Parkinson's disease (PD) is the most common movement disorder in Europe, affecting more than two million people between 50 and 70 years of age. The current therapeutic approaches are of symptomatic nature and fail to halt the progressive neurodegenerative course of the disease. The development of innovative and complementary approaches to promote cellular repair may pave the way for disease-modifying therapies which may lead to less suffering for the patients and their families and finally to more cost-effective therapies. To date, cell replacement trials in PD aiming at replacing lost dopamine neurons were mainly focused on placing the transplanted cells within the target site, the striatum, and not within the lesioned site, the substantia nigra (SN). This was based on the misconception that the adult brain constitutes a non-permissive barrier not allowing the outgrowth of long distance axons originating from transplanted embryonic neurons. A growing body of evidence is challenging this concept and proposing instead to place the graft within its ontogenic site. This has been performed in several lesional animal models for various traumatic or neurodegenerative pathologies of the brain. For instance, transplanted neurons within the lesioned motor cortex were shown to be able to send distant and appropriate projections to target areas including the spinal cord. Similarly, in an animal model of PD, mesencephalic embryonic cells transplanted within the lesioned SN send massive projections to the striatum and, to a lesser extent, the frontal cortex and the nucleus accumbens. This has lead to the proposal that homotopic transplantation may be an alternative in cell-based therapies as transplanted neurons can integrate within the host brain, send projections to target areas, restore the damaged circuitry, increase neurotransmitter levels and ameliorate behavior. We will discuss also the potential of replacing embryonic neuronal cells by stem cell derived neurons as the use of embryonic cells is not without an ethical and logistical burden; in this line many have thrived to derive neurons from embryonic stem cells (ESC) in order to use them for cell transplantation. These studies are already yielding important information for future approaches in the field of cell therapies in PD but also in other neurodegenerative disorders where cell transplantation therapy may be considered. While the field of cell replacement therapies has been recently called into question with contrasting results in transplanted PD patients, these new sets of findings are raising new hopes and opening new avenues in this rejuvenated field.

La thérapie cellulaire a été proposée comme un moyen de remplacer les neurones dopaminergiques dégénérés dans la maladie de Parkinson. Dans la plupart des études, les cellules transplantées ont été placées au sein de la structure cible, le striatum, et non au sein du site de lésion, la substance noire. En effet, la voie nigro-striée, et plus généralement le cerveau adulte, étaient considérés non permissifs à la repousse axonale des neurones transplantés. Un faisceau d’éléments nouveaux, suite à des travaux effectués dans des modèles animaux, a dernièrement mis en doute ce concept proposant plutôt de placer le transplant au sein de sa structure ontogénique. En effet, des neurones transplantés au sein des sites lésés sont capables d’envoyer des axones à très grandes distances et de rétablir ainsi la connectivité physiologique des réseaux neuronaux. Ainsi, des transplants du mésencéphale ventral embryonnaire placés au sein de la substance noire lésée se sont révélés capables d’envoyer des projections vers le striatum et le cortex pré-frontal, d’augmenter le niveau de dopamine striatale et de rétablir un comportement moteur normal. Ces séries d’études ouvrent la voie vers des nouvelles perspectives thérapeutiques dans le domaine de la transplantation cellulaire donnant ainsi un nouveau souffle à cette approche.