Exercise your graft - An important lesson for cell replacement therapy for Parkinson's disease

Parkinson's disease (PD) is a complex multisystem, chronic and so far, incurable disease affecting millions of people worldwide. With the continuing need for better therapeutic options for PD, there is a global renewed interest in cell replacement therapy due to progress in using pluripotent stem cells as an unlimited source of dopaminergic (DA) neurons for cell transplantation. Despite the significant progress made, obstacles remain that interfere with the restoration of functional circuits by DA grafts. The functional connectivity between DA grafts and host cells may be enhanced by adjunctive therapies, such as physical activity. Exercise modalities, such as use of treadmill, enhance neuroplasticity and improve motor and cognitive functions in PD patients. The patients are able to re-learn movement and adjust their posture, which, in turn, results in short term-reduced rigidity and improved stride length and cadence. By stabilizing selected active inputs and eliminating inactive ones, activity-dependent mechanisms fine-tune new neural circuits for optimal connection and physiological function. This communication will review the mechanisms and synergies between cell replacement therapy and physical and cognitive training to enhance induced pluripotent stem cell-mediated functional reinnervation of the striatum in PD.