Chapter 5 - Survival, differentiation, and connectivity of ventral mesencephalic dopamine neurons following transplantation

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Abstract

The reconstruction of midbrain dopamine (DA) circuitry through intracerebral transplantation of new DA neurons contained in embryonic ventral mesencephalon (VM) is a promising therapeutic approach for Parkinson's disease (PD). Although some of the early open-label trials have provided proof-of-principal that VM grafts can provide sustained improvement of motor function in some patients, subsequent trials showed that the functional response can be highly variable. This chapter reviews an extensive body of basic and clinical research on the survival, differentiation, and connectivity of DA neurons in VM grafts, and also looks at how these parameters are affected by certain host- and donor-specific variables. We also review how technical advances in the tools available to study the integration of grafted DA neurons, such as transgenic reporter mice, have made significant contributions to our understanding of the capacity of different DA neuronal subtypes for target-directed growth and innervation of appropriate host brain structures. Our established and on-going understanding of the capacity of grafted DA neurons to structurally and functionally integrate following transplantation forms an important basis for the refinement and optimization of VM grafting procedures, and also the development of new procedures based on the use of stem cells.

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

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