Faculty Book
JACQUELINE SAGEN, Ph.D., M.B.A.
Professor, Neurosurgery
Cellular implants for the alleviation of chronic pain and CNS injury
Research
Interests
The field of neural transplantation has witnessed resurgence due to the potential for cellular implants to provide therapeutic benefits and restore function in the nervous system. Cells implanted into the central nervous system (CNS) can be utilized in several ways: 1) as living cellular minipumps, providing a continually renewable supply of naturally derived therapeutic molecules such as neurotransmitters or trophic factors; 2) as supportive matrices or bridges for axonal regrowth; 3) as replacement of lost neuronal populations consequent to neurological injury or disease. Our laboratory uses all of these neural transplantation strategies in order to explore more promising approaches in the treatment of debilitating CNS disorders.
Particularly amenable to the minipump approach are chronic pain syndromes, which require long-term therapeutic management. Research in my laboratory has indicated that cellular implants in the spinal subarachnoid space can alleviate many symptoms of chronic pain in animal models. For these studies, chromaffin cells from the adrenal medulla have been utilized as a graft source because these cells produce a cocktail of agents - including opioid peptides, catecholamines, endogenous NMDA antagonists, and trophic factors - which can reduce pain when administered directly into the spinal fluid. Results from animal studies have led to the initiation of clinical trials at several centers in patients with intractable pain, with encouraging results. However, before large-scale implementation, several issues need to be addressed, particularly the identification of more practical and improved sources of donor cells such as xenografts or engineered cell lines. This is a current focus of research in my laboratory. If successful, the findings from these studies could lead to novel therapies in the long-term management of chronic pain syndromes, particularly for patients refractory to traditional pharmacotherapies, who would benefit greatly by improved quality of life free from pain.
Another current research focus utilizes the cellular replacement approach in order to restore function following spinal cord and brain injury. An emergent breakthrough in recent years was the discovery that stem cells possessing the capacity to generate new neural cells and replace lost cellular populations exist in the CNS. Like stem cells identified in other biological systems, neural stem cells are capable of self-renewal, proliferation, and generation of a large number of progeny. In addition, these cells have the capacity to give rise to progenitor neural cell lineages appropriate for their location and metabolic circumstances when exposed to microenvironmental cues, and have been demonstrated to differentiate in vitro into the three major neural phenotypes: neurons, astrocytes, and oligodendrocytes. However, when transplanted to the adult CNS, neuronal differentiation is limited, possibly due to the lack of developmental cues present in the embryonic environment normally encountered by these cells. Thus, additional manipulations, such as exposure to trophic factors, genetic engineering, and/or cellular pre-differentiation will likely be necessary. Our laboratory is exploring the use of neural stem cell transplants for spinal cord injury, traumatic brain injury, and chronic pain. For each of these applications, unique strategies will be required for distinctive cellular populations. Our current strategies for neural stem cell transplantation in spinal cord injury include genetic premodification, co-grafting with trophic factor-producing cells, and combinations with axonal bridges in order to promote more complete restoration of spinal circuitry.
In summary, the overall aim of research in my laboratory is the utilization of neural transplants to restore quality of life and alleviate suffering from the most devastating of human disorders resulting from injury to the nervous system.
Hama A, Sagen J (2007) Behavioral characterization and effect of clinical drugs in a rat model of pain following spinal cord compression. Brain Res Sep 16;.
Hentall ID, Hargraves WA, Sagen J (2007) Inhibition by chromaffin cell-derived peptide serine-histogranin in the rat’s dorsal horn. Neurosci Lett 419: 88-92.
Guenot M, Nasirinezhad F, Lee JW, Sagen J (2007) Deafferentation pain resulting from cervical posterior rhizotomy is alleviated by chromaffin cell transplants into the rat spinal subarachnoid space. Neurosurgery 60 :919-925.
Hama A, Sagen J (2007) Antinociceptive effect of cannabinoid agonist WIN 55,212-2 in rats with a spinal cord injury. Exp Neurol 204: 454-457.
Castellanos DA, Daniels LA, Morales MP, Hama AT, Sagen J (2007) Expansion of formalin-evoked Fos-immunoreactivity in rats with a spinal cord injury. Neurosci Res 58: 386-393. PMID: 17531342
Sagen J, Castellanos DA, Gajavelli S (2006): Transplants for chronic pain. In: Cellular Transplants: From Lab to Clinic, C. Halberstadt and D. Emerich, eds, Elsevier, Burlington MA, Chapter 26, 455-474.
Eaton MJ, Sagen J (2006): Cell therapy for models of pain and traumatic brain injury. In: Cell Therapy for Brain Repair, Sanberg CD and Sanberg PR, eds. Humana Press, Totowa, NJ, Chapter 8, 199-239.
Hama A, Basler A, Sagen J (2006) Enhancement of morphine antinociception with the peptide N-methyl-D-aspartate receptor antagonist [Ser1]-histogranin in the rat formalin test. Brain Res, 1095: 59-64.
NasiriNezhad F, Sagen J (2005) NMDA Antagonist peptide supplementation enhances pain alleviation by adrenal medullary transplants. Cell Transpl, 14: 203-211.
Schumm MA, Castellanos, DA, Frydel BR, Sagen J (2004) Improved neural progenitor cell survival when co-grafted with chromaffin cells in the rat striatum. Exp Neurol 185: 133-142.
Schumm MA, Castellanos DA, Frydel BR, Sagen J (2003) Direct cell-cell contact required for neurotrophic effect of chromaffin cells on neural progenitor cells. Dev Brain Res 146: 1-13.
Schumm MA, Castellanos, DA, Frydel BR, Sagen J (2003) Improved neural progenitor cell survival when co-grafted with chromaffin cells in the rat striatum. Exp Neurol 185: 133-142.
Sagen J, Eaton MJ (2003): Cellular implantation for the treatment of chronic pain. In: Pain: Current Understanding, Emerging Therapies, and Novel Approaches to Drug Discover., C. Bountra, R. Munglani, and W.K. Schmidt, eds., Marcel Dekker, NY, pp. 815-833.
Siegan JB, Herzberg U, Frydel BR, Sagen J (2002) Adrenal medullary transplants reduce formalin-evoked c-fos expression in the rat spinal cord. Brain Res 944: 174-183.
Oudega M, Sagen J (2002) Tissue enginering in the spinal cord. In: Methods of Tissue Engineering. Atala A, Lanza R (eds). Academic Press, pp. 1143-1155.
Schumm M, Castellanos DA, Frydel BR, Sagen J (2002) Enhanced viability and neuronal differentiation of neural progenitors by chromaffin cell co-culture. Dev Brain Res 137: 115-125.
Castellanos DA, Tsoulfas P, Gajavelli S, Frydel BR, Sagen J (2002) TrkC receptor overexpression enhances survival and migration of neural stem cell transplants in the rat spinal cord. Cell Transpl 11: 297-307.
Hentall ID, Noga BR, Sagen J (2001) Spinal allografts of adrenal medulla block nociceptive facilitation in the dorsal horn. J Neurophysiol 85:1788-1792.
Lazorthes Y, Sagen J, Sallerin B, Tkaczuk J, Duplan H, Sol JC, Tafani M, Bes JC (2000) Human chromaffin cell graft into the CSF for cancer pain management: a prospective phase II clinical study. Pain 87:19-32.
Last updated October, 2007
Last updated December 29, 2003
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