Historical perspective of cell transplantation in Parkinson’s disease

Abstract

Cell grafting has been considered a therapeutic approach for Parkinson’s disease (PD) since the 1980s. The classical motor symptoms of PD are caused by the loss of dopaminergic neurons in the substantia nigra pars compacta, leading to a decrement in dopamine release in the striatum. Consequently, the therapy of cell-transplantation for PD consists in grafting dopamine-producing cells directly into the brain to reestablish dopamine levels. Different cell sources have been shown to induce functional benefits on both animal models of PD and human patients. However, the observed motor improvements are highly variable between individual subjects, and the sources of this variability are not fully understood. The purpose of this review is to provide a general overview of the pioneering studies done in animal models of PD that established the basis for the first clinical trials in humans, and compare these with the latest findings to identify the most relevant aspects that remain unanswered to date. The main focus of the discussions presented here will be on the mechanisms associated with the survival and functionality of the transplants. These include the role of the dopamine released by the grafts and the capacity of the grafted cells to extend fibers and to integrate into the motor circuit. The complete understanding of these aspects will require extensive research on basic aspects of molecular and cellular physiology, together with neuronal network function, in order to uncover the real potential of cell grafting for treating PD.

Keywords: Parkinson’s disease; Cell replacement; Animal models; Nigrostriatal pathway; Striatum; Dopaminergic loss

Core tip: The first studies on cell transplantation for Parkinson’s disease were published during the early 80s. Since then, it has been shown that different cell types induce functional benefits but with high variability among subjects. Here, we first provide a general overview of the field during its early years. Then, we discuss some factors associated with the functionality of the graft based on the latest findings, and highlight the importance of understanding basic aspects (e.g., factors influencing graft integration) which ultimately could contribute to reducing the variability of the functional outcome-an important requirement for its application in the clinic.