Transplantable midbrain dopamine neurons: A moving target

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder, characterized by a loss of dopaminergic (DA) neurons in the midbrain. Current therapies offer temporary symptomatic relief, but do not modify the course of disease. Alternative therapeutic strategies aiming at changing the course of disease have been developed over the last years. Amongst them, cell replacement therapy has been considered as a promising alternative. Grafts of fetal ventral mesencephalic tissue have been found to ameliorate the symptoms and change the course of disease in some Parkinsonian patients, but the limited availability of human tissue and the difficulties to standardize their quality have led to the search of novel cell sources. Pluripotent stem cells are nowadays considered as ideal tools for cell replacement therapy because they are highly expandable in vitro, and standardized protocols to control their differentiation are being developed. However, despite substantial progress during recent years, translation into an in vivo setting has been challenging. Indeed, transplantable DA neurons need to be correctly specified and differentiated in order to obtain appropriate innervation of the striatum and avoid the risks of graft overgrowth or cell death. It has been previously reported that nigral A9, but not ventral tegmental area A10 DA neurons, are able to re-innervate the host striatum and are thus considered the desired cell type for transplantation (Thompson et al., 2005). However, previous studies using whole or partially dissected ventral midbrain (VM) tissue have not been able to identify the cell type that was responsible for the therapeutic effect observed after grafting. DA neurons themselves have been thought to be the desired cell type and, along this line of