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Spinal cord stoke is a condition caused by a reduction in the spinal blood flow. The subsequent ischemia leads to cell deaths and severe motor deficits. However, spinal strokes remain understudied compared to cerebral strokes. The arterial occlusion models used routinely to study cerebral strokes have been difficult to reproduce in the spinal cords of smaller rodents due to size constraints; therefore, a chemically-induced focal ischemia model using endothelin-1 has been developed recently. Endothelin-1 is a potent vasoconstrictor and has been used successfully in cerebral stroke models, thus making it an ideal candidate for use in spinal stroke studies. Currently, there are no effective therapies for spinal strokes. However, recent studies in neural stem/progenitors cells have yielded promising results as the transplanted cells are shown capable of migrating towards the lesion site, and differentiating into nervous tissues. Similar results have been reported with other stem cell types such as bone marrow stromal cells and embryonic stem cells; consequently, the relative efficacies of each cell types and the ideal source for the transplant cells remains controversial today.
Spinal Stroke and Stem Cells: Experimental and Clinical Challenges
Spinal cord stroke is a rare condition with severe motor consequences. It is primarily caused by obstructions in the vertebral vasculatures, leading to ischemia and cell death in the affected regions. Due to the vascular nature of the pathology, it is believed there are significant atherosclerotic and embolic contributions in spinal strokes1. Furthermore, spinal strokes have been reported as surgical complications in procedures where the patient undergoes prolonged intra-operative hypotension and positioning2. Despite the severe deficits associated, spinal strokes remain understudied compared to cerebral strokes due to the pathologyâ€™s lower clinical prevalence1.
Currently, there are no effective therapies for trauma and ischemic strokes in the central nervous system3 (CNS). One of the proposed treatments is the transplantation of neural stem/progenitor cells (NSPCs) into the injury site to facilitate cellular replacement and neuroprotection at the lesion core. NSPCs are multipotent cells capable of self renewal and can differentiate into multiple types of neural cells. It is hypothesized that after transplantation, the NSPCs will differentiate into appropriate cell types such as neurons and astrocytes, replacing the damaged cells and buffering the extracellular environments, thus promoting cellular recovery at the lesion site. In addition, NSPCs are shown to actively secrete multiple types of trophic factors, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and glia-derived neutrophilic factor (GDNF). These factors have shown to enhance cellular survival and endogenous injury responses, thus would further support the recovery of the injury. NSPC transplantations have been attempted in multiple cerebral stroke models and acute spinal trauma studies with promising results; the NSPCs are shown to migrate to the lesion site and differentiate into different types of neural cells 4,5,6,7. Although the mechanisms that correlate the observed cellular recovery to the functional recovery are not yet fully understood, the general consensus is that NSPCs have tremendous potentials for treating ischemia in the CNS.
In addition to NSPCs, other types of stem cells, such as bone marrow stromal cells (BMSCs), induced pluripotent stem cells (iPSCs), and embryonic stem cells (ESCs), have been suggested as possible alternative transplant cell types8; studies have found that BMSCs stimulate oligodendrogenesis at the lesion site after transplantations, which indirectly promote the remyelination of damaged axons and may correspond to functional recovery9. In vitro experiments using iPSCs and ESCs have yielded similar results. Therefore, the ideal source of the transplant cells remains controversial today as the relative efficacies between the types of cell are not empirically clear8. However, there are numerous ethical issues surrounding the collection and usage of ESCs. Many concerns regarding the safety of embryonic or adult stem cell transplant therapies have also been raised since cells with almost unlimited growth potential are introduced into an organism; theses cells may be oncogenic if not properly controlled. Li et alâ€™s study confirms such concerns as it is reported that teratomas are formed after stem cell transplantations10. The usage of iPSCs has similar concerns since the pluripotency is induced through genetic manipulations or the introduction of transgenes, thus iPSCs have the inherent potential for abnormal cellular growth8. Thus, these issues must be addressed before stem cell transplantations can be employed in a clinical setting.
The arterial occlusion model has been extensively used to study cerebral stroke; the model involves surgically occluding a cerebral artery using sutures, and the subsequent reduction in blood flow will induce ischemia in the adjacent areas. The model is ideal for cerebral stroke studies as it offers sufficient reproducibility and temporal controls over the durations of the ischemic events11. However, arterial occlusion models are difficult to replicate in the spinal cords of smaller rodents due to the size constraints of the animals and the complexities of the required surgeries. Because of these complications, a chemically-induced ischemia model using endothelin-1 (ET-1) has been recently developed12,13. This chemical model is superior to the occlusion model because the surgical requirements are much lower, and the severity of the ischemia can be varied by adjusting the concentrations of the ET-1 applied.
ET-1 is one of the three 21 amino-acid peptide isoforms of the endothelin family14,15. It is primarily secreted from endothelial cells and has been shown to be a potent vasoconstrictor with long-lasting effects. The vasoconstrictive properties of the endothelin family are mediated by the ETA and ETB G-protein coupled receptors, found throughout the bodyâ€™s vasculatures16. With the widespread prevalence of the receptors, the endothelin family is believed to have significant physiological roles in the maintenance of blood pressure. Exploiting its vasoconstrictive properties, ET-1 has been successfully used in modeling cerebral stroke in multiple experiments11,13,17. Recent studies have shown that ET-1 is not directly neurotoxic, and its vasoconstrictive effects are generally localized without systemic involvements14. In addition, it has been demonstrated that after injection, ET-1 will induce an immediate and rapid reduction in the blood flow; the flow is reduced up to 92% from baseline level, and the reduction is sustained for 15 to 30 minutes. Reperfusion is also observed after ischemic event13. Thus, the ischemic conditions induced by ET-1 are very comparable to the clinical conditions and the procedures are minimally invasive, making ET-1 an ideal candidate for chemically-induced ischemia models14,15.
However, the success in cerebral stroke models using ET-1 has not been transferred to spinal stroke research. Currently, there is only one published spinal stroke study that utilizes ET-1. Thus, the purpose of this project is to further characterize the ET-1 induced spinal stroke model, and to examine the efficacies of NSPC transplantations after spinal ischemia. The experimental animals received bilateral intraspinal injections of 25uM ET-1 at the T8 level under anesthesia. One week after injury induction, the animals were sorted into two groups, receiving either NSPC or media injections at the injury site. The BBB locomotor test was used to functionally assess the animalsâ€™ hind limb motor functions for 6 weeks. After the functional assessments were completed, the animals were sacrificed and the spinal tissues were prepared for histological analyses. Preliminary data showed that the levels of recovery in the NSPC group were consistently higher than the media group, though the levels were not statistically significant (P<0.05).