Red light means stop and green light means go? Apparently not for a few bright researchers who have recently used a novel technique to shed light on how cell replacement therapy for Parkinson’s Disease (PD) functions. Studies suggest that therapeutic success requires the functional integration of grafted dopamine releasing (DA) neurons, but this has actually been difficult to test. Other possibilities include grafted cells providing support to endogenous cells and/or repairing damaged cells.
The research groups of Eugene V Mosharov (Columbia University Medical Center) and Lorenz Studer (Sloan-Kettering Institute for Cancer Research) have employed a light-reactive control system known as optogenetics to illuminate how exactly grafted cells mediate behavioral improvements.
Specifically, researchers engineered human embryonic stem cells (hESCs) to express halorhodopsin after directed differentiated to dopaminergic (DA) neurons, the cells destroyed in PD. Halorhodopsin functions by harnessing energy from green light to shuttle chloride ions into a cell, and in this case will inhibit action potentials, and stop graft neuronal function.
Under normal in vitro conditions:
- DA neuron stimulation led to the expected transient calcium increases linked to an action potential and dopamine neurotransmitter release.
- Exposing the cells to pulses of green light halted the stimulated calcium response and dopamine release, and so inhibited DA neuronal function.
After grafting of cells into a mouse model of PD:
- Mice receiving DA grafts demonstrated behavioral recovery from lesion-induced PD.
- Stimulation of graft cells with green light from an implanted fiber-optic device led to loss of this behavioral recovery, suggesting that neuronal activity of the grafted cells, and not trophic support or endogenous cell repair, is the vital factor.
- Optogenic silencing also demonstrated that DA neurons integrated into the host system, and both received and transmitted signals in a similar manner to endogenous DA neurons.
Optogenetics provides a quick and selective experimental strategy to understand how DA neuron replacement therapy functions, and has provided direct evidence indicating neural network repair as the important factor which mediates behavioral recovery.
Read about the opportunities that this mode of regulation provides and how it is lighting up cell replacement therapy in Nat Biotechnol, January 2015.