Stem Cell Therapy and Spinal Cord Injury repair

Collect 4000 + 10x Everyday Rewards points when you spend $100+ on your first shop* Learn more

User
Cart
$0.00
  1. Home
  2. Search Results

The latest research for Stem Cell Therapy and Spinal Cord Injury repair

Healthylife Pharmacy20 June 2016|4 min read

The Current Approach to the Treatment of spinal cord injury includes surgery to decompress and stabilise the injury, prevention of secondary complications, management of any that do occur, and rehabilitation. Unfortunately, neurological recovery is limited, and most spinal cord injury patients still face substantial neurological dysfunction and lifelong disability.

Stem cell therapy offers several highly attractive strategies for spinal cord repair, including:

  • replacement of damaged neuronal and glial cells
  • re-myelination of spared axons
  • restoration of neuronal circuitry
  • bridging of lesion cavities
  • production of neurotrophic factors
  • anti-inflammatory cytokines
  • molecules to promote tissue sparing and neovascularisation
  • and a permissive environment for plasticity and axonal regeneration.

What are stem cells?

Stem cells are the foundation cells for every organ and tissue in our bodies. The highly specialised cells that make up these tissues originally came from an initial pool of stem cells formed shortly after fertilisation.

Throughout our lives, we continue to rely on stem cells to replace injured tissues and cells that are lost every day, such as those in our skin, hair, blood and the lining of our gut.

Stem cells have two key properties:

1) the ability to self-renew, dividing in a way that makes copies of themselves

2) the ability to differentiate, giving rise to the mature types of cells that make up our organs and tissues

The two main stem cell types are:

  • embryonic stem cells (ES) cells
  • adult stem cells (i.e. somatic stem cells)

Embryonic stem cells

Embryonic stem cells have been derived from a variety of species, including humans, and are described as “pluripotent,” meaning that they can generate all the different types of cells in the body. 

Embryonic stem cells can be obtained from the blastocyst (a very early embryo that has the shape of a ball and consists of approximately 150-200 cells) which is barely visible to the naked eye. At this stage, there are no organs, not even blood, just an “inner cell mass” from which embryonic stem cells can be obtained. Human embryonic stem cells are derived primarily from blastocysts that were created by in vitro fertilisation for assisted reproduction but were no longer needed.

Adult stem cells

These are also called tissue-specific stem cells or ‘somatic’ stem cells. These types of stem cells are already somewhat specialised and can produce some or all of the mature cell types found within the particular tissue or organ in which they reside. Because of their ability to generate multiple, organ-specific, cell types, they are described as “multipotent.” In contrast to a ‘pluripotent’ stem cell, a ‘multipotent’ adult stem cell is restricted to producing cells of a certain organ or tissue type. For example, blood stem cells are multipotent cells that can produce all the different blood cell types but cannot produce the cells of other organs such as the liver or brain. 

Nevertheless, it is significant to note that stem cells found within the adult brain are known to be capable of making neurons and two types of glial cells, astrocytes and oligodendrocytes. Prior to just the past decade, the prevailing view categorically denied the possibility of neurogenesis. It was universally accepted that nerve cells in the adult brain did not divide. However, in the mid-to-late nineties, mounting scientific evidence established the fact that stem cells do occur in the adult mammalian brain and that these cells can generate into any of its three major cell lines:

  • neurons,
  • astrocytes, and
  • oligodendrocytes

Induced pluripotent stem cells (iPSC)

One of the hottest topics in stem cell research today is the study of induced pluripotent stem cells (iPSC). These are adult cells (e.g. skin cells) that are engineered, or “reprogrammed,” to become pluripotent, i.e. behave like an embryonic stem cell. Three groups of central nervous system (CNS) stem cells have been reported to date. All occur in the adult rodent brain and preliminary evidence indicates they also occur in the adult human brain.

How could stem cells contribute to spinal cord repair?

A spinal cord injury involves a primary mechanical injury that directly disrupts axons, blood vessels, and cell membranes. This primary mechanical injury is followed by a secondary injury phase involving inflammation and additional  cell death. Following injury, the mammalian central nervous system fails to adequately regenerate due to intrinsic inhibitory factors expressed on central myelin and the extracellular matrix of the posttraumatic glial scar.

Spinal cord injury has been extensively studied in many experimental animal models including mice, rats, cats, and nonhuman primates. A combination of therapies is needed, acting at the appropriate time-point and on the correct targets.

Studies in animals have shown that a transplantation of stem cells or stem-cell-derived cells may contribute to spinal cord repair by:

  • replacing the nerve cells that have died as a result of the injury
  • generating new supporting cells that will re-form the insulating nerve sheath (myelin) and act as a bridge across the injury to stimulate re-growth of damaged axons
  • protecting the cells at the injury site from further damage by releasing protective substances such as growth factors, and soaking up toxins such as free radicals, when introduced into the spinal cord shortly after injury
  • preventing spread of the injury by suppressing the damaging inflammation that can occur after injury

Cell-based regenerative therapy

This has two primary aims: 1) to directly replace cells lost due to injury (oligodendrocytes or neurons), and 2) to influence the environment in such a way as to either enhance or support axonal regeneration, provide  neuroprotection, or both. It is a promising strategy for spinal cord injury, and preclinical models demonstrate that cell transplantation can ameliorate some secondary events through neuroprotection and also restore lost tissue through regeneration.

Neural stem progenitor cells (NSPCs)

The transplantation of glial cells has shown great potential for remyelinating demyelinated axons and improving recovery in animal models of spinal cord injury.  

The isolation of adult neural stem cells in mammals was first reported in 1992. Neural stem progenitor cells (NSPCs) reside within specific niches in the adult central nervous system. Transplantation of these NPSCs into spinal cord injury rats promoted functional recovery with neuroprotective and neuro-regenerative effects. Most studies with transplanted NSPCs have shown modest recovery of the injured spinal cord.

Schwann cells

Schwann cells are the myelinating glia of the peripheral nervous system. The seminal work of David and Aguayo using peripheral nerve grafts provided early evidence that Schwann cells could support axonal regeneration of CNS neurons after SCI and ushered in the current era of neuro-regeneration research for SCI. The use of intact peripheral nerve segments as bridges to facilitate axonal regeneration within the injured spinal cord has continued.

Olfactory ensheathing cells (OECs)

Olfactory ensheathing cells are unique in their ability to facilitate the passage of new axons from regenerating olfactory receptor neurons (which reside in the peripheral nervous system [PNS] within the olfactory mucosa) over long distances up to a target neuron within the olfactory bulb glomeruli (CNS). This ability to seemingly escort axons across the "PNS to CNS barrier" has made OECs an extremely attractive potential transplantation substrate in spinal cord injuries. Almost a decade of further work has curtailed the enthusiasm surrounding these cells to some extent, because it has become evident that some of the regeneration observed in OEC transplantation experiments may in fact be attributable to invading endogenous Schwann cells.

Embryonic stem cells (ESCs)

Over the past decade, significant advances have been made in the ability to preferentially drive the differentiation of ESCs into neural and specifically oligodendroglial lineages (oligodendrocyte precursor cells [OPCs]). The production of a high-purity population of OPCs from human ESCs was first achieved by researchers, Hans Keirstead and coworkers. They subsequently demonstrated that these human ESC-derived OPCs resulted in remyelination and significantly improved locomotor function when transplanted 1 week after SCI in the rat. Currently, this approach is being considered to begin preliminary clinical trials.

References

  1. Tator CH. Review of treatment trials in human spinal cord injury: issues, difficulties, and recommendations. Neurosurgery. 2006;59(5):957–982.
  2. Ackery A, Tator C, Krassioukov A. A global perspective on spinal cord injury epidemiology. J Neurotrauma. 2004;21(10):1355–1370.
  3. Furlan JC, Sakakibara BM, Miller WC, Krassioukov AV. Global Incidence and Prevalence of Traumatic Spinal Cord Injury. Can J Neurol Sci. 2013; 40: 456-464.
  4. Natioal Spinal Cord Injury Statistical Center. Facts and Figures at a Glance. Birmingham, AL: University of Alabama at Birmingham, 2016.
  5. No authors listed]. One Degree of Separation: Paralysis and SCI in the United States. Short Hills, New Jersey, USA: Christopher and Dana Reeve Foundation; 2009.
  6. AIHW: Norton L 2010. Spinal cord injury, Australia 2007–08. Injury research and statistics series no. 52. Cat. no. INJCAT 128. Canberra: AIHW.
  7. Wyndaele M, and Wyndaele J-J. Incidence, prevalence and epidemiology of spinal cord injury: what learns a worldwide literature survey? Spinal Cord. 2006;44, 523–508.
  8. Mothe AJ, and Tator CH. Advances in stem cell therapy for spinal cord injury. Journal of Clinical Investigation. Nov 2012;122(11):3824-3834.
  9. Stem Cell Facts. International Society for Stem Cell Research. (n.d.)
  10. Gage FH, Coates PW, Palmer TD, et al. (1995). Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain. Proc. Natl. Acad. Sci. USA 1995; 92, 11879–11883.
  11. Johe KK, Haze, TG, Muller T, Dugich-Djordjevic, MM, and McKay R.D. Single factors direct the differentiation of stem cells from the fetal and adult central nervous system. Genes Dev.1996; 10, 3129–3140.
  12. McKay R. Stem cells in the central nervous system. Science. 1997;276, 66–71.
  13. Momma S, Johansson CB, and Frisen J. Get to know your stem cells. Curr Opin Neurobiol. 2000; 10, 45–49.
  14. Morshead CM. and van der Koo, KD. A new ‘spin' on neural stem cells? Curr Opin Neurobiol. 2001;11, 59–65.
  15. Lois C and Alvarez-Buylla A. Long-distance neuronal migration in the adult mammalian brain. Science. 1994; 264, 1145–1148.
  16. Luskin MB. Restricted proliferation and migration of postnatally generated neurons derived from the forebrain subventricular zone. Neuron.1993; 11, 173–189.
  17. Eriksson PS, Perfilieva E, Bjork-Eriksso, T, et al. Neurogenesis in the adult human hippocampus. Nat Med. 1998; 4, 1313–1317.
  18. Gage FH, Ray J, and Fisher LJ. Isolation, characterization, and use of stem cells from the CNS. Annu Rev Neurosci 1995; 18, 159–192.
  19. Rowland JW, Hawryluk GWJ, Kwon B. et al. Current Status of Acute Spinal Cord Injury Pathophysiology and Emerging Therapies: Promise on the Horizon. Neurosurg Focus. 2008;25(5): E2.
  20.  Sekhon LH, Fehlings MG: Epidemiology, demographics, and pathophysiology of acute spinal cord injury. Spine 2001; 26: S2-S12.
  21. 21 Baptiste DC, Fehlings MG. Pharmacological approaches to repair the injured spinal cord. J Neurotrauma 2006; 23:318-334.
  22. Bunge RP, Puckett WR, Becerra JL, et al. Observations on the pathology of human spinal cord injury. A review and classification of 22 new cases with details from a case of chronic cord compression with extensive focal demyelination. Adv Neurol 1993; 59:75-89.
  23. McDonald JW, Belegu V. Demyelination and re-myelination after spinal cord injury. J Neurotrauma 2006; 23:345-359.
  24. Nashmi R, Fehlings MG. Changes in axonal physiology and morphology after chronic compressive injury of the rat thoracic spinal cord. Neuroscience 2001;104: 235-251.
  25. Radojicic M, Reier PJ, Steward O, et al. Septations in chronic spinal cord injury cavities contain axons. Exp Neurol 2005; 196:339-341.
  26. Totoiu MO, Keirstead HS. Spinal cord injury is accompanied by chronic progressive demyelination. J Comp Neurol 2005; 486:373-383.
  27. Toma JG, Akhavan M, Fernandes KJ, et al. Isolation of multipotent adult stem cells from the dermis of mammalian skin. Nat Cell Biol 2001;3: 778-784.
  28. Kakulas BA: Neuropathology: the foundation for new treatments in spinal cord injury. Spinal Cord 2004; 42:549-563.
  29. Richardson PM, McGuinness UM, Aguayo AJ. Axons from CNS neurons regenerate into PNS grafts. Nature. 1980;284(5753):264–265.
  30. Bregman BS, Reier PJ. Neural tissue transplants rescue axotomized rubrospinal cells from retrograde death. J Comp Neurol. 1986;244(1):86–95.
  31. Fehlings MG, Vawda R. Cellular treatments for spinal cord injury: the time is right for clinical trials. Neurotherapeutics. 2011;8(4):704–720.
  32. Tetzlaff W, et al. A systematic review of cellular transplantation therapies for spinal cord injury. J Neurotrauma. 2011;28(8):1611–1682.
  33. Sahni V, Kessler JA. Stem cell therapies for spinal cord injury. Nat Rev Neurol. 2010;6(7):363–372.
  34. Thomas KE, Moon LD. Will stem cell therapies be safe and effective for treating spinal cord injuries? Br Med Bull. 2011; 98:127–142.
  35. Wright KT, El Masri W, Osman A, Chowdhury J, Johnson WE. Bone marrow for the treatment of spinal cord injury: mechanisms and clinical application. Stem Cells. 2011;29(2):169–178.
  36. Enzmann GU, Benton RL, Talbott JF, Cao Q, Whittemore SR. Functional considerations of stem cell transplantation therapy for spinal cord repair. J Neurotrauma. 2006;23(3–4):479–495.
  37. Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science. 1992; 255(5052):1707–1710.
  38. Kulbatski I, Mothe AJ, Keating A, Hakamata Y, Kobayashi E, Tator CH. Oligodendrocytes and radial glia derived from adult rat spinal cord progenitors: morphological and immunocytochemical characterization. J Histochem Cytochem. 2007; 55(3):209–222.
  39. Martens DJ, Seaberg RM, van der Kooy D. In vivo infusions of exogenous growth factors into the fourth ventricle of the adult mouse brain increase the proliferation of neural progenitors around the fourth ventricle and the central canal of the spinal cord. Eur J Neurosci. 2002;16(6):1045–1057.
  40. Kulbatski I, Mothe AJ, Keating A, Hakamata Y, Kobayashi E, Tator CH. Oligodendrocytes and radial glia derived from adult rat spinal cord progenitors: morphological and immunocytochemical characterization. J Histochem Cytochem. 2007; 55(3):209–222.
  41. Mothe AJ, Tator CH. Transplanted neural stem/ progenitor cells generate myelinating oligodendrocytes and Schwann cells in spinal cord demyelination and dysmyelination. Exp Neurol. 2008; 213(1):176–190.
  42. Mothe AJ, Kulbatski I, Parr A, Mohareb M, Tator CH. Adult spinal cord stem/progenitor cells transplanted as neurospheres preferentially differentiate into oligodendrocytes in the adult rat spinal cord. Cell Transplant. 2008;17(7):735–751.
  43. Hofstetter CP, et al. Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome. Nat Neurosci. 2005; 8(3):346–353.
  44. Moreno-Manzano V, et al. Activated spinal cord ependymal stem cells rescue neurological function. Stem Cells. 2009;27(3):733–743.
  45. Parr AM, et al. Transplanted adult spinal cord derived neural stem/progenitor cells promote early functional recovery after rat spinal cord injury. Neuroscience. 2008;155(3):760–770.
  46. Tetzlaff W, et al. A systematic review of cellular transplantation therapies for spinal cord injury. J Neurotrauma. 2011;28(8):1611–1682.
  47. Enzmann GU, Benton RL, Talbott JF, Cao Q, Whittemore SR. Functional considerations of stem cell transplantation therapy for spinal cord repair. J Neurotrauma. 2006;23(3–4):479–495.
  48. David S, Aguayo AJ. Axonal elongation into peripheral nervous system "bridges" after central nervous system injury in adult rats. Science 1981; 214:931-933.
  49. David S, Aguayo AJ. Axonal regeneration after crush injury of rat central nervous system fibres innervating peripheral nerve grafts. J Neurocytol 1985; 14:1-12.
  50. Cheng H, Cao Y, Olson L: Spinal cord repair in adult paraplegic rats: partial restoration of hind limb function. Science 1996; 273:510-513.
  51. Lee YS, Hsiao I, Lin VW: Peripheral nerve grafts and aFGF restore partial hindlimb function in adult paraplegic rats. J Neurotrauma 2002; 19:1203-1216.
  52. Boyd JG, Doucette R, Kawaja MD: Defining the role of olfactory ensheathing cells in facilitating axon remyelination following damage to the spinal cord. FASEB J 2005;19:694-703.
  53. Boyd JG, Skihar V, Kawaja M, et al: Olfactory ensheathing cells: historical perspective and therapeutic potential. Anat Rec B New Anat 2003; 271:49-60.
  54. Nistor GI, Totoiu MO, Haque N, et al: Human embryonic stem cells differentiate into oligodendrocytes in high purity and myelinate after spinal cord transplantation. Glia 2005; 49:385-396.
  55. Keirstead HS, Nistor G, Bernal G, et al: Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci 2005; 25:4694-4705.
  56. Vogel G: Cell biology. Ready or not? Human ES cells head toward the clinic. Science 2005; 308:1534-1538.
  57. Human embryonic stem cell research in the US: time for change? Nature Cell Biology 2010; 12, 627.
  58. Fact Sheet 6: Ethics & Law of Stem Cell Research. Australian Stem Cell Centre. Available at: http://www.stemcellfoundation.net.au/docs/fact-sheets/fact-sheet-6---law-and-ethics-of-stem-cell-research.pdf?sfvrsn=13 Updated July 2010. Accessed 31 May 2016.