Chapter 5 - Survival, differentiation, and connectivity of ventral mesencephalic dopamine neurons following transplantation
Introduction
Parkinson's disease (PD) is an irreversible neurodegenerative condition involving the progressive loss of midbrain dopamine (DA) neurons as the primary pathological feature (German et al., 1989, Hornykiewicz, 1975). The mDA neurons reside in the ventral part of the mammalian brain and send long-distance axonal projections to various forebrain targets, including the putamen and caudate nucleus (Björklund and Dunnett, 2007, Fallon and Moore, 1978). When the loss of DA neurons reaches around 50%, resulting in a substantial reduction in striatal DA, the first signs of motor dysfunction become apparent, including tremor at rest and difficulties in initiating and executing movements (Fearnley and Lees, 1991, Hornykiewicz, 1975). Most of the current therapies for PD are aimed at restoring dopaminergic signaling in order to reinstate a normal pattern of information flow through the basal ganglia, thereby improving motor function. The most widely used and successful approach to date has been through the systemic delivery of DA agonists or the DA precursor l-DOPA. Although these pharmacotherapies can provide excellent results in the early phase of the disease, prolonged treatment invariably leads to complications, including a substantial waning of the therapeutic effect and the development of unwanted side effects such as dyskinesias. Thus, there is an on-going need for better therapies for PD, either through the refinement of currently available treatments or the development of new ones.
Cell therapy is an experimental approach with significant potential as a restorative treatment for the motor deficit in PD. The concept was originally developed through experiments showing that DA progenitors in fetal ventral mesencephalic (VM) tissue could survive, differentiate, and functionally integrate into a host brain after intracerebral transplantation in order to restore motor function in a rodent model of PD (Björklund and Stenevi, 1979, Perlow et al., 1979; see Fig. 1). This led to the first, open-label clinical trials in patients with advanced PD, which showed that a number of patients can experience long-term symptomatic relief of motor dysfunction after VM grafting, with substantially fewer side effects compared to long-term drug treatment (Dunnett et al., 2001, Lindvall and Björklund, 2004, Lindvall and Hagell, 2000). Since these early experiences, more than 30 years of basic and clinical research in this field has led to a considerable body of work describing the survival, differentiation, growth, and connectivity of VM grafts following intracerebral transplantation. This chapter reviews some of the key studies in this area, with an emphasis on the role of donor- and host-specific variables that impact on the survival and integration of VM grafts.
Section snippets
Survival of DA neurons in VM grafts
Restoration of motor function following grafting of primary VM tissue requires the survival and integration of DA neurons so that a new terminal network is established in the host striatum that can functionally compensate for the degeneration of the intrinsic system. In PD patients, where striatal uptake of [18F]-fluorodopa (FD) is typically only 30–35% of normal values, meaningful clinical outcomes following grafting require restoration to 50–60% of normal (see Hagell and Brundin, 2001, for
Nondopaminergic cells in VM grafts
Grafts of primary VM tissue are highly heterogeneous with respect to cell type. The DA neuron component, in fact, represents only a minor fraction of the total cell population in mature grafts. The neuronal population in VM grafts will include serotonin-, γ-aminobutyric acid (GABA)-, enkephalin-, and substance P-containing neurons, as well as many that cannot be readily identified based on neurochemical phenotype (Bolam et al., 1987, Dunnett et al., 1988, Kordower et al., 1996, Mahalik and
Connectivity of VM grafts
Intrastriatal grafts of primary VM are capable of establishing extensive afferent and efferent connectivity with the host brain. Fundamental to the functional impact of the grafts is the capacity of the grafted DA neurons to form a functional terminal network with the host striatum. An extensive body of work in this area shows that transplanted midbrain DA neurons possess an intrinsic capacity for innervation of the adult striatum (Björklund et al., 1983b, Brundin and Björklund, 1987, Dunnett
Closing remarks
An extensive body of basic and clinical research has led to a detailed understanding of the growth and connectivity of intracerebral VM grafts and, importantly, how these properties relate to restoration of motor function. This forms an important platform for the refinement and optimization of current transplantation procedures using fetal tissue and, importantly, for the development of new procedures using stem cells.
A major challenge for the establishment of a cell-based therapy as a
References (143)
- et al.
Fetal mesencephalic neurons survive and extend long axons across peripheral nervous system grafts inserted into the adult rat striatum
Neurosci. Lett.
(1984) - et al.
Contributions of donor and host blood vessels in CNS allografts
Exp. Neurol.
(1996) - et al.
A comparative study of preparation techniques for improving the viability of nigral grafts using vital stains, in vitro cultures, and in vivo grafts
Cell Transplant.
(1995) - et al.
The time course of loss of dopaminergic neurons and the gliotic reaction surrounding grafts of embryonic mesencephalon to the striatum
Exp. Neurol.
(1996) - et al.
Efferent connections of the substantia nigra and ventral tegmental area in the rat
Brain Res.
(1979) - et al.
Reformation of the nigrostriatal pathway by fetal dopaminergic micrografts into the substantia nigra is critically dependent on the age of the host
Exp. Neurol.
(1999) - et al.
Dopamine neuron systems in the brain: an update
Trends Neurosci.
(2007) - et al.
Reconstruction of the nigrostriatal dopamine pathway by intracerebral nigral transplants
Brain Res.
(1979) - et al.
Functional and anatomical reconstruction of the 6-hydroxydopamine lesioned nigrostriatal system of the adult rat
Neuroscience
(1996) - et al.
Angiogenesis and the blood-brain barrier in solid and dissociated cell grafts within the CNS
Prog. Brain Res.
(1990)