabsorbable Schwann cell coated conduits through tissue engineering. Biomed Mater Eng 13:223–229

    CAS  PubMed  Google Scholar 

  • Ladak A, Olson J, Tredget EE et al (2011) Differentiation of mesenchymal stem cells to support peripheral nerve regeneration in a rat model. Exp Neurol 228:242–252

    CAS  PubMed  Google Scholar 

  • Lassner F, Schaller E, Steinhoff G et al (1989) Cellular mechanisms of rejection and regeneration in peripheral nerve allografts. Transplantation 48:386–392

    CAS  PubMed  Google Scholar 

  • Lavdas AA, Franceschini I, Dubois-Dalcq M et al (2006) Schwann cells genetically engineered to express PSA show enhanced migratory potential without impairment of their myelinating ability in vitro. Glia 53:868–878

    PubMed  Google Scholar 

  • Le Douarin N (1982) The neural crest. Cambridge University Press, New York

    Google Scholar 

  • Lebkowski JS (2014) Phase I clinical trial of human embryonic stem cell-derived oligodendrocyte progenitors in patients with neurologically complete thoracic spinal cord injury: results and next steps. American Society for Gene and Cell Therapy, 17th annual meeting, Washington, DC

  • Lee WP, Yaremchuk MJ, Pan YC et al (1991) Relative antigenicity of components of a vascularized limb allograft. Plast Reconstr Surg 87:401–411

    CAS  PubMed  Google Scholar 

  • Lee G, Kim H, Elkabetz Y et al (2007a) Isolation and directed differentiation of neural crest stem cells derived from human embryonic stem cells. Nat Biotechnol 25:1468–1475

    CAS  PubMed  Google Scholar 

  • Lee HK, Seo IA, Park HK et al (2007b) Nidogen is a prosurvival and promigratory factor for adult Schwann cells. J Neurochem 102:686–698

    CAS  PubMed  Google Scholar 

  • Lee G, Papapetrou EP, Kim H et al (2009) Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature 461:402–406

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lee G, Chambers SM, Tomishima MJ et al (2010) Derivation of neural crest cells from human pluripotent stem cells. Nat Protoc 5:688–701

    CAS  PubMed  Google Scholar 

  • Lei L, Han D, Gong S et al (2010a) Mpz gene suppression by shRNA increases Schwann cell apoptosis in vitro. Neurol Sci 31:603–608

    PubMed  Google Scholar 

  • Lei Y, Huang S, Sharif-Kashani P et al (2010b) Incorporation of active DNA/cationic polymer polyplexes into hydrogel scaffolds. Biomaterials 31:9106–9116

    CAS  PubMed Central  PubMed  Google Scholar 

  • Levi AD (2013) The Miami Project to Cure Paralysis; University of Miami. Safety of autologous human schwann cells (ahSC) in subjects with subacute SCI. In: ClinicalTrials.gov [Internet]. National Library of Medicine (US), Bethesda. http://clinicaltrials.gov/ct2/show/NCT01739023 (Cited 11 Feb 2014)

  • Levi AD, Bunge RP (1994) Studies of myelin formation after transplantation of human Schwann cells into the severe combined immunodeficient mouse. Exp Neurol 130:41–52

    CAS  PubMed  Google Scholar 

  • Levi AD, Guénard V, Aebischer P et al (1994) The functional characteristics of Schwann cells cultured from human peripheral nerve after transplantation into a gap within the rat sciatic nerve. J Neurosci 14:1309–1319

    CAS  PubMed  Google Scholar 

  • Levi AD, Bunge RP, Lofgren JA et al (1995) The influence of heregulins on human Schwann cell proliferation. J Neurosci 15:1329–1340

    CAS  PubMed  Google Scholar 

  • Levi AD, Sonntag VK, Dickman C et al (1997) The role of cultured Schwann cell grafts in the repair of gaps within the peripheral nervous system of primates. Exp Neurol 143:25–36

    CAS  PubMed  Google Scholar 

  • Li Y, Raisman G (1997) Integration of transplanted cultured Schwann cells into the long myelinated fiber tracts of the adult spinal cord. Exp Neurol 145:397–411

    CAS  PubMed  Google Scholar 

  • Lin W, Chen X, Wang X et al (2008) Adult rat bone marrow stromal cells differentiate into Schwann cell-like cells in vitro. In Vitro Cell Dev Biol Anim 44:31–40

    CAS  PubMed  Google Scholar 

  • Lin CS, Lin G, Lue TF (2012) Allogeneic and xenogeneic transplantation of adipose-derived stem cells in immunocompetent recipients without immunosuppressants. Stem Cells Dev 21:2770–2778

    PubMed Central  PubMed  Google Scholar 

  • Liu Q, Spusta SC, Mi R et al (2012) Human neural crest stem cells derived from human ESCs and induced pluripotent stem cells: induction, maintenance, and differentiation into functional Schwann cells. Stem Cells Transl Med 1:266–278

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lopez MJ, McIntosh KR, Spencer ND et al (2009) Acceleration of spinal fusion using syngeneic and allogeneic adult adipose derived stem cells in a rat model. J Orthop Res 27:366–373

    PubMed Central  PubMed  Google Scholar 

  • Lundborg G, Dahlin LB, Danielsen N et al (1986) Tissue specificity in nerve regeneration. Scand J Plast Reconstr Surg 20:279–283

    CAS  PubMed  Google Scholar 

  • Lundborg G, Dahlin L, Danielsen N et al (1994) Trophism, tropism, and specificity in nerve regeneration. J Reconstr Microsurg 10:345–354

    CAS  PubMed  Google Scholar 

  • Mackinnon S, Hudson A, Falk R et al (1982) Nerve allograft response: a quantitative immunological study. Neurosurgery 10:61–69

    CAS  PubMed  Google Scholar 

  • Mackinnon SE, Dellon AL, Lundborg G et al (1986) A study of neurotropism in a primate model. J Hand Surg Am 11:888–894

    CAS  PubMed  Google Scholar 

  • Mackinnon SE, Dellon AL, O’Brien JP (1991) Changes in nerve fiber numbers distal to a nerve repair in the rat sciatic nerve model. Muscle Nerve 14:1116–1122

    CAS  PubMed  Google Scholar 

  • Madduri S, Gander B (2010) Schwann cell delivery of neurotrophic factors for peripheral nerve regeneration. J Peripher Nerv Syst 15:93–103

    CAS  PubMed  Google Scholar 

  • Magnaghi V, Procacci P, Tata AM (2009) Chapter 15: Novel pharmacological approaches to Schwann cells as neuroprotective agents for peripheral nerve regeneration. Int Rev Neurobiol 87:295–315

    CAS  PubMed  Google Scholar 

  • Mahay D, Terenghi G, Shawcross SG (2008) Schwann cell mediated trophic effects by differentiated mesenchymal stem cells. Exp Cell Res 314:2692–2701

    CAS  PubMed  Google Scholar 

  • Marchesi C, Pluderi M, Colleoni F et al (2007) Skin-derived stem cells transplanted into resorbable guides provide functional nerve regeneration after sciatic nerve resection. Glia 438:425–438

    Google Scholar 

  • Matsuse D, Kitada M, Kohama M et al (2010) Human umbilical cord-derived mesenchymal stromal cells differentiate into functional Schwann cells that sustain peripheral nerve regeneration. J Neuropathol Exp Neurol 69:973–985

    CAS  PubMed  Google Scholar 

  • McIntosh K, Zvonic S, Garrett S et al (2006) The immunogenicity of human adipose-derived cells: temporal changes in vitro. Stem Cells 24:1246–1253

    CAS  PubMed  Google Scholar 

  • Menasché P (2013) Transplantation of human embryonic stem cell-derived progenitors in severe heart failure (ESCORT). In: ClinicalTrials.gov [Internet]. National Library of Medicine (US), Bethesda. http://clinicaltrials.gov/ct2/show/NCT02057900 (Cited 27 Jun 2014)

  • Mews M, Meyer M (1993) Modulation of Schwann cell phenotype by TGF-beta 1: inhibition of P0 mRNA expression and downregulation of the low affinity NGF receptor. Glia 8:208–217

    CAS  PubMed  Google Scholar 

  • Mirsky R, Jessen KR (1996) Schwann cell development, differentiation and myelination. Curr Opin Neurobiol 6:89–96

    CAS  PubMed  Google Scholar 

  • Mitchell JB, McIntosh K, Zvonic S et al (2006) Immunophenotype of human adipose-derived cells: temporal changes in stromal-associated and stem cell-associated markers. Stem Cells 24:376–385

    PubMed  Google Scholar 

  • Morrissey TK, Levi AD, Nuijens A et al (1995) Axon-induced mitogenesis of human Schwann cells involves heregulin and p185erbB2. Proc Natl Acad Sci USA 92:1431–1435

    CAS  PubMed Central  PubMed  Google Scholar 

  • Najar M, Raicevic G, Boufker HI et al (2010) Adipose-tissue-derived and Wharton’s jelly-derived mesenchymal stromal cells suppress lymphocyte responses by secreting leukemia inhibitory factor. Tissue Eng Part A 16:3537–3546

    CAS  PubMed  Google Scholar 

  • Neuberger TJ, Cornbrooks CJ, Kromer LF (1992) Effects of delayed transplantation of cultured Schwann cells on axonal regeneration from central nervous system cholinergic neurons. J Comp Neurol 315:16–33

    CAS  PubMed  Google Scholar 

  • Niapour A, Karamali F, Karbalaie K et al (2010) Novel method to obtain highly enriched cultures of adult rat Schwann cells. Biotechnol Lett 32:781–786

    CAS  PubMed  Google Scholar 

  • Nishiura Y, Brandt J, Nilsson A et al (2004) Addition of cultured Schwann cells to tendon autografts and freeze-thawed muscle grafts improves peripheral nerve regeneration. Tissue Eng 10:157–164

    CAS  PubMed  Google Scholar 

  • Ogden MA, Feng FY, Myckatyn TM et al (2000) Safe injection of cultured Schwann cells into peripheral nerve allografts. Microsurgery 20:314–323

    CAS  PubMed  Google Scholar 

  • Papastefanaki F, Chen J, Lavdas AA et al (2007) Grafts of Schwann cells engineered to express PSA-NCAM promote functional recovery after spinal cord injury. Brain 130:2159–2174

    PubMed  Google Scholar 

  • Park IH, Arora N, Huo H et al (2008) Disease-specific induced pluripotent stem cells. Cell 134:877–886

    CAS  PubMed Central  PubMed  Google Scholar 

  • Petruzzo P, Dubernard JM (2011) The international registry on hand and composite tissue allotransplantation. Clin Transpl 2011:247–253

    Google Scholar 

  • Petruzzo P, Lanzetta M, Dubernard JM et al (2010) The international registry on hand and composite tissue transplantation. Transplantation 90:1590–1594

    PubMed  Google Scholar 

  • Pfister LA, Papaloïzos M, Merkle HP et al (2007) Nerve conduits and growth factor delivery in peripheral nerve repair. J Peripher Nerv Syst 12:65–82

    CAS  PubMed  Google Scholar 

  • Phizer (2012) A study of implantation of human embryonic stem cell derived retinal pigment epithelium in subjects with acute wet age related macular degeneration and recent rapid vision decline. In: ClinicalTrials.gov [Internet]. National Library of Medicine (US), Bethesda. http://clinicaltrials.gov/ct2/show/NCT01691261 (Cited 27 Jun 2014)

  • Planat-Benard V, Silvestre JS, Cousin B et al (2004) Plasticity of human adipose lineage cells toward endothelial cells: physiological and therapeutic perspectives. Circulation 109:656–663

    PubMed  Google Scholar 

  • Puissant B, Barreau C, Bourin P et al (2005) Immunomodulatory effect of human adipose tissue-derived adult stem cells: comparison with bone marrow mesenchymal stem cells. Br J Haematol 129:118–129

    PubMed  Google Scholar 

  • Ra JC, Shin IS, Kim SH et al (2011) Safety of intravenous infusion of human adipose tissue-derived mesenchymal stem cells in animals and humans. Stem Cells Dev 20:1297–1308

    CAS  PubMed  Google Scholar 

  • Rasmusson I, Ringden O, Sundberg B et al (2005) Mesenchymal stem cells inhibit lymphocyte proliferation by mitogens and alloantigens by different mechanisms. Exp Cell Res 305:33–41

    CAS  PubMed  Google Scholar 

  • Ren YJ, Zhang S, Mi R et al (2013) Enhanced differentiation of human neural crest stem cells towards the Schwann cell lineage by aligned electrospun fiber matrix. Acta Biomater 9:7727–7736

    CAS  PubMed  Google Scholar 

  • Rodrigues MCO, Rodrigues AA, Glover LE et al (2012) Peripheral nerve repair with cultured Schwann cells: getting closer to the clinics. Sci World J 2012:413091

    Google Scholar 

  • Rogister B, Delree P, Leprince P et al (1993) Transforming growth factor beta as a neuronoglial signal during peripheral nervous system response to injury. J Neurosci Res 34:32–43

    CAS  PubMed  Google Scholar 

  • Ryu HH, Lim JH, Byeon YE et al (2009) Functional recovery and neural differentiation after transplantation of allogenic adipose-derived stem cells in a canine model of acute spinal cord injury. J Vet Sci 10:273–284

    PubMed Central  PubMed  Google Scholar 

  • Sabelman EE, Keeley R, Koran P et al (1995) Peripheral nerve graft containing parallel collagen matrix and Schwann cells—preliminary results. Calif Soc of Plastic Surgeons, 45th Annual Meeting, Napa

  • Safford KM, Hicok KC, Safford SD et al (2002) Neurogenic differentiation of murine and human adipose-derived stromal cells. Biochem Biophys Res Commun 294:371–379

    CAS  PubMed  Google Scholar 

  • Saheb-Al-Zamani M, Yan Y, Farber SJ et al (2013) Limited regeneration in long acellular nerve allografts is associated with increased Schwann cell senescence. Exp Neurol 247:165–177

    CAS  PubMed  Google Scholar 

  • Sarhane KA (2012) Tissue CLN3: a potential biomarker for breast cancer? M.Sc. Thesis. Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut

  • Sarhane KA, Ibrahim Z, Leto Barone AA et al (2012) Minimization of immunosuppression and tolerance induction in reconstructive transplantation. Curr Surg Rep 1:40–46

    Google Scholar 

  • Sarhane KA, Cashman C, Krick K et al (2014a) Biomarkers of nerve regeneration in peripheral nerve injuries: an emerging field. Biomarkers Brain Injury Neurol Disorders (in press)

  • Sarhane KA, Ibrahim Z, Krick K et al (2014b) Selectively permeable nanofiber constructs to prevent inflammatory scarring and enhance nerve regeneration in peripheral nerve injury. Plast Reconstr Surg 133:16–17

    Google Scholar 

  • Sarhane KA, Khalifian S, Ibrahim Z et al (2014c) Diagnosing skin rejection in vascularized composite allotransplantation: advances and challenges. Clin Transplant 28:277–285

    PubMed  Google Scholar 

  • Schwartz S (2011) Sub-retinal transplantation of hESC derived RPE(MA09-hRPE) cells in patients with Stargardt’s macular dystrophy In: Clinical Trials.gov [Internet]. National Library of Medicine (US), Bethesda. http://clinicaltrials.gov/ct2/show/NCT01345006 (Cited 27 Jun 2014)

  • Serakinci N, Fahrioglu U, Christensen R (2014) Mesenchymal stem cells, cancer challenges and new directions. Eur J Cancer 50:1522–1530

    CAS  PubMed  Google Scholar 

  • Shakhbazau A, Kawasoe J, Hoyng SA et al (2012) Early regenerative effects of NGF-transduced Schwann cells in peripheral nerve repair. Mol Cell Neurosci 50:103–112

    CAS  PubMed  Google Scholar 

  • Shanmugarajah K, Hettiaratchy S, Butler PE (2012) Facial transplantation. Curr Opin Otolaryngol Head Neck Surg 20:291–297

    PubMed  Google Scholar 

  • Shea GKH, Tsui AY, Chan YS et al (2010) Bone marrow-derived Schwann cells achieve fate commitment—a prerequisite for remyelination therapy. Exp Neurol 224:448–458

    CAS  PubMed  Google Scholar 

  • Shimizu S, Kitada M, Ishikawa H et al (2007) Peripheral nerve regeneration by the in vitro differentiated-human bone marrow stromal cells with Schwann cell property. Biochem Biophys Res Commun 359:915–920

    CAS  PubMed  Google Scholar 

  • Siu D (2010) A new way of targeting to treat nerve injury. Int J Neurosci 120:1–10

    PubMed  Google Scholar 

  • Song W (2012) A phase I/IIa, open-label, single-center, prospective study to determine the safety and tolerability of sub-retinal transplantation of human embryonic stem cell derived retinal pigmented epithelial (MA09-hRPE) cells in patients with advanced dry age-related macular degeneration (AMD). In: ClinicalTrials.gov [Internet]. National Library of Medicine (US), Bethesda. http://clinicaltrials.gov/ct2/show/NCT01674829 (Cited 27 Jun 2014)

  • Stoll G, Jander S (1999) The role of microglia and macrophages in the pathophysiology of the CNS. Prog Neurobiol 58:233–247

    CAS  PubMed  Google Scholar 

  • Strem BM, Hicok KC, Zhu M et al (2005) Multipotential differentiation of adipose tissue-derived stem cells. Keio J Med 54:132–141

    CAS  PubMed  Google Scholar 

  • Sunderland S (1990) The anatomy and physiology of nerve injury. Muscle Nerve 13:771–784

    CAS  PubMed  Google Scholar 

  • Takahashi K, Tanabe K, Ohnuki M et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872

    CAS  PubMed  Google Scholar 

  • Thoenen H, Bandtlow C, Heumann R et al (1988) Nerve growth factor: cellular localization and regulation of synthesis. Cell Mol Neurobiol 8:35–40

    CAS  PubMed  Google Scholar 

  • Tobin GR, Breidenbach WC, Ildstad ST et al (2009) The history of human composite tissue allotransplantation. Transplant Proc 41:466–471

    CAS  PubMed  Google Scholar 

  • Toft PB, Fugleholm K, Schmalbruch H (1988) Axonal branching following crush lesions of peripheral nerves of rat. Muscle Nerve 11:880–889

    CAS  PubMed  Google Scholar 

  • Tohill M, Mantovani C, Wiberg M et al (2004) Rat bone marrow mesenchymal stem cells express glial markers and stimulate nerve regeneration. Neurosci Lett 362:200–203

    CAS  PubMed  Google Scholar 

  • Tokatlian T, Cam C, Segura T (2014) Non-viral DNA delivery from porous hyaluronic acid hydrogels in mice. Biomaterials 35:825–835

    CAS  PubMed Central  PubMed  Google Scholar 

  • Trumble TE, Shon FG (2000) The physiology of nerve transplantation. Hand Clin 16:105–122

    CAS  PubMed  Google Scholar 

  • Tse WT, Pendleton JD, Beyer WM et al (2003) Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation 75:389–397

    CAS  PubMed  Google Scholar 

  • Tseng CY, Hu G, Ambron RT et al (2003) Histologic analysis of Schwann cell migration and peripheral nerve regeneration in the autogenous venous nerve conduit (AVNC). J Reconstr Microsurg 19:331–340

    PubMed  Google Scholar 

  • Tuszynski MH, Weidner N, McCormack M et al (1998) Grafts of genetically modified Schwann cells to the spinal cord: survival, axon growth, and myelination. Cell Transplant 7:187–196

    CAS  PubMed  Google Scholar 

  • Udina E, Rodríguez FJ, Verdú E et al (2004) FK506 enhances regeneration of axons across long peripheral nerve gaps repaired with collagen guides seeded with allogeneic Schwann cells. Glia 47:120–129

    PubMed  Google Scholar 

  • Wakao S, Hayashi T, Kitada M et al (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 223:537–547

    CAS  PubMed  Google Scholar 

  • Walsh S, Biernaskie J, Kemp SW et al (2009) Supplementation of acellular nerve grafts with skin derived precursor cells promotes peripheral nerve regeneration. Neuroscience 164:1097–1107

    CAS  PubMed  Google Scholar 

  • Wang Y, Zhang A, Ye Z et al (2009) Bone marrow-derived mesenchymal stem cells inhibit acute rejection of rat liver allografts in association with regulatory T-cell expansion. Transplant Proc 41:4352–4356

    CAS  PubMed  Google Scholar 

  • Wang Y, Zhao Z, Ren Z et al (2012) Recellularized nerve allografts with differentiated mesenchymal stem cells promote peripheral nerve regeneration. Neurosci Lett 514:96–101

    CAS  PubMed  Google Scholar 

  • Webber C, Zochodne D (2010) The nerve regenerative microenvironment: early behavior and partnership of axons and Schwann cells. Exp Neurol 223:51–59

    CAS  PubMed  Google Scholar 

  • Whitlock EL, Myckatyn TM, Tong AY et al (2010) Dynamic quantification of host Schwann cell migration into peripheral nerve allografts. Exp Neurol 225:310–319

    CAS  PubMed Central  PubMed  Google Scholar 

  • Winter A, Breit S, Parsch D et al (2003) Cartilage-like gene expression in differentiated human stem cell spheroids: a comparison of bone marrow-derived and adipose tissue-derived stromal cells. Arthritis Rheum 48:418–429

    CAS  PubMed  Google Scholar 

  • Wislet-Gendebien S, Leprince P, Moonen G et al (2003) Regulation of neural markers nestin and GFAP expression by cultivated bone marrow stromal cells. J Cell Sci 116:3295–3302

    CAS  PubMed  Google Scholar 

  • Wolbank S, Peterbauer A, Fahrner M et al (2007) Dose-dependent immunomodulatory effect of human stem cells from amniotic membrane: a comparison with human mesenchymal stem cells from adipose tissue. Tissue Eng 13:1173–1183

    CAS  PubMed  Google Scholar 

  • Yanez R, Lamana ML, Garcia-Castro J et al (2006) Adipose tissue-derived mesenchymal stem cells have in vivo immunosuppressive properties applicable for the control of the graft-versus-host disease. Stem Cells 24:2582–2591

    CAS  PubMed  Google Scholar 

  • Yoo KH, Jang IK, Lee MW et al (2009) Comparison of immunomodulatory properties of mesenchymal stem cells derived from adult human tissues. Cell Immunol 259:150–156

    CAS  PubMed  Google Scholar 

  • Yu LT, Rostami A, Silvers WK et al (1990) Expression of major histocompatibility complex antigens on inflammatory peripheral nerve lesions. J Neuroimmunol 30:121–128

    CAS  PubMed  Google Scholar 

  • Zhang F, Blain B, Beck J et al (2002) Autogenous venous graft with one-stage prepared Schwann cells as a conduit for repair of long segmental nerve defects. J Reconstr Microsurg 18:295–300

    PubMed  Google Scholar 

  • Zhang Y, Yeh J, Richardson PM et al (2008) Cell adhesion molecules of the immunoglobulin superfamily in axonal regeneration and neural repair. Restor Neurol Neurosci 26:81–96

    CAS  PubMed  Google Scholar 

  • Zhang YG, Sheng QS, Qi FY et al (2013) Schwann cell-seeded scaffold with longitudinally oriented micro-channels for reconstruction of sciatic nerve in rats. J Mater Sci Mater Med 24:1767–1780

    CAS  PubMed  Google Scholar 

  • Zhao FQ, Zhang PX, He XJ et al (2005) Study on the adoption of Schwann cell phenotype by bone marrow stromal cells in vitro and in vivo. Biomed Environ Sci 18:326–333

    PubMed  Google Scholar 

  • Zujovic V, Doucerain C, Hidalgo A et al (2012) Exogenous schwann cells migrate, remyelinate and promote clinical recovery in experimental auto-immune encephalomyelitis. PLoS ONE 7:e42667

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zuk PA, Zhu M, Ashjian P et al (2002) Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 13:4279–4295

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zurita M, Bonilla C, Otero L et al (2008) Neural transdifferentiation of bone marrow stromal cells obtained by chemical agents is a short-time reversible phenomenon. Neurosci Res 60:275–280

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

All images courtesy of Amy Dixon with select storyboards from the animation “Peripheral Nerve Regeneration After Hand Transplantation” by A. Dixon. The authors acknowledge partial support to this work by the Maryland Stem Cell Research Fund (2012-MSCRF-0083-00 G.B.). Saami Khalifian acknowledges partial support by The Paul and Daisy Soros Fellowship. Markus Tammia acknowledges partial support by fellowships from Stiftelsen Olle Engkvist Byggmästare, the Foundation Blanceflor Boncompagni-Ludovisi, née Bildt, and Hans Werthén fonden.

Author information

Authors and Affiliations

  1. Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Ross Research Building 749D, 720 Rutland Avenue, Baltimore, MD, 21205, USA

    Saami Khalifian, Karim A. Sarhane, Zuhaib Ibrahim, Damon S. Cooney, Jaimie T. Shores, W. P. Andrew Lee & Gerald Brandacher

  2. Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD, USA

    Markus Tammia & Hai-Quan Mao

  3. Translational Tissue Engineering Center and Whitaker Biomedical Engineering Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Hai-Quan Mao

Authors
  1. Saami Khalifian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karim A. Sarhane
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Markus Tammia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zuhaib Ibrahim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hai-Quan Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Damon S. Cooney
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jaimie T. Shores
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. W. P. Andrew Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Gerald Brandacher
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gerald Brandacher.

Additional information

S. Khalifian and K. A. Sarhane contributed equally to this work.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Khalifian, S., Sarhane, K.A., Tammia, M. et al. Stem Cell-Based Approaches to Improve Nerve Regeneration: Potential Implications for Reconstructive Transplantation?. Arch. Immunol. Ther. Exp. 63, 15–30 (2015). https://doi.org/10.1007/s00005-014-0323-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00005-014-0323-9

Keywords

Search

Navigation