Current stem cell treatments for spinal cord injury

Indian J Orthop. 2012 Jan-Feb; 46(1): 1018.

Department of University Health Network, Toronto Western Hospital, Toronto, Canada, ON M5T 2S8

This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Spinal cord injury (SCI) is a devastating condition associated with significant functional and sensory deficits, emotional, social, and financial burdens, and an increased risk of cardiovascular complications, deep vein thrombosis, osteoporosis, pressure ulcers, autonomic dysreflexia, and neuropathic pain.

The estimated annual global incidence of SCI is 1540 cases per million. In the USA, approximately 1.275 million individuals are affected, with over 12,000 new cases each year.15 The most common causes of traumatic SCI are road traffic accidents, falls, occupational and sports-related injuries that result in contusion and compression of the spinal cord.1 Approximately 55% of SCIs occur at the cervical level (C1 to C7-T1) with a mortality of 10% in the first year following injury and an expected lifespan of only 1015 years post-injury, and thoracic (T1T11), thoracolumbar (T11T12 to L1L2) and lumbosacral (L2S5) injuries each account for approximately 15% of SCI.14 Depending on the age of the patient, severity, and levels of SCI, the lifetime cost of health care and other injury-related expenses can reach $25 million.15

Despite advances in pre-hospital care, medical and surgical management and rehabilitation approaches, many SCI sufferers still experience substantial neurological disability. Intensive efforts are underway to develop effective neuroprotective and regenerative strategies.

SCI involves a primary (the physical injury) and a secondary injury (the subsequent cascade of molecular and cellular events which amplify the original injury).6 The primary injury damages both upper and lower motor neurons and disrupts motor, sensory and autonomic functions. Pathophysiological processes occurring in the secondary injury phase are rapidly instigated in response to the primary injury in an attempt to homeostatically control and minimize the damage. Paradoxically, this response is largely responsible for exacerbating the initial damage and creating an inhibitory milieu that prevents endogenous efforts of repair, regeneration and remyelination. These secondary processes include inflammation, ischemia, lipid peroxidation, production of free radicals, disruption of ion channels, axonal demyelination, glial scarring (astrogliosis), necrosis and programmed cell death. Nevertheless, endogenous repair and regenerative mechanisms during the secondary phase of injury minimize the extent of the lesion (through astrogliosis), reorganize blood supply through angiogenesis, clear cellular debris, and reunite and remodel damaged neural circuits. The spatial and temporal dynamics of these secondary mediators7 are fundamental to SCI pathophysiology and as such offer exploitable targets for therapeutic intervention.

A multitude of characteristics of cells tested pre-clinically and clinically make them attractive to potentially address the multifactorial nature of the pathophysiology of secondary SCI they are anti-inflammatory, immunomodulatory,812 anti-gliotic,13 pro-oligodendrogliogenic,14 pro-neuronogenic,15 and secrete various anti-apoptotic and pro-angiogenic neurotrophic factors. Given the pathophysiological targets of SCI,7 transplanted cells should: 1) enable regenerating axons to cross barriers; 2) functionally replace lost cells; and/or 3) create an environment supportive of neural repair.16 However, given the multifactorial nature of SCI and its dynamic pathophysiological consequences, the success of future clinical trials of cell therapy will likely depend on the informed co-administration of multiple strategies, including pharmacological and rehabilitation therapies.7

Different sources and types of cells have been and/or are being tested in clinical trials for SCI, including embryonic stem cells (ESCs), neural progenitor cells (NPCs), bone marrow mesenchymal cells (BMSCs) and non-stem cells such as olfactory ensheathing cells and Schwann cells.17 Other cell types are being developed for the clinic, including other sources of mesenchymal cells (fetal blood,18 adipose tissue, umbilical cord1936), adult21,37 and immortalized neural progenitors (PISCES, NCT01151124), skin-derived progenitors,3847 induced pluripotent stem cells4852 and endogenous spinal cord progenitors5358 []. The advantages and disadvantages of each cell source and type being considered or already in clinical trials for SCI have been extensively described and compared elsewhere,17,5963 and reflect their potential in the clinic []. There are currently more than a dozen cell therapy clinical trials for SCI listed on clinicaltrials.gov.64 Most are Phase I or I/II clinical safety and feasibility studies, indicating that cellular treatments for SCI developed in the laboratory are still in the very early stages of clinical translation.

A comparison of the different cell types and sources currently in (*) or under consideration for clinical trials for SCI

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Current stem cell treatments for spinal cord injury