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Cellular and Molecular Life Sciences

, Volume 72, Issue 14, pp 2719–2737 | Cite as

Increased migration of olfactory ensheathing cells secreting the Nogo receptor ectodomain over inhibitory substrates and lesioned spinal cord

  • Diego Reginensi
  • Patricia Carulla
  • Sara Nocentini
  • Oscar Seira
  • Xavier Serra-Picamal
  • Abel Torres-Espín
  • Andreu Matamoros-Angles
  • Rosalina Gavín
  • María Teresa Moreno-Flores
  • Francisco Wandosell
  • Josep Samitier
  • Xavier Trepat
  • Xavier Navarro
  • José Antonio del RíoEmail author
Research Article

Abstract

Olfactory ensheathing cell (OEC) transplantation emerged some years ago as a promising therapeutic strategy to repair injured spinal cord. However, inhibitory molecules are present for long periods of time in lesioned spinal cord, inhibiting both OEC migration and axonal regrowth. Two families of these molecules, chondroitin sulphate proteoglycans (CSPG) and myelin-derived inhibitors (MAIs), are able to trigger inhibitory responses in lesioned axons. Mounting evidence suggests that OEC migration is inhibited by myelin. Here we demonstrate that OEC migration is largely inhibited by CSPGs and that inhibition can be overcome by the bacterial enzyme Chondroitinase ABC. In parallel, we have generated a stable OEC cell line overexpressing the Nogo receptor (NgR) ectodomain to reduce MAI-associated inhibition in vitro and in vivo. Results indicate that engineered cells migrate longer distances than unmodified OECs over myelin or oligodendrocyte-myelin glycoprotein (OMgp)-coated substrates. In addition, they also show improved migration in lesioned spinal cord. Our results provide new insights toward the improvement of the mechanisms of action and optimization of OEC-based cell therapy for spinal cord lesion.

Keywords

Olfactory ensheathing cells Traction force microscopy Chondroitin sulphate proteoglycans Cell migration Nogo receptor ectodomain 

Abbreviations

CGN

Cerebellar granule neurons

ChABC

Chondroitinase ABC

CNS

Central nervous system

CSPG

Chondroitin sulphate proteoglycan

eGFP

Enhanced green fluorescence protein

FTTM

Fourier transform traction microscopy

GDNF

Glial-derived neurotrophic factor

GFAP

Glial fibrillary acidic protein

HRP

Horseradish peroxidase

MAIs

Myelin-derived molecules

NgR

Nogo receptor

OEC

Olfactory ensheathing cell

OMgp

Oligodendrocyte-myelin glycoprotein

SCI

Spinal cord injury

TFM

Traction force microscopy

TUJ-1

β3-Tubulin

Notes

Acknowledgments

The authors thank Tom Yohannan for editorial advice and Oscar Castaño, Miguel Ángel Mateos-Timoneda and E. Engel for helping in S.E.M studies and offering comments on the manuscript. We also thank M. Segura and M. Morell for technical assistance, and members of the Del Río, Samitier and Trepat laboratories for stimulating discussions and ideas. This research was supported by the Spanish Ministry of Science and Innovation (BFU2012-32617), the Generalitat de Catalunya (SGR2014-1218), La Caixa Obra Social Foundation, and the Basque Foundation of Health and Innovation Research (BIO12/AL/004) to JADR. RG was supported by Fondo de Investigaciones Sanitarias (PI11-00075) and work in FW’s lab was supported by grants from the Dirección General de Ciencia y Tecnologia-DGCYT-(SAF2012-39148-C03-01), and EU-FP7-2009-(CT222887), as well as an institutional grant from the ‘Fundación Areces’. Work at XN’s lab was supported by grants from the Spanish Ministry of Science and Innovation (SAF2009-12495), and funds from CIBERNED and Cell Therapy Network (TERCEL) of the Instituto de Salud Carlos III of Spain. XT was supported by the Spanish Ministry of Economy and Competitiveness (BFU2012-38146) and the European Research Council (Grant Agreement 242993). JS was supported by the Fundación Botín and Institute Salud Carlos III PI10/01171. PC was supported by AGAUR, and SN and OS were supported by MINECO and IBEC. DR was supported by a fellowship from the National Commission for Science and Technology (CONICYT, Chile) and A. M-A was supported by a fellowship from the Fundación Tatiana Pérez de Guzmán el Bueno.

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Copyright information

© Springer Basel 2015

Authors and Affiliations

  • Diego Reginensi
    • 1
    • 2
    • 3
  • Patricia Carulla
    • 1
    • 2
    • 3
  • Sara Nocentini
    • 1
    • 2
    • 3
  • Oscar Seira
    • 1
    • 2
    • 3
    • 4
  • Xavier Serra-Picamal
    • 5
  • Abel Torres-Espín
    • 6
    • 7
  • Andreu Matamoros-Angles
    • 1
    • 2
    • 3
  • Rosalina Gavín
    • 1
    • 2
    • 3
  • María Teresa Moreno-Flores
    • 8
  • Francisco Wandosell
    • 9
  • Josep Samitier
    • 10
    • 11
  • Xavier Trepat
    • 12
    • 13
  • Xavier Navarro
    • 6
    • 7
  • José Antonio del Río
    • 1
    • 2
    • 3
    Email author
  1. 1.Molecular and Cellular NeurobiotechnologyInstitute of Bioengineering of Catalonia (IBEC)BarcelonaSpain
  2. 2.Department of Cell BiologyUniversitat de BarcelonaBarcelonaSpain
  3. 3.Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)BarcelonaSpain
  4. 4.Blusson Spinal Cord Centre and Department of Zoology, Faculty of ScienceInternational Collaboration On Repair Discoveries (ICORD), University of British ColumbiaVancouverCanada
  5. 5.Integrative cell and tissue dynamicsInstitute for Bioengineering of CataloniaBarcelonaSpain
  6. 6.Department of Cell Biology, Physiology and ImmunologyInstitute of Neurosciences, Edif. MBellaterraSpain
  7. 7.Grupo de Neurobiología, Instituto de Investigaciones Biosanitarias, Facultad de Ciencias BiosanitariasUniversidad Francisco de VitoriaMadridSpain
  8. 8.Centro de Biología Molecular ‘Severo Ochoa’Universidad Autónoma de Madrid (CBM-UAM)MadridSpain
  9. 9.Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)CBM-UAMMadridSpain
  10. 10.Nanobioengineering Laboratory. Institute for Bioengineering of CataloniaBarcelonaSpain
  11. 11.Department of ElectronicsUniversity of Barcelona, Centro de Investigaciòn Médica en Red, Biomecánica, Biomateriales y Nanotecnologìa (CIBERBBN)BarcelonaSpain
  12. 12.University of BarcelonaBarcelonaSpain
  13. 13.Institució Catalana de Recerca i Estudis Avançats (ICREA)BarcelonaSpain

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