Cellular and Molecular Neurobiology

, Volume 37, Issue 5, pp 941–947 | Cite as

Transplantation of Human Skin-Derived Mesenchymal Stromal Cells Improves Locomotor Recovery After Spinal Cord Injury in Rats

  • Fernanda Rosene Melo
  • Raul Bardini Bressan
  • Stefânia Forner
  • Alessandra Cadete Martini
  • Michele Rode
  • Priscilla Barros Delben
  • Giles Alexander Rae
  • Claudia Pinto Figueiredo
  • Andrea Gonçalves TrentinEmail author
Brief Communication


Spinal cord injury (SCI) is a devastating neurologic disorder with significant impacts on quality of life, life expectancy, and economic burden. Although there are no fully restorative treatments yet available, several animal and small-scale clinical studies have highlighted the therapeutic potential of cellular interventions for SCI. Mesenchymal stem cells (MSCs)—which are conventionally isolated from the bone marrow—recently emerged as promising candidates for treating SCI and have been shown to provide trophic support, ameliorate inflammatory responses, and reduce cell death following the mechanical trauma. Here we evaluated the human skin as an alternative source of adult MSCs suitable for autologous cell transplantation strategies for SCI. We showed that human skin-derived MSCs (hSD-MSCs) express a range of neural markers under standard culture conditions and are able to survive and respond to neurogenic stimulation in vitro. In addition, using histological analysis and behavioral assessment, we demonstrated as a proof-of-principle that hSD-MSC transplantation reduces the severity of tissue loss and facilitates locomotor recovery in a rat model of SCI. Altogether, the study provides further characterization of skin-derived MSC cultures and indicates that the human skin may represent an attractive source for cell-based therapies for SCI and other neurological disorders. Further investigation is needed to elucidate the mechanisms by which hSD-MSCs elicit tissue repair and/or locomotor recovery.


Mesenchymal stem cells Spinal cord injury Human skin Cell transplantation 



This work was supported by the Ministério da Saúde (MS-SCTIE-DECIT), Ministério da Ciência, Tecnologia e Inovação/Conselho Nacional de Desenvolvimento Científico e Tecnológico (MCTI/CNPq/Brazil), CNPq/PIBIC/PIBIT (Brazil), Coordenação de Aperfeiçamento de Pessoal de Nível Superior (CAPES, Brazil), Instituto Nacional de Neurociência Translacional (MCTI/INNT), and Fundação de Amparo à Pesquisa do Estado de Santa Catarina (FAPESC, Brazil). RBB is supported by a fellowship from the Science Without Borders Program (CAPES, Brazil).

Author Contributions

Conceived and designed the experiments: FRM, RBB, SF, GAR, AGT. Performed the experiments: FRM, SF, ACM, MR, PBD. Analyzed the data: FRM, SF, ACM, RBB, CPF. Wrote the manuscript: RBB, CPF, AGT.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10571_2016_414_MOESM1_ESM.docx (19 kb)
Supplementary material 1 (DOCX 18 kb)
10571_2016_414_MOESM2_ESM.pdf (62 kb)
Supplementary Fig S1 Percentage of ßIII-tubulin- and GFAP-positive in the different cultures conditions tested. Values represent the percentage of posive cells in relation to total cell number are expressed as mean ± S.E.M of 20 random fields in three independent experiments. Differences were not statistically significant by one-way ANOVA. (PDF 61 kb)


  1. Abrams MB, Dominguez C, Pernold K, Reger R, Wiesenfeld-Hallin Z, Olson L, Prockop D (2009) Multipotent mesenchymal stromal cells attenuate chronic inflammation and injury-induced sensitivity to mechanical stimuli in experimental spinal cord injury. Restor Neurol Neurosci 27(4):307–321PubMedGoogle Scholar
  2. Ackery A, Tator C, Krassioukov A (2004) A global perspective on spinal cord injury epidemiology. J Neurotrauma 21(10):1355–1370CrossRefPubMedGoogle Scholar
  3. Andersen J, Urbán N, Achimastou A, Ito A, Simic M, Ullom K, Martynoga B, Lebel M, Göritz C, Frisén J, Nakafuku M, Guillemot F (2014) A transcriptional mechanism integrating inputs from extracellular signals to activate hippocampal stem cells. Neuron 83(5):1085–1097CrossRefPubMedPubMedCentralGoogle Scholar
  4. Barzilay R, Kan I, Ben-Zur T, Bulvik S, Melamed E, Offen D (2008) Induction of human mesenchymal stem cells into dopamine-producing cells with different differentiation protocols. Stem Cells Dev 17(3):547–554CrossRefPubMedGoogle Scholar
  5. Basso DM, Beattie MS, Bresnahan JC (1995) A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma 12(1):1–21CrossRefPubMedGoogle Scholar
  6. Blondheim NR, Levy YS, Ben-Zur T, Burshtein A, Cherlow T, Kan I, Barzilay R, Bahat-Stromza M, Barhum Y, Bulvik S, Melamed E, Offen D (2006) Human mesenchymal stem cells express neural genes, suggesting a neural predisposition. Stem Cells Dev 15(2):141–164CrossRefPubMedGoogle Scholar
  7. Boido M, Garbossa D, Fontanella M, Ducati A, Vercelli A (2014) Mesenchymal stem cell transplantation reduces glial cyst and improves functional outcome after spinal cord compression. World Neurosurg 81(1):183–190CrossRefPubMedGoogle Scholar
  8. Bressan RB, Melo FR, Almeida PA, Bittencourt DA, Visoni S, Jeremias TS, Costa AP, Leal RB, Trentin AG (2014) EGF-FGF2 stimulates the proliferation and improves the neuronal commitment of mouse epidermal neural crest stem cells (EPI-NCSCs). Exp Cell Res 327(1):37–47CrossRefPubMedGoogle Scholar
  9. Caplan AI, Dennis JE (2006) Mesenchymal stem cells as trophic mediators. J Cell Biochem 98(5):1076–1084CrossRefPubMedGoogle Scholar
  10. Chen Y, Teng FY, Tang BL (2006) Coaxing bone marrow stromal mesenchymal stem cells towards neuronal differentiation: progress and uncertainties. Cell Mol Life Sci 63:1649–1657CrossRefPubMedGoogle Scholar
  11. Chopp M, Xue CA, Zhang H, Li Y, Wang L, Chen J, Lu D, Lu M, Rosenblum M (2000) Spinal cord injury in rat: treatment with bone marrow stromal cell transplantation. Neuroreport 11:3001–3005CrossRefPubMedGoogle Scholar
  12. Dasari VR, Veeravalli KK, Dinh DH (2014) Mesenchymal stem cells in the treatment of spinal cord injuries: a review. World J Stem Cells 6(2):120–133CrossRefPubMedPubMedCentralGoogle Scholar
  13. Faiz M, Sachewsky N, Gascón S, Bang KW, Morshead CM, Nagy A (2015) Adult neural stem cells from the subventricular zone give rise to reactive astrocytes in the cortex after stroke. Cell Stem Cell 17(5):624–634CrossRefPubMedGoogle Scholar
  14. Foudah D, Redondo J, Caldara C, Carini F, Tredici G, Miloso M (2013) Human mesenchymal stem cells express neuronal markers after osteogenic and adipogenic differentiation. Cell Mol Biol Lett 18(2):163–186CrossRefPubMedGoogle Scholar
  15. Hofstetter CP, Schwarz EJ, Hess D, Widenfalk J, El Manira A, Prockop DJ, Olson L (2002) Marrow stromal cells form guiding strands in the injured spinal cord and promote recovery. Proc Natl Acad Sci 99:2199–2204CrossRefPubMedPubMedCentralGoogle Scholar
  16. Jeremias TS, Machado RG, Visoni SB, Pereima MJ, Leonardi DF, Trentin AG (2014) Dermal substitutes support the growth of human skin-derived mesenchymal stromal cells: potential tool for skin regeneration. PLoS One 9(2):e89542CrossRefPubMedCentralGoogle Scholar
  17. Jung DI, Ha J, Kang BT, Kim JW, Quan FS, Lee JH, Woo EJ, Park HM (2009) A comparison of autologous and allogenic bone marrow-derived mesenchymal stem cell transplantation in canine spinal cord injury. J Neurol Sci 285:67–77CrossRefPubMedGoogle Scholar
  18. Kean TJ, Lin P, Caplan AI, Dennis JE (2013) MSCs: delivery routes and engraftment, cell-targeting strategies, and immune modulation. Stem Cells Int 2013:732742CrossRefPubMedPubMedCentralGoogle Scholar
  19. Kim N, Cho SG (2015) New strategies for overcoming limitations of mesenchymal stem cell-based immune modulation. Int J Stem Cells 8(1):54–68CrossRefPubMedPubMedCentralGoogle Scholar
  20. Kim BG, Hwang DH, Lee SI, Kim EJ, Kim SU (2007) Stem cell-based cell therapy for spinal cord injury. Cell Transplant 16(4):355–364CrossRefPubMedGoogle Scholar
  21. Krabbe C, Zimmer J, Meyer M (2005) Neural transdifferentiation of mesenchymal stem cells—a critical review. APMIS 113:831–844CrossRefPubMedGoogle Scholar
  22. Kwon BK, Tetzlaff W, Grauer JN, Beiner J, Vaccaro AR (2004) Pathophysiology and pharmacologic treatment of acute spinal cord injury. Spine J 4(4):451–464CrossRefPubMedGoogle Scholar
  23. Lalu M, McIntyre L, Pugliese C, Fergusson D, Winston BW, Mashall JC, Granton J, Stewart DJ (2012) Safety of cell therapy with mesenchymal stromal cells (safecell): a systematic review and meta-analysis of clinical trials. Plos One 7(10):e47559CrossRefPubMedPubMedCentralGoogle Scholar
  24. Marcos AB, Forner S, Martini AC, Patrício ES, Clarke JR, Costa R, Felix-Alves J, Vieira VJ, de Andrade EL, Mazzuco TL, Calixto JB, Figueiredo CP (2015) Temporal and regional expression of glucose-dependent insulinotropic peptide and its receptor in spinal cord injured rats. J Neurotrauma 33(3):261–268CrossRefPubMedGoogle Scholar
  25. Murray IR, West CC, Hardy WR, James AW, Park TS, Nguyen A, Tawonsawatruk T, Lazzari L, Soo C, Péault B (2014) Natural history of mesenchymal stem cells, from vessel walls to culture vessels. Cell Mol Life Sci 71(8):1353–1374CrossRefPubMedGoogle Scholar
  26. 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 29:1614–1625CrossRefPubMedPubMedCentralGoogle Scholar
  27. Nandoe Tewarie RS, Hurtado A, Bartels RH, Grotenhuis A, Oudega M (2009a) Stem cell-based therapies for spinal cord injury. J Spinal Cord Med 32(2):105–114CrossRefPubMedGoogle Scholar
  28. Nandoe Tewarie RS, Hurtado A, Ritfeld GJ, Rahiem ST, Wendell DF, Barroso MM, Grotenhuis JA, Oudega M (2009b) Bone marrow stromal cells elicit tissue sparing after acute but not delayed transplantation into the contused adult rat thoracic spinal cord. J Neurotrauma 26:2313–2322CrossRefPubMedGoogle Scholar
  29. Novikova LN, Brohlin M, Kingham PJ, Novikov LN, Wiberg M (2011) Neuroprotective and growth-promoting effects of bone marrow stromal cells after cervical spinal cord injury in adult rats. Cytotherapy 13:873–887CrossRefPubMedGoogle Scholar
  30. Oliveri RS, Bello S, Biering-Sorensen F (2014) Mesenchymal stem cells improve locomotor recovery in traumatic spinal cord injury: systematic review with meta-analyses of rat models. Neurobiol Dis 62:338–353CrossRefPubMedGoogle Scholar
  31. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284(5411):143–147CrossRefPubMedGoogle Scholar
  32. Quertainmont R, Cantinieaux D, Botman O, Sid S, Schoenen J, Franzen R (2012) Mesenchymal stem cell graft improves recovery after spinal cord injury in adult rats through neurotrophic and pro-angiogenic actions. PLoS One 7:e39500CrossRefPubMedPubMedCentralGoogle Scholar
  33. Sekhon LH, Fehlings MG (2001) Epidemiology, demographics, and pathophysiology of acute spinal cord injury. Spine 26:S2–12CrossRefPubMedGoogle Scholar
  34. Thuret S, Moon LDF, Gage FH (2006) Therapeutic interventions after spinal cord injury. Nat Rev Neurosci 7:628–643CrossRefPubMedGoogle Scholar
  35. Vanicky I, Urdzikova L, Saganova K, Cizkova D, Galik J (2001) A simple and reproducible model of spinal cord injury induced by epidural balloon inflation in the rat. J Neurotrauma 18:1399–1407CrossRefPubMedGoogle Scholar
  36. Vawda R, Fehlings MG (2013) Mesenchymal cells in the treatment of spinal cord injury: current & future perspectives. Curr Stem Cell Res Ther 8(1):25–38CrossRefPubMedGoogle Scholar
  37. Zhu T, Tang Q, Gao H, Shen Y, Chen L, Zhu J (2014) Current status of cell-mediated regenerative therapies for human spinal cord injury. Neurosci Bull 30(4):671–682CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Fernanda Rosene Melo
    • 1
  • Raul Bardini Bressan
    • 3
  • Stefânia Forner
    • 2
  • Alessandra Cadete Martini
    • 2
  • Michele Rode
    • 1
  • Priscilla Barros Delben
    • 1
  • Giles Alexander Rae
    • 2
  • Claudia Pinto Figueiredo
    • 4
  • Andrea Gonçalves Trentin
    • 1
    Email author
  1. 1.Departamento de Biologia Celular, Embriologia e Genética, Centro de Ciências BiológicasUniversidade Federal de Santa CatarinaFlorianópolisBrazil
  2. 2.Departamento de Farmacologia, Centro de Ciências BiológicasUniversidade Federal de Santa CatarinaFlorianópolisBrazil
  3. 3.MRC Centre for Regenerative MedicineThe University of EdinburghEdinburghUK
  4. 4.Faculdade de Farmácia, Centro de Ciências Da SaúdeUniversidade Federal Do Rio de JaneiroRio de JaneiroBrazil

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