Cell Therapy for Models of Pain and Traumatic Brain Injury (2007)

This chapter reviews the cell transplantation strategies that have been explored as potential options in the treatment of pain and traumatic brain injury (TBI). As the goals of these two therapeutic targets are widely disparate, approaches have evolved along distinctive paths. Thus, although the provision of a local cellular source of pharmacologic analgesic molecules may be most appropriate in the management of chronic pain, central nervous system (CNS) repair after traumatic injury will most likely require replacement of lost neural populations and reestablishment of appropriate neurocircuitry to be maximally effective. The development of cellular strategies that would replace, or be used as, an adjunct to current clinical treatments for neuropathic pain have progressed over the past 30 yr. There are a variety of useful surgical and pharmacologic interventions, including electric stimulation, implantable mechanical pumps, and a myriad of drugs for pain relief, but cell and molecular technologies are a new frontier in pain medicine.The earliest cell therapy studies for pain relief tested adrenal chromaffin cells from rat or bovine sources that were placed in the subarachnoid space and functioned as cell minipumps, secreting a cocktail of antinociceptive agents around the spinal cord for peripheral nerve injury, inflammatory, or arthritic pain. These animal, and later clinical, studies suggested that the spinal intrathecal space was a safe and accessible location for cell grafts. A major problem remained: a lack of homogeneous expandable cell source to supply the antinociceptive agents. Cell lines that are either naturally immortalized or can be reversibly immortalized are the next phase for a practical homogenous source. These technologies have been modeled with various murine cell lines, where cells are transplanted that downregulate their proliferative or oncogenic phenotype either before or after transplant.Most recently, cell lines for pain have used molecular switches to remove the oncogenic sequence before grafting, to take advantage of the proliferative property induced by an oncogene for expansion, followed by its removal before grafting to make it safe, without the danger of tumor formation in the host. An alternate approach for current human cell lines is the use of neural or adrenal precursors, where their antinociceptive properties are induced by in vitro treatment with molecules that drive the cells to an irreversible neural or chromaffin phenotype. Although such human cell lines are at an early stage of investigation, their potential for clinical antinociception are enormous against the daunting problem of neuropathic spinal cord injury (SCI) pain.For TBI, early transplants using fetal neural tissue has more recently led to stem cell transplants and various manipulations, including the generation of immortalized neural stem cell lines, use of neurally differentiated embryonic stem cells and neurons derived from a human teratocarcinoma cell line, and nonneural sources, e.g., bone marrow and umbilical cord. Although the ideal goal of these grafts would be to replace neural cells lost to injury and to reintegrate within the host CNS circuitry, it is more likely that their beneficial effects (when observed) are attributable to the provision of trophic support. Thus, a promising approach in transplantation strategies for improved therapeutic outcomes following TBI may be to utilize grafted cells engineered to produce appropriate neuroprotective and trophic agents as vehicles for delivery to damaged CNS sites, similar to the approach taken in the cell-based delivery for pain management.