Lin Kooi Ong, PhD

Yu SP, Tung JK, Wei ZZ, Chen D, Berglund K, Zhong W, et al. Optochemogenetic Stimulation of Transplanted iPS-NPCs Enhances Neuronal Repair and Functional Recovery after Ischemic Stroke. J Neurosci. 2019; 39:6571-6594.

Stem cell-based therapies certainly do hold potential as therapeutic tools for promoting brain repair and functional recovery after stroke. However, there are several fundamental issues to be considered, such as whether the transplanted stem cells can survive, differentiate and form meaningful connections with the host brain. This recent article by Yu and colleagues described an innovative method called “optochemogenetic” to promote the integration of transplanted stem cells into a stroked (or injured) brain that could lead to neuronal restoration and functional recovery. The team genetically introduced luminopsin 3 into neural progenitor cells that have been derived from induced pluripotent stem cells, which they called LMO3-iPS-NPCs. Luminopsin 3 is a bioluminescent protein that can be simulated by either a physical light source or light-emitting molecule such as coelenterazine.

The team first investigated the properties of LMO3-iPS-NPCs in cell culture. Microscopy and biochemical analysis showed that coelenterazine-stimulated LMO3-iPS-NPCs have increased expression of neurotrophic factors and synaptic markers, as well as growth of neuronal structure. The team then experimentally induced stroke in mice and transplanted LMO3-iPS-NPCs into the ischemic brain a week after stroke. A group of mice received intranasal delivery of coelenterazine twice a day for 2 weeks. The mice were assessed with a battery of functional assessments, such as removing adhesive dot from their paws and reaching and grasping food pallets. The mice treated with the combination of LMO3-iPS-NPCs transplantation and coelenterazine stimulation showed improvement in sensorimotor and behavioral functions. The observed functional improvement occurred in parallel with the enhanced neural network connections, increased insulated axons and augmented neuronal plasticity. It should be noted that the team examined the effects of coelenterazine stimulation of LMO3-iPS-NPCs transplantation therapy in male, female, young and aged mice, and found some beneficial effects may be less robust in aged mice.

The results from this study are promising and provide a novel approach to address some of the issues regarding stem cell-based therapies. In order to move closer toward clinical application, further information about efficacy and safety must be obtained.