Skip to main content
SpringerLink
Log in

Strategies for Endogenous Spinal Cord Repair: HPMA Hydrogel to Recruit Migrating Endogenous Stem Cells

  • Chapter
  • First Online:
Regenerative Biology of the Spine and Spinal Cord

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 760))

Abstract

Injury to the spinal cord disrupts ascending and descending axonal pathways and causes tissue damage with a subsequent limited cellular regeneration. Successful treatment would encompass the restoration of the cytoarchitecture, homeostasis and function all in dear need. Transplantation-based treatments using exogenous cells are the most favoured approach. Yet, with the advent of the stem cell concept and continuous progress in the field it became clear that the endogenous potential for repair is greater than previously thought. As an alternative to neural grafting, we and other researchers have aimed at understanding what are the elements needed for a successful repair with self progenitors that would give rise to the cell types needed to restore function of the central nervous system. Some studies involve both scaffolds and cell grafts. Here we describe studies on spinal cord repair using what we call “endogenous tissue engineering for regenerative medicine”. The approach involves a hydrogel that mimics the natural milieu where endogenous pre-existing and newly formed cells populate the gel progressively allowing for the integration of CNS self populations leading to a successful recovery of function. Highlight aspects learned from this type of studies are that: Endogenous reconstruction of the injured spinal cord is possible by using the adequate support. The contribution of nestinexpressing progenitors to spinal cord regeneration is continuous and substantial both, in the reconstructed segment as well as, along the distal and caudal segments of the reconstructed spinal cord. Most of these cells appear to have been in a quiescent state until the injury occurred and only a small fraction of these neural progenitors was produced via cell proliferation. The hydrogel combined with exercise was necessary and sufficient to restore locomotor function in cats that underwent spinal transaction followed by reconstructive surgery. This recovery of function was first seen 28 days after surgery and continued to improve for at least 21 months. Therefore, endogenous pre-existing and newly formed cells populated the gel scaffold established contact with the non injured tissue and lead to recovery of function.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian nervous system. Science 1992; 255(5052):1707–1710.

    Article  CAS  PubMed  Google Scholar 

  2. Dromard C, Guillon H, Rigau V et al. Adult human spinal cord harbors neural precursor cells that generate neurons and glial cells in vitro. J Neurosci Res 2008; 86(9):1916–1926.

    Article  CAS  PubMed  Google Scholar 

  3. Gage FH. Mammalian neural stem cells. Science 2000; 287(5457):1433–1438.

    Article  CAS  PubMed  Google Scholar 

  4. Horner PJ, Power AE, Kempermann G et al. Proliferation and differentiation of progenitor cells throughout the intact adult spinal cord. J Neurosci 2000; 20:2218–2228.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yamamoto S, Yamamoto N, Kitamura T et al. Proliferation of parenchymal neural progenitors in response to injury in the adult rat spinal cord. Exp Neurol 2001; 172(1):115–127.

    Article  CAS  PubMed  Google Scholar 

  6. Picard-Riera N, Nait-Oumesmar B, Baron-Van Evercoom A. Endogenous adult neural stem cells: Limits and potential to repair the injured central nervous system. J Neurosci Res 2004; 76:223–231.

    Article  CAS  PubMed  Google Scholar 

  7. Taupin P, Gage FH. Adult neurogenesis and neural stem cells of the central nervous system in mammals. J Neurosci Res 2002; 69(6):745–749.

    Article  CAS  PubMed  Google Scholar 

  8. Tamura A, Kirino T, Nakafuku M. Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell 2002; 110(4):429–441.

    Article  PubMed  Google Scholar 

  9. Yagita Y, Kitagawa K, Ohtsuki T et al. Neurogenesis by progenitor cells in the ischemic cerebral cortex and striatum. Stroke 2001; 32:1890–1896.

    Article  CAS  PubMed  Google Scholar 

  10. Jin K, Sun Y, Xie L et al. Directed migration of neuronal precursors into the ischemic cerebral cortex and striatum. Mol Cell Neurosci 2003; 24:171–189.

    Article  CAS  PubMed  Google Scholar 

  11. Imitola J, Raddassi K, In Park K et al. Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1a/CXC chemokine receptor 4 pathway. Proc Natl Acad Sci USA 2004; 101(52):18117–18122.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Okano H, Sakaguchi M, Ohki K et al. Regeneration of the central nervous system using endogenous repair mechanisms. J Neurochem 2007; 102(5):1459–1465.

    Article  CAS  PubMed  Google Scholar 

  13. Horky LL, Galimi F, Gage FH et al. Fate of endogenous stem/progenitor cells following spinal cord injury. J Comp Neurol 2006; 498(4):525–538.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Ke Y, Chi L, Xu R et al. Early response of endogenous adult neural progenitor cells to acute spinal cord injury in mice. Stem cells 2006; 24(4):1011–1019.

    Article  PubMed  Google Scholar 

  15. Namiki J, Tator CH. Cell proliferation and nestin expression in the ependyma of the adult rat spinal cord after injury. J Neuropathol Exp Neurol 1999; 58:489–498.

    Article  CAS  PubMed  Google Scholar 

  16. Peppas NA, Bures P, Leobandung W et al. Hydrogels in pharmaceutical formulations. Eur J Pharm Biopharm 2000; 50(1):27–46.

    Article  CAS  PubMed  Google Scholar 

  17. Subramanian A, Krishnan U, Sethuraman S. Development of biomaterial scaffold for nerve tissue engineering: Biomaterial mediated neural regeneration. J Biomed Sci 2009; 16(1):108–119.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Hoffman AS. Hydrogel for biomedical applications. Adv Drug Del Rev 2002; 54(1):3–12.

    Article  CAS  Google Scholar 

  19. Woerly S, Pinet E, de Robertis L et al. Heterogeneous PHPMA hydrogels for tissue repair and axonal regeneration in the injured spinal cord. J Biomaterial Sci Polymer Ed 1998; 9(7):681–711.

    Article  CAS  Google Scholar 

  20. Woerly S, Doan VD, Sosa N et al. Reconstruction of the double transected cat spinal cord after Neurogel implantation, axonal tracing, immunohistochemical and ultrastructural studies. Int J Dev Neurosci 2001; 19(1):63–83.

    Article  CAS  PubMed  Google Scholar 

  21. Woerly S, Doan VD, Paramore CG et al. Spinal cord reconstruction and functional recovery using Neurogel after chronic injury. J Neurosci Res 2001; 66:1187–1197.

    Article  CAS  PubMed  Google Scholar 

  22. Woerly S, Doan VD, Sosa N et al. Prevention of gliotic scar formation by Neurogel allows partial endogenous repair of transected cat spinal cord. J Neurosci Res 2004; 7:262–272.

    Article  CAS  Google Scholar 

  23. Woerly S, Awosika O, Zhao P et al. Expression of Heat Shock Protein (HSP)-25 and HSP-32 in rat spinal cord reconstructed with Neurogel. Neurochem Res 2005; 30:721–735.

    Article  CAS  PubMed  Google Scholar 

  24. Bradbury E, McMahon SB. Spinal cord repair strategies, why do they work? Nature Rev Neurosci 2006; 7(8):644–653.

    Article  CAS  Google Scholar 

  25. Murray M, Fischer I. Transplantation and gene therapy, combined approaches for repair of spinal cord injuriez. Neuroscientist 2001; 7:28–41.

    Article  CAS  PubMed  Google Scholar 

  26. Jones LL, Oudega M, Bunge MB et al. Neurotrophic factors, cellular bridges and gene therapy for spinal cord injury. J Physiol 2001; 533(1):83–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lu P, Yang H, Jones LL et al. Combinatorial Therapy with Neurotrophins and cAMP Promotes Axonal Regeneration beyond Sites of Spinal Cord Injury. J Neurosci 2004; 24(28):6402–6409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Xu Y, Kitada M, Yamaguchi M et al. Increase in bFGF-responsive neural progenitor population following contusion injury of the adult rodent spinal cord. Neurosci Lett 2006; 397(3):174–179.

    Article  CAS  PubMed  Google Scholar 

  29. Profyis C, Cheema SS, Zang D et al. Degenerative and regenerative mechanisms governing spinal cord injury. Neurobiol Disease 2004; 15(3):415–436.

    Article  Google Scholar 

  30. Nomura H, Tator CH, Shoichet MS. Bioengineered Strategies for Spinal Cord Repair. J Neurotrauma 2006; 23:496–507.

    Article  PubMed  Google Scholar 

  31. Samadikuchaksaraei A. An overview of tissue engineering approaches for management of spinal cord injuries. J NeuroEng Rehab 2007; 4:5–31.

    Article  Google Scholar 

  32. Teixeira AI, Duckworth JK, Hermanson O. Getting the right stuff, controlling neural stem cell state and fate in vivo and in vitro with biomaterials. Cell Res 2007; 17(1):56–61.

    Article  CAS  PubMed  Google Scholar 

  33. Teng YD, Lavik EB, Qu X et al. Functional recovery following traumatic spinal cord injury mediated by a unique polymer scaffold seeded with neural stem cells. Proc Natl Acad Sci USA 2002; 99(5):3024–3029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Silva GA, Czeisler C, Niece KL et al. Selective differentiation of neural progenitor cells by high-epitope density nanofibers. Science 2004; 303:1352–1355.

    Article  CAS  PubMed  Google Scholar 

  35. Silva NA, Salgado AJ, Sousa RA et al. Development and characterization of a novel hybrid tissue engineering-based scaffold for spinal cord injury. Tissue Eng 2010; 16(1):45–54.

    Article  CAS  Google Scholar 

  36. Woerly S, Fort S, Pignot-Paintrand P et al. Development of a Sialic Acid-Containing Hydrogel of Poly[N-(2-hydroxypropyl) methacrylamide]: Characterization and Implantation Study. Biomacromol 2008; 9(9):2329–2337.

    Article  CAS  Google Scholar 

  37. Itoh T, Satou S, Hashimoto H et al. Isolation of neural stem cells from damaged rat cerebral cortex after traumatic brain injury. NeuroReport 2005; 16(15):1687–1691.

    Article  PubMed  Google Scholar 

  38. Duggal NR, Schmidt-Kastner, Hakim AM. Nestin expression in reactive astrocytes following focal cerebral ischemia in rats. Brain Res 1997; 768(1–2):1–9.

    Article  CAS  PubMed  Google Scholar 

  39. Rice C, Khaldi A, Harvey HB et al. Proliferation and neuronal differentiation of mitotically active cells following traumatic brain injury. Exp Neurol 2003; 183(2):406–417.

    Article  CAS  PubMed  Google Scholar 

  40. Cizkova D, Vanicky I et al. Response of ependymal progenitors to spinal cord injury or enhanced physical activity in adult rat. Cell Mol Neurobiol 2009; 29:999–1013.

    Article  PubMed  Google Scholar 

  41. Salman H, Ghosh P, Kernie SG. Subventricular zone neural stem cells remodel the brain following traumatic injury in adult mice. J Neurotrauma 2004; 21:283–292.

    Article  PubMed  Google Scholar 

  42. Zai LJ, Yoo S, Wrathall JR. Increased growth factor expression and cell proliferation after contusive spinal cord injury. Brain Res 2005; 1052(2):147–155.

    Article  CAS  PubMed  Google Scholar 

  43. Shen Q, Goderie SK, Jin L et al. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 2004; 304:1338–1340.

    Article  CAS  PubMed  Google Scholar 

  44. Stujkovic M, Sanchez-Puelles JM, Moreno-Manzano V et al. Activated spinal cord ependymal stem cells rescue neurological function. Stem Cell 2009; 27:733–743.

    Article  CAS  Google Scholar 

  45. Roufosse CA, Direkze NC, Otto WR et al. Circulating mesenchymal stem cells. Int J Biochem Cell Bioly 2004; 36:585–597.

    Article  CAS  Google Scholar 

  46. Kaya SA, Mahmood Aa*, Li Y et al. Expression of nestin after traumatic brain injury in rat brain. Brain Research 1999; 840(1–2, 4):153–157.

    Article  CAS  Google Scholar 

  47. Foret A, Quertainmont R, Botman O et al. Stem cells in the adult rat spinal cord: plasticity after injury and treadmill training exercise. J Neurochem 2010; 112(3):762–772.

    Article  CAS  PubMed  Google Scholar 

  48. Uda M, Ishido M, Kami K et al. Effects of chronic treadmill running on neurogenesis in the dentate gyrus of the hippocampus of adult rat. Brain Res 2006; 1104(1):64–72.

    Article  CAS  PubMed  Google Scholar 

  49. Lee SH, Kim YH, Kim YJ et al. Enforced physical training promotes neurogenesis in the subgranular zone after focal cerebral ischemia. J Neurol Sci 2008; 269:54–61.

    Article  PubMed  Google Scholar 

  50. Teng YD, Liao WL, Choi H et al. Physical activity-mediated functional recovery after spinal cord injury: potential roles of neural stem cells. Regen Med 2006; 1(6):763–776.

    Article  CAS  PubMed  Google Scholar 

  51. Eidelberg E, Story JL, Walden JG et al. Anatomical correlates of return of locomotor function after partial spinal cord lesions in cats. Exp Brain Res 1981; 42:81–88.

    Article  CAS  PubMed  Google Scholar 

  52. Blight AR. Cellular morphology of chronic spinal cord injury in the cat: analysis of myelinated axons by line-sampling. Neurosci 1983; 10:521–543.

    Article  CAS  Google Scholar 

  53. Fehlings MG, Tator CH. The relationships among the severity of spinal cord injury, residual neurological function, axon counts, and counts of retrogradely labeled neurons after experimental spinal cord injury. Exp Neurol 1995; 132(2):220–228.

    Article  CAS  PubMed  Google Scholar 

  54. Zhang Y, Klassen HJ, Tucker BA et al. CNS Progenitor cells cromote a cermissive Environment for neurite outgrowth via a matrix metalloproteinase-2-dependent mechanism. J Neurosci 2007; 27(17):4499–4506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Jones LL, Yamaguchi Y, Stallcup WB et al. NG2 Is a Major Chondroitin Sulfate Proteoglycan Produced after Spinal Cord Injury and Is Expressed by Macrophages and Oligodendrocyte Progenitors. J Neurosci 2002; 22(7):2792–3280.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Espinosa-Jeffrey A, Zhao P, Awosika A et al. Activation, proliferation and commitment of endogenous, stem/ progenitor cells to the oligodendrocyte lineage by a combination of neurotrophic factors in a rat model of dysmyelination. Dev Neurosci 2006; 28(6):488–498.

    Article  CAS  PubMed  Google Scholar 

  57. Espinosa-Jeffrey A, Zhao Seiji HP, Awosika O et al. Prospects for the use of stem cells in myelin repair. J Neurosci Res 2011; 88(8):1682–1694.

    Google Scholar 

  58. Krityakiarana W, Espinosa-Jeffrey A, Paul M et al. Combination of trophic factors enhances nestin expressing progenitors and neuroprotection after spinal cord injury (Presented at the Society for Neuroscience 2 Annual meeting 2010).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience, University of California Los Angeles, Los Angeles, California, USA

    Araceli Espinosa-Jeffrey, Karlos Oregel, Laurent Wiggins, Remelyn Valera, Kathrin Bosnoyan, Chioma Agbo, Oluwole Awosika, Paul M. Zhao & Jean de Vellis

  2. Organogel, Québec, Canada

    Stéphane Woerly

Authors
  1. Araceli Espinosa-Jeffrey
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karlos Oregel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Laurent Wiggins
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Remelyn Valera
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kathrin Bosnoyan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chioma Agbo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Oluwole Awosika
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Paul M. Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jean de Vellis
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Stéphane Woerly
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Division of Neurosurgery, City of Hope Cancer Center and Beckman Research Institute, Los Angeles, California, USA

    Rahul Jandial MD, PhD  & Mike Y. Chen MD, PhD  & 

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Landes Bioscience and Springer Science+Business Media

About this chapter

Cite this chapter

Espinosa-Jeffrey, A. et al. (2012). Strategies for Endogenous Spinal Cord Repair: HPMA Hydrogel to Recruit Migrating Endogenous Stem Cells. In: Jandial, R., Chen, M.Y. (eds) Regenerative Biology of the Spine and Spinal Cord. Advances in Experimental Medicine and Biology, vol 760. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-4090-1_3

Download citation

Publish with us

Policies and ethics

Search

Navigation