Articles, Spine

Update: Spinal cord injury stem cell therapy

Leave a comment

At present, Spinal cord injury stem cell therapy is a therapeutic promise in this field of research 1) 2) 3) 4) 5) 6) 7) 8) 9) but still subject to many uncertainties, with significant confusion due to the disparity of protocols, selection of subjects, cell type, dose and routes of administration used. In experimental studies, it is noteworthy that the functional recovery of paraplegic animals after mesenchymal stem cell (MSC) transplantation starts before tissue regeneration occurs to allow the passage of ascending and descending axons. Therefore, it is obvious that after MSC transplantation into injured central nervous system (CNS) must exist various repair processes, including the release of neurotrophic factors by the transplanted stem cells, or the activation of endogenous processes, including the release of neurotrophic factors by the transplanted stem cells, or the activation of endogenous mechanisms of the spinal cord, able to partially restore neurological functions previously abolished 10) 11) 12) 13) 14)15) 16) 17) 18).

Unflammation and toxins released by damaged cells at the site of a spinal injury often cause further harm to surrounding cells. Researchers are developing treatments that reduce inflammation and soak up toxins and free radicals to minimise additional damage.

Spinal cord injuries often damage neurons and the supporting cells that wrap & insulate neurons. Damaging the supporting cells can cause otherwise functional neurons to die. Researchers are studying how stem cells might be used to replace neurons and their supporting cells to greatly improve a patient’s chances for recovering function.

As a potentially unlimited autologous cell source, patient induced pluripotent stem cells (iPSCs) provide great capability for tissue regeneration, particularly in spinal cord injury (SCI). However, despite significant progress made in translation of iPSC-derived neural stem cells to clinical settings, a few hurdles remain. Among them, non-invasive approach to obtain source cells in a timely manner, safer integration-free delivery of reprogramming factors, and purification of NSCs before transplantation are top priorities to overcome.

Liu et al., developed a safe and cost-effective pipeline to generate clinically relevant NSCs. They first isolated cells from patients’ urine and reprogrammed them into iPSCs by non-integrating Sendai virus vectors, and carried out experiments on neural differentiation. NSCs were purified by A2B5, an antibody specifically recognizing a glycoganglioside on the cell surface of neural lineage cells, via fluorescence activated cell sorting. Upon further in vitro induction, NSCs were able to give rise to neurons, oligodendrocytes and astrocytes. To test the functionality of the A2B5+ NSCs, they grafted them into the contused mouse thoracic spinal cord. Eight weeks after transplantation, the grafted cells survived, integrated into the injured spinal cord, and differentiated into neurons and glia.

The specific focus on cell source, reprogramming, differentiation and purification method purposely addresses timing and safety issues of transplantation to SCI models. It is Liu et al., belief that this work takes one step closer on using human iPSC derivatives to SCI clinical settings 19).

1) Syková E, Homola A, Mazanec R, Lachmann H, Konrádová SL, Kobylka P, et al. Autologous bone marrow transplantation in patients with subacute and chronic spinal cord injury. Cell Transplant 2006;15:675–87.
2) Yoon SH, Shim YS, Park YH, Chung JK, Nam JH, Kim MO, et al. Complete spinal cord injury treatment using autologous bone marrow cell transplantation and bone marrow stimulation with granulocyte macrophage-colony stimulating factor: phase I/II clinical trial. Stem Cells 2007;25:2066–73.
3) Deda H, Inci MC, Kürekçi AE, Kayihan K, Ozgün E, Ustünsoy GE, et al. Treatment of chronic spinal cord injured patients with autologous bone marrow-derived hematopoietic stem cell transplantation: 1-year follow-up. Cytotherapy 2008;10:565–74.
4) Saito F, Nakatani T, Iwase M, Maeda Y, Hirakawa A, Murao Y, et al. Spinal cord injury treatment with intrathecal autologous bone marrow stromal cell transplantation: the first clinical trial case report. J Trauma 2008;64:53–9.
5) Pal R, Venkataramana NK, Bansai A, Balaraju S, Jan M, Chandra R, et al. Ex vivo-expanded autologous bone marrowderived mesenchymal stromal cells in human spinal cord injury/paraplegia: a pilot clinical study. Cytotherapy 2009;11:897–911.
6) Park JH, Kim DY, Sung I, Choi GH, Jeon MH, Kim KK, et al. Long-term results of spinal cord injury therapy using mesenchymal stem cells derived from bone marrow in humans. Neurosurgery 2012;70:1238–47.
7) Saito F, Nakatani T, Iwase M, Maeda Y, Murao Y, Suzuki Y, et al. Administration of cultured autologous bone marrow stromal cells into cerebrospinal fluid in spinal injury patients: a pilot study. Restor Neurol Neurosci 2012;30:127–36.
8) Jiang PC, Xiong WP, Wang G, Ma C, Yao WQ, Kendell SF, et al. A clinical trial report of autologous bone marrow-derived mesenchymal stem cell transplantation in patients with spinal cord injury. Exp Ther Med 2013;6:140–6.
9) Mendonça MVP, Larocca TF, Souza BS, de Freitas Souza BS, Villarreal CF, Silva LF, et al. Safety and neurological assessments after autologous transplantation of bone marrow mesenchymal stem cells in subjects with chronic spinal cord injury. Stem Cell Res Ther 2014;5:126
10) Zurita M, Vaquero J. Functional recovery in chronic paraplegia after bone marrow stromal cells transplantation. Neuroreport 2004;15:1105–8.
11) Zurita M, Vaquero J. Bone marrow stromal cells can achieve cure of chronic paraplegic rats: functional and morphological outcome one year after transplantation. Neurosci Lett 2006;402:51–6.
12) Vaquero J, Zurita M, Oya S, Santos M. Cell therapy using bone marrow stromal cells in chronic paraplegic rats: systemic or local administration? Neurosci Lett 2006;398:129–34.
13) Zurita M, Vaquero J, Bonilla C, Santos M, De Haro J, Oya S, et al. Functional recovery of chronic paraplegic pigs after autologous transplantation of bone marrow stromal cells. Transplantation 2008;86:845–53.
14) Vaquero J, Zurita M. Bone marrow stromal cells for spinal cord repair: a challenge for contemporary neurobiology. Histol Histopathol 2009;24:107–16.
15) Bonilla C, Zurita M, Otero L, Aguayo C, Vaquero J. Delayed intralesional transplantation of bone marrow stromal cells increases endogenous neurogenesis and promotes functional improvement after severe traumatic brain injury. Brain Inj 2009;23:760–9.
16) Vaquero J, Zurita M. Functional recovery after severe CNS trauma: current perspectives for cell therapy with bone marrow stromal cells. Prog Neurobiol 2011;93:341–9.
17) Otero L, Zurita M, Bonilla C, Aguayo C, Vela A, Rico MA, et al. Late transplantation of allogeneic bone marrow stromal cells improves neurological deficits subsequent to intracerebral hemorrhage. Cytotherapy 2011;13:562–71.
18) Otero L, Zurita M, Bonilla C, Aguayo C, Rico MA, Rodriguez A, et al. Allogeneic bone marrow stromal cell transplantation after cerebral hemorrhage achieves cell transdifferentiation and modulates endogenous neurogenesis. Cytotherapy 2012;14: 34–44.
19) Liu Y, Zheng Y, Li S, Xue H, Schmitt K, Hergenroeder GW, Wu J, Zhang Y, Kim DH, Cao Q. Human neural progenitors derived from integration-free iPSCs for SCI therapy. Stem Cell Res. 2017 Jan 5;19:55-64. doi: 10.1016/j.scr.2017.01.004. [Epub ahead of print] PubMed PMID: 28073086.

Leave a Reply