Combined Treatment for Spinal Cord Injury:

Stem Cell Therapy and HAL

MONDAY, 19 AUGUST 2019 | Michael Stehling

Combined Treatment for Spinal Cord Injury: Stem Cell Therapy and HAL

Traumatic Spinal Cord Injury is a prevalent problem that affects millions of people world-wide. Current treatment options do not provide help for the regeneration of the spinal cord. The combination of Stem Cell Therapy with neuromuscular feedback training with HAL may advance success rates in patients with Spinal Cord Injury.

The causes of Spinal Cord Injury (SCI)

Spinal Cord Injury (SCI) is affecting 40 to 80 million people every year1. In case of traumatic SCI, a fast surgical decompression is the only way to limit further damage2. To date, none of the available therapies achieve recovery or regeneration of the injured spinal cord. Unfortunately, all current treatments do not provide regeneration of the damaged spinal cord. Whilst it is often thought that the mechanical forces to the spinal cord at the time of the accident are responsible for most of the functional deficits, much of the damage actually occurs after the initial trauma by different pathophysiological processes such as neuronal death by apoptosis and necrosis, inflammation, dysfunction of the blood–brain barrier, ionic dysregulation, lipid peroxidation and the generation of free radicals.

Patho-mechanisms of SCI

SCI can be caused by stretch, contusion, laceration, compression or direct massive destruction. These events result in the disruption of neuronal pathways3. During the first two hours after the injury, which is called the acute phase4, glial cells and neurons at the site of the lesion die via necrosis (inflammatory cell death) or by apoptosis (programmed cell death)5.

The most crucial phase of SCI, however, is the phase of secondary injury. Vasospasm, micro-haemorrhages and thrombosis leads to a reduction in blood flow, and in turn to a disruption of the blood brain barrier6, 7. Additionally, disruption of ion pumps leads to ion misbalance across cell membranes and in turn to cessation of neuronal function and eventually death8, 9, 10. Cellular debris and free radicals lead to inflammation and infiltration by immune cells. These in turn produce pro-inflammatory cytokines such as interleukins and tumour necrosis factor alpha (TNF α), which promote neurodegeneration.11, 12, 13, 14

In the chronic phase, disturbed neuro-architecture, glial scarring, disruption of axons and obstruction of axonal re-growth along the fibre tracts of the spinal cord impede functional neuro-regeneration. But this is not universally so: Some lower life forms can restructure the spinal cord and heal SCI15. Whilst immensely complex, the mechanisms involved in spinal cord repair are now increasingly better understood.16, 17, 18

Neuro-regeneration in SCI with MSC Secretome

There is growing evidence that mesenchymal stem cells (MSCs) could change the fate of SCI victims by re-establishing spinal cord function.

MSCs exhibit an active auto- and paracrine activity. They secrete a variety of soluble cytokines and microRNAs contained in exosomes and vesicles, which can induce angiogenetic, anti-inflammatory, immuno-modulatory, neurotrophic and neuroprotective effects.19, 20

While still subject of ongoing research, any of the ingredients of the mesenchymal stem cell secretome and their specific activities have been identified. Soluble cytokines with anti-inflammatory activity comprise interleukins (IL)-10, IL-12p70, IL-13, IL-17E, IL-27 and other such as ciliary neurotrophic factor (CNTF), neurotrophin 3 factor (NT-3), IL-18 binding protein and tumour necrosis factor (TNF) β1.21, 22 Neuroprotection is affected by factors like neurotrophin (NT)-1 and NT-3, brain and glial derived growth factor (BDGF, GDGF) and nerve growth factor (NGF), to name just a few. These factors can prevent neuro-degeneration and apoptosis, and also stimulate neuro-regeneration, by activating neurogenesis, axonal growth and re-myelination.23, 24, 25, 26, 27, 28, 29, 30, 31

Recent research has shown that MSCs also support the re-establishment of blood supply to the damaged spinal cord by inducing angiogenesis. The effect is caused by the release of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), interleukins (IL)-6 and IL-8, as well as the secretion of the tissue inhibitor of metalloproteinase-1, all factors particularly important for the neurologic healing process.32, 33 All of these factors are potent ingredients of stem cell secretome.

A study by the John Hopkins University tested the effect of MSCs in rats which were paralyzed with the Sindbis virus. Rats were treated with their own stem cells and greatly recovered within 6 months:

HAL® Therapy: functional improvement training after spinal cord injury and stroke using robotic exoskeletons

The brain, spinal cord, nerves and muscles form a closed circuit. When a person wants to move a muscle, a signal is sent from the brain to the muscle (efferent signal). Less well known is the fact that the muscle sends back signals to the brain (afferent signal), indicating that it has moved. With damage to the spinal cord or brain, both the efferent and afferent parts of this feedback circuit are damaged. In many patients with SCI, however, the efferent signals from the brain to the muscle, although too weak to move a muscle, can still be detected as electrical activity in the peripheral nerves.

The HAL robotic exoskeleton picks up these weak signals and via its electrical motors makes the limb move, as the relevant muscles did before the injury to the spinal cord.

Moving of the limb also moves the muscles and in turn generates the afferent signals, thus re-establishing the full feedback circuit required for voluntary limb movements. This is called interactive bio-feedback. This way, HAL provides functional recovery for patients after SCI and stroke. Many patients have been able to get out of the wheelchair and walk again after HAL training.

The combination of two powerful tools to treat SCI

ANOVA want to go one step further. We opt to combine neuro-regeneration on a cellular level, using MSC Stem Cell Secretome, with functional HAL training to optimize functional recovery. For that, we are working on a collaboration with leading specialists of HAL robotic exoskeletons to accelerate the process of integral treatment options for patients with SCI.

Get in touch with us today to find out more about your options at ANOVA.

To fully evaluate the status of your Spinal Cord Injury and to develop an optimized treatment plan, it would be very helpful if you could share with us all the relevant medical information available to you, such as medical records, current medication, surgeries, imaging results, etc. If you could answer the following question, this would be particularly helpful:

  • How and when have you sustained your spinal cord injury?
  • At what level is the injury?
  • Is it a partial or complete dissection of the spinal cord?
  • What are your main symptoms?
  • What other therapies have you had or have you considered?
  • Have you had any imaging studies (MRI) and/or other tests performed?
  • Have you ever been diagnosed with cancer?

ANOVA Institute for Regenerative Medicine provides regenerative treatment options for patients from all over the world. Experience German Stem Cell Engineering.

References and Literature - Stem Cell Therapy and HAL (Click for more)

1. Based on: Cofano F, Boido M, Monticelli M, et al. Mesenchymal Stem Cells for Spinal Cord Injury: Current Options, Limitations, and Future of Cell Therapy. Int J Mol Sci. 2019 Jun; 20(11): 2698.
2. Yılmaz T, Kaptanoğlu E. Current and future medical therapeutic strategies for the functional repair of spinal cord injury. World J. Orthop. 2015, 6, 42–55.
3. Ackery A, Tator C, Krassioukov A. A global perspective on spinal cord injury epidemiology. J. Neurotrauma 2004, 21, 1355–1370.
4. Rowland JW, Hawryluk GW, Kwon B, et al. Current status of acute spinal cord injury pathophysiology and emerging therapies: Promise on the horizon. Neurosurg. Focus 2008, 25, E2.
5. Zhang N, Yin Y, Xu SJ, et al. Inflammation & apoptosis in spinal cord injury. Indian J. Med. Res. 2012, 135, 287–296.
6. Silva NA, Sousa N, Reis RL, et al. From basics to clinical: A comprehensive review on spinal cord injury. Prog. Neurobiol. 2014, 114, 25–57.
7. Vismara I, Papa S, Forloni G, et al. Current Options for Cell Therapy in Spinal Cord Injury. Trends Mol. Med. 2017, 23, 831–849.
8. Gazdic M, Volarevic V, Harrell CR, et al. Stem Cells Therapy for Spinal Cord Injury. Int. J. Mol. Sci. 2018, 19, 1039.
9. Garcia E, Aguilar-Cevallos J, Silva-Garcia R, et al. Cytokine and Growth Factor Activation In Vivo and In Vitro after Spinal Cord Injury. Mediat. Inflamm. 2016, 2016, 9476020.
10. Hayta E, Elden H. Acute spinal cord injury: A review of pathophysiology and potential of non-steroidal anti-inflammatory drugs for pharmacological intervention. J. Chem. Neuroanat. 2017, 87, 25–31.
11. David S, Lopez Vales R, Wee Yong V. Harmful and beneficial effects of inflammation after spinal cord injury: Potential therapeutic implications. Handb. Clin. Neurol. 2012, 109, 485–502.
12. Papa S, Caron I, Erba E, et al. Early modulation of pro-inflammatory microglia by minocycline loaded nanoparticles confers long lasting protection after spinal cord injury. Biomaterials 2016, 75, 13–24.
13. Papa S, Caron I, Rossi F, et al. Modulators of microglia: A patent review. Expert Opin. Ther. Pat. 2016, 26, 427–437.
14. Shechter R, Schwartz M. Harnessing monocyte-derived macrophages to control central nervous system pathol-ogies: No longer ‘if’ but ‘how’. J. Pathol. 2013, 229, 332–346.
15. Sabin KZ, Jiang P, Gearhart MD, et al. AP-1(cFos/JunB)/miR-200a regulate the pro-regenerative glial cell response during axolotl spinal cord regeneration. Commun. Biol. 2019, 2, 91.
16. Van Niekerk EA, Tuszynski MH, Lu P, et al. Molecular and Cellular Mechanisms of Axonal Regeneration After Spinal Cord Injury. Mol. Cell Proteom. 2016, 15, 394–408.
17. Tran AP, Warren PM, Silver J. The Biology of Regeneration Failure and Success After Spinal Cord Injury. Physiol. Rev. 2018, 98, 881–917.
18. O’Shea TM, Burda JE, Sofroniew MV. Cell biology of spinal cord injury and repair. J. Clin. Investig 2017, 127, 3259–3270.
19. Sobacchi C, Palagano E, Villa A, et al. Soluble Factors on Stage to Direct Mesenchymal Stem Cells Fate. Front. Bioeng. Biotechnol. 2017, 5, 32.
20. Baez-Jurado E, Hidalgo-Lanussa O, Barrera-Bailón B, et al. Secretome of Mesenchymal Stem Cells and Its Potential Protective Effects on Brain Pathologies. Mol. Neurobiol. 2019, 1–26.
21. Boido M, Piras A, Valsecchi V, et al. Human mesenchymal stromal cell transplantation modulates neuroinflammatory milieu in a mouse model of amyotrophic lateral sclerosis. Cytotherapy 2014, 16, 1059–1072.
22. Vizoso FJ, Eiro N, Cid S, et al. Mesenchymal Stem Cell Secretome: Toward Cell-Free Therapeutic Strategies in Regenerative Medicine. Int. J. Mol. Sci. 2017, 25, 1852.
23. Boido M, Piras A, Valsecchi V, et al. Human mesenchymal stromal cell transplantation modulates neuroinflammatory milieu in a mouse model of amyotrophic lateral sclerosis. Cytotherapy 2014, 16, 1059–1072.
24. PotapovaI A, Gaudette GR, Brink PR, et al. Mesenchymal stem cells support migration, extracellular matrix invasion, proliferation, and survival of endothelial cells in vitro. Stem Cells 2007, 25, 1761–1768.
25. Mead B, Logan A, Berry M, et al. Paracrine-mediated neuroprotection and neuritogenesis of axotomised retinal ganglion cells by human dental pulp stem cells: Comparison with human bone marrow and adipose-derived mesenchymal stem cells. PLoS ONE 2014, 9, e109305.
26. Hofer HR, Tuan RS. Secreted trophic factors of mesenchymal stem cells support neurovascular and musculoskeletal therapies. Stem Cell Res. Ther. 2016, 7, 131.
27. Razavi S, Ghasemi N, Mardani M, et al. Remyelination improvement after neurotrophic factors secreting cells transplantation in rat spinal cord injury. Iran. J. Basic Med. Sci. 2017, 20, 392–398.
28. Lu P, Jones LL, Tuszynski MH. BDNF-expressing marrow stromal cells support extensive axonal growth at sites of spinal cord injury. Exp. Neurol. 2005, 191, 344–360.
29. Neuhuber B, Timothy HB, Shumsky JS; et al. Axon growth and recovery of function supported by human bone marrow stromal cells in the injured spinal cord exhibit donor variations. Brain Res. 2005, 1035, 73–85.
30. Wright, K.T.; Masri, W.E.; Osman, A.; Roberts, S.; Chamberlain, G.; Ashton, B.A.; Johnson, W.E. Bone marrow stromal cells stimulate neurite outgrowth over neural proteoglycans (CSPG), myelin associated glycoprotein and Nogo-A. Biochem. Biophys. Res. Commun. 2007, 354, 559–566.
31. Teixeira, F.G.; Carvalho, M.M.; Sousa, N.; Salgado, A.J. Mesenchymal stem cells secretome: A new paradigm for central nervous system regeneration? Cell. Mol. Life Sci. 2013, 70, 3871–3882.
32. Zanotti, L.; Angioni, R.; Calì, B.; Soldani, C.; Ploia, C.; Moalli, F.; Gargesha, M.; D’Amico, G.; Elliman, S.; Tedeschi, G.; et al. Mouse mesenchymal stem cells inhibit high endothelial cell activation and lymphocyte homing to lymph nodes by releasing TIMP-1. Leukemia 2016, 30, 1143–1154.
33. De Luca, A.; Gallo, M.; Aldinucci, D.; Ribatti, D.; Lamura, L.; D’Alessio, A.; De Filippi, R.; Pinto, A.; Normanno, N. Role of the EGFR ligand/receptor system in the secretion of angiogenic factors in mesenchymal stem cells. J. Cell. Physiol. 2011, 226, 2131–2138.

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