Clinical Trials of Stem Cell Treatment for Spinal Cord Injury

Abstract

There are more than one million patients worldwide suffering paralysis caused by spinal cord injury (SCI). SCI causes severe socioeconomic problems not only to the patients and their caregivers but also to society; therefore, the development of innovative treatments is crucial. Many pharmacological therapies have been attempted in an effort to reduce SCI-related damage; however, no single therapy that could dramatically improve the serious long-term sequelae of SCI has emerged. Stem cell transplantation therapy, which can ameliorate damage or regenerate neurological networks, has been proposed as a promising candidate for SCI treatment, and many basic and clinical experiments using stem cells for SCI treatment have been launched, with promising results. However, the cell transplantation methods, including cell type, dose, transplantation route, and transplantation timing, vary widely between trials, and there is no consensus regarding the most effective treatment strategy. This study reviews the current knowledge on this issue, with a special focus on the clinical trials that have used stem cells for treating SCI, and highlights the problems that remain to be solved before the widespread clinical use of stem cells can be adopted.

Keywords: inflammation; neurogenesis; regenerative medicine; spinal cord injury; stem cell; transplantation.

Figure 1

Systemic medical problems after spinal cord injury (SCI). SCI can cause motor functional deficits of paralysis and increased spasticity. Sensory disturbance includes severe analgesia below the level of injury and allodynia. SCI can also affect sufferers mentally by causing depression and possible suicide. Circulatory, digestive, and urogenital impairments need to be treated, as well as skin problems.

Figure 2

Pathophysiology of spinal cord injury (SCI). Secondary injury can be divided into three phases, which are acute (within a few days), sub-acute (2 days to 6 months), and chronic (over 6 months). During the acute phase, both vascular and cell membrane damage takes place. Vascular damage can cause hemorrhage and blood spinal cord barrier (BSCB) disruption. The mass effect created by massive hemorrhage can additionally damage the surrounding viable tissues. The BSCB draws the rapid infiltration of inflammatory cells such as neutrophils, resulting in the release of various pro-inflammatory cytokines. Damaged and/or necrotic cells release ATP, potassium ions, and DNA into their microenvironment, which can activate microglia to release additional proinflammatory cytokines and induce the recruitment of more peripheral inflammatory cells. During the sub-acute phase, arterial vessel damage compromises the vascular supply, which can aggravate ischemic damage to the surviving neuronal cells; meanwhile, edema caused by the alteration of vascular membrane permeability leads to further neuronal and vascular damage. Inflammatory cytokines are released from resident and blood-derived cells, and glutamate is released from damaged neuronal cells. The failure of the astrocytic re-uptake of these damage-associated molecular-pattern molecules (DAMPs) can further compromise the neuronal network, resulting in a worsening of demyelination. Inflammatory cytokines can upregulate astrocytes into the active state of astrogliosis, causing them to migrate to the damaged area to isolate it from unaffected areas; this can be considered as a physiological rescue process. In the chronic phase of SCI, the loss of cell volume leads to the vacuo formation of cystic micro-cavitation which is also called as syringomyelia, and this coalesce and forms a barrier for cell migration and regeneration of axon regrowth. In reactive astrogliosis, astrocytes secrete inhibitory chondroitin sulfate proteoglycans, which are initially protective in blocking the DAMPs from spreading, but which eventually interfere with the regeneration and extension of the neuronal network. On the other hand, low-gear reorganization also commences in the chronic phase, including vascular remodeling, alterations in the extracellular matrix composition, regenerative cell migration, and re-organization of neural circuits.