The current treatment options for spinal cord injury (SCI) are inadequate. New therapeutic interventions are needed to prevent secondary tissue damage and promote spinal cord repair. Cellular transplants offer a multifaceted approach to SCI repair, which may support axon regeneration by providing a permissive substrate to span the lesion, replace damaged cells, and enhance tissue preservation via neuroprotection. Despite clear evidence of long term survival of transplanted cells, the majority of cells die early after transplantation. To determine if transplanted cell death attenuates the beneficial effects of cell transplants a better understanding of the effects of transplanted cell death on both transplant and spinal cord function is needed. A necessary first step in elucidating the effect of acute transplanted cell death is the development of strategies that substantially counteract it. Current strategies primarily target single factors and only modestly improve survival. Better strategies are needed. Activating multiple pathways in cells prior to transplantation is an alternative approach to achieve robust survival. This can be done by activating transcription factors. Here enhanced adaptive survival signaling primes the cells against subsequent cell death. This abrogates the need to identify and block all the factors that contribute to cell death induction and signaling. The proposed experiments test the overall hypothesis that transplanted cells die early after implantation as a result of inadequate activation of transcription factor pathways necessary for cells to adapt to the stress and survive. Activation of transcription factor pathways, genetically or pharmacologically, enhances transplant survival, and the survival is sufficient to address the effects of transplanted cell death on transplant efficacy. We will test tis hypothesis by manipulating the activity of a transcription factor, the hypoxia inducible factor (HIF), which is implicated in both initiating adaptive cellular responses to stress and promoting cell survival. We will employ both genetic and pharmacological strategies to manipulate HIF and its adaptive prosurvival gene transcription pathways in cells prior to transplantation. Transplant survival will be measured using both standard stereology and in vivo bioluminescence imaging, a new technology that will facilitate more rapid screening of prosurvival strategies. Using cells transplanted into the rodent spinal cord seven days after SCI, we will examine 1) the extent to which activation of the HIF pathway genetically enhances transplanted cell survival 2) the extent to which cell survival can be enhanced by activating this pathway pharmacologically in cells prior to transplantation;a clinically meaningful strategy and 3) the effect of altering transplant survival on both transplant and spinal cord function. These studies are part of a long term goal to maximize transplant efficacy as they move towards human clinical trials for SCI repair. They test a new method for improving transplant survival and address the question: Does the death of transplanted cells limit the benefits of cell transplants?
The proposed research is relevant to public health because the cost burden of SCI is expensive not only in terms of health care costs but also in terms of lost productivity and quality of life. Better strategies are needed to repair the injured spinal cod and meaningfully improve functional recovery. Cell transplants are one strategy. As they move towards clinical use there is a critical need for the development of research strategies that 1) identify transplanted cells in vivo 2) enhance the acute transplant survival and 3) determine whether transplanted cell death within the spinal cord limits the beneficial effects of transplants The proposed research addresses these three unmet needs and is within the NINDS's mission to reduce the burden of neurological disease by fostering research on the causes and treatment of neurological disorders.