Case Control Series of Intrathecal Autologous Bone Marrow Mesenchymal Stem Cell Therapy for Chronic Spinal Cord Injury

Abstract

Background: Autologous bone marrow mesenchymal cells that include stem cells (MSCs) are a clinically attractive cellular therapy option to try to treat severe spinal cord injury (SCI). Objective: To study the possible value of MSCs injected intrathecally to enhance rehabilitation. Methods: This case control, convenience sample included 64 patients, at a mean of 3.6 years after SCI. Forty-four subjects received monthly intrathecal autologous MSCs for 6 months and 20 subjects, who would not agree to the procedures, served as controls. All subjects received rehabilitation therapies 3 times weekly. Subjects were evaluated at entry and at 12 months after completing the 6-months intervention. By the ASIA Impairment Scale, ASIA grading of completeness of injury, Ashworth Spasticity Scale, Functional Ambulation Classification, and bladder and bowel control questionnaire. Results: No differences were found in baseline measures and descriptors between the MSC group and control group. Although a higher percentage of the MSC group increased motor scores by 1-2 points and changed from ASIA A to B, no significant between-group improvements were found in clinical measures. Adverse effects of cells included spasticity and, in 24 out of the 43 patients developed neuropathic pain. One subject with a history of post-infectious myelitis developed encephalomyelitis after her third injection. Conclusion: Autologus MSCs may have side effects and may be contraindicated in patients with a history of myelitis. Their utility in treating chronic traumatic SCI needs further study in pre-clinical models and in randomized controlled trials before they should be offered to patients.

Keywords

mesenchymal stem cell spinal cord injury SSEP

References

Blesch A. , Lu P. , Tuszynski M. Neurotrophic factors, gene therapy, and neural stem cells for spinal cord repair. Brain Res Bull. 2002;57:833-838.

Lima C. , Escada P. , Pratas-Vital J. , et al. Olfactory mucosal autografts and rehabilitation for chronic traumatic spinal cord injury. Neurorehabil Neural Repair. 2010;24:10-24.

Jiang Y. , Balkrishna N. , Jahagirdar R. , et al. Pluripotency of mesenchymal stem cells derived from adult marrow . Nature. 2002;418:41-49.

Mazurier F. , Doedens M. , Gan OI , et al. Rapid myeloerythroid repopulation after intrafemoral transplantation of NOD-SCID mice reveals a new class of human stem cells. Nature Med. 2003;9:959-963.

Kabos P. , Ehtesham M. , Kabosova A. , et al. Generation of neural progenitor cells from whole adult bone marrow. Experimental Neurol. 2002;178:288-293.

Mezey E. , Karen J. , Gyöngyi H. , et al. Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science. 2000;290:1779-1782.

Bakshi A. , Barshinger AL , Swanger SA , et al. Lumbar puncture delivery of bone marrow stromal cells in spinal cord contusion: a novel method for minimally invasive cell transplantation . J Neurotrauma. 2006;23:55-65.

Callera F. , de Melo CM Magnetic resonance tracking of magnetically labeled autologous bone marrow CD34 stem cells transplanted into the spinal cord via lumbar puncture: technique in patients with chronic spinal cord injury CD34+cells’ migration into the injured site. Stem Cells Dev. 2007 ;16: 461-466.

Brazelton TR , Rossi FMV , Keshet GI , Blau HM From marrow to brain: expression of neuronal phenotypes in adult mice. Science . 2000;290:1775-1779.

10.

Zhang J. , Li Y. , Zheng X. , et al. Bone marrow stromal cells protect oligodendrocytes from oxygen-glucose deprivation injury. J Neurosci Res. 2008;86:1501-1510.

11.

Akiyama Y. , Radtke C. , Jeffery DK Remyelination of the rat spinal cord by transplantation of identified bone marrow stromal cells. Neuroscience. 2002 ;22:6623-6630.

12.

Levit K. Trunk control during functional performance. Paper presented at the American Occupational Therapy Association Annual Conference ; April 1997; Baltimore, MD.

13.

Scott J. , Huskisson EC Graphic representation of pain. Pain. 1976 ;2:175-184.

14.

Bohannon RW , Smith MB Interrater reliability of a modified Ashworth scale of muscle spasticity. Phys Ther. 1987 ;67:206-207.

15.

Holden M. , Gill K. , Magliozzi M. Gait assessment for neurologically impaired patients. Phys Ther. 1986;66:1530-1539.

16.

American Spinal Injury Association. Standard for Neurological Classification of Spinal Injury Patients. Chicago, IL: American Spinal Injury Association; 1984.

17.

Mahoney FI , Barthel DW Functional evaluation: The Barthel Index. In: O’Sullivan SB , Schmitz TJ , eds. Physical Rehabilitation Assessment and Treatment . 3rd ed. New York, NY: Davis; 1994:198.

18.

Park HC , Shims YS , Ha Y. , et al. Treatment of complete spinal cord injury patients by autologous bone marrow cell transplantation and administration of granulocytemacrophage colony stimulating factor. Tissue Eng. 2005 ;11: 913-922.

19.

Sykova E. , Homola A. , Mazanec R. , et al. Autologous bone marrow transplantation in patients with subacute and chronic spinal cord injury. Cell Transplant. 2006;15:1-100.

20.

Geffner LF , Santacruz P. , Izurieta M. , et al. Administration of autologous bone marrow stem cells into spinal cord injury patients via multiple routes is safe and improves their quality of life: comprehensive case studies. Cell Transplant. 2008; 17:1277-1293.

21.

Dobkin BH Behavioral, temporal, and spatial targets for cellular transplants as adjuncts to rehabilitation for stroke. Stroke. 2007 ;38(2 suppl):832-839.

22.

Kadoya K. , Tsukada S. , Lu P. , et al. Combined intrinsic and extrinsic neuronal mechanisms facilitate bridging axonal regeneration one year after spinal cord injury. Neuron. 2009;64: 165-172.

23.

Chae WP , Keun SK , Sohyun B. , et al. Cytokine secretion profiling of human mesenchymal stem cells by antibody array. Int J Stem Cells. 2009;2:59-68.

24.

Abrams MB , Dominguez C. , Pernold K. , et al. Multipotent mesenchymal stromal cells attenuate chronic inflammation and injury-induced sensitivity to mechanical stimuli in experimental spinal cord injury. Restor Neurol Neurosci. 2009;27: 307-321.

25.

Dobkin BH

What matters in cellular transplantation for spinal cord injury: the cells, the rehabilitation, or the best mix?

Neurorehabil Neural Repair . 2010;24:7-9.

26.

Fawcett JW , Curt A. , Steeves JD , et al. Guidelines for the conductof clinical trials for spinal cord injury as developed by the ICCP panel: spontaneous recovery after spinal cord injury and statistical power needed for therapeutic clinical trials. Spinal Cord. 2007;45:190-205.