Delivery Routes for Cell Therapy in Stroke
Cells that have been used as experimental treatments in animal models of stroke have used one of three types of delivery routes – parenchymal, vascular, or ventricular, depending on the cell type transplanted, the stroke model used, the experimental quest
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Delivery Routes for Cell Therapy in Stroke Alison E. Willing and Md Shahaduzzaman
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Introduction
Stroke was not originally thought to be a good target for development of a neural transplantation therapy. Unlike Parkinson’s disease in which a specific cell population is lost and therefore could conceivably be replaced, cell loss post stroke is not limited to a specific neuronal cell type or even neurons, making it more complicated to rebuild the neural circuitry. Even so, the first studies that used cell therapy for the treatment of stroke were performed over 20 years ago and published in 1988. In one study, fetal cortical neurons were transplanted directly into the cortex of adult rats that had undergone temporary middle cerebral artery occlusion (MCAO) (Mampalam et al. 1988). These grafts survived, developed appropriate neurotransmitter phenotype as demonstrated with nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) and acetylcholinesterase (AChE) expression, and had neurites that left the transplant and integrated into the host brain. The other study focused on a labeling strategy to identify the transplanted fetal neurons in the host after ischemia induced by 4-vessel occlusion (4VO) (Farber et al. 1988). Shortly, thereafter, another research group demonstrated that grafted fetal hippocampal neurons integrated into hippocampal CA1, receiving fiber ingrowth from septum that made synaptic contacts with the grafted neurons and projecting to posterior levels of host CA1 (Tonder et al. 1989). These early studies demonstrated proof of principle that fetal neurons could survive and engraft in infarcted brain. Subsequent studies examined the ability to rebuild neural circuits and reduce functional deficits. In these earlier days of cell therapy, it was inconceivable that cells could be transplanted outside the central nervous system (CNS) and have a therapeutic effect. Therefore, all the early studies employed either direct implantation into the injured A.E. Willing (*) • M. Shahaduzzaman Department of Neurosurgery and Brain Repair, Center for Excellence in Aging and Brain Repair, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd, MDC78, Tampa, FL 33612, USA e-mail: [email protected] J. Jolkkonen, P. Walczak (eds.), Cell-Based Therapies in Stroke, DOI 10.1007/978-3-7091-1175-8_2, © Springer-Verlag Wien 2013
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A.E. Willing and M. Shahaduzzaman
brain (parenchymal) or into the nearby ventricular system (intracerebroventricular or i.c.v.). In more recent years, observations that bone marrow-derived cells could enter the brain and express microglial or astrocytic antigens after intravenous (i.v.) administration (Eglitis and Mezey 1997) led researchers to ask if other routes of cell delivery could be efficacious. The first report of i.v. delivery examined cell efficacy in a rodent model of traumatic brain injury (Lu et al. 2001), followed shortly thereafter by a publication from the same research group demonstrating that intra-arterial (i.a.) administration
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