11-cis-retinal and Stroke

Treatment for stroke is very limited, and potential new therapies are focusing on promoting brain repair and plasticity, as they offer a longer therapeutic time window than the current U.S. Food and Drug Administration approved drug. Functional recovery can occur after stroke, and strategies such as direct brain stimulations that promote recovery are promising. Here we review how selective stimulation of neurons in the motor cortex using optogenetics enhances plasticity mechanisms and promotes functional recovery after stroke.

Topics: Animals; Brain; Humans; Neuronal Plasticity; Optogenetics; Photic Stimulation; Recovery of Function; Rhodopsin; Stroke

Compelling evidence suggests that transplantation of neural stem cells (NSCs) from multiple sources ameliorates motor deficits after stroke. However, it is currently unknown to what extent the electrophysiological activity of grafted NSC progeny participates in the improvement of motor deficits and whether excitatory phenotypes of the grafted cells are beneficial or deleterious to sensorimotor performances. To address this question, we used optogenetic tools to drive the excitatory outputs of the grafted NSCs and assess the impact on local circuitry and sensorimotor performance. We genetically engineered NSCs to express the Channelrhodopsin-2 (ChR2), a light-gated cation channel that evokes neuronal depolarization and initiation of action potentials with precise temporal control to light stimulation. To test the function of these cells in a stroke model, rats were subjected to an ischemic stroke and grafted with ChR2-NSCs. The grafted NSCs identified with a human-specific nuclear marker survived in the peri-infarct tissue and coexpressed the ChR2 transgene with the neuronal markers TuJ1 and NeuN. Gene expression analysis in stimulated versus vehicle-treated animals showed a differential upregulation of transcripts involved in neurotransmission, neuronal differentiation, regeneration, axonal guidance, and synaptic plasticity. Interestingly, genes involved in the inflammatory response were significantly downregulated. Behavioral analysis demonstrated that chronic optogenetic stimulation of the ChR2-NSCs enhanced forelimb use on the stroke-affected side and motor activity in an open field test. Together these data suggest that excitatory stimulation of grafted NSCs elicits beneficial effects in experimental stroke model through cell replacement and non-cell replacement, anti-inflammatory/neurotrophic effects.

Topics: Animals; Cell Separation; Disease Models, Animal; Down-Regulation; Gene Expression Profiling; Human Embryonic Stem Cells; Humans; Inflammation; Male; Neostriatum; Neural Stem Cells; Oligonucleotide Array Sequence Analysis; Optogenetics; Rats, Sprague-Dawley; Rhodopsin; Stroke; Synaptic Transmission; Transduction, Genetic; Transgenes

The utility of stem cells and their progeny in adult transplantation models has been limited by poor survival and integration. We designed an injectable and bioresorbable hydrogel blend of hyaluronan and methylcellulose (HAMC) and tested it with two cell types in two animal models, thereby gaining an understanding of its general applicability for enhanced cell distribution, survival, integration, and functional repair relative to conventional cell delivery in saline. HAMC improves cell survival and integration of retinal stem cell (RSC)-derived rods in the retina. The pro-survival mechanism of HAMC is ascribed to the interaction of the CD44 receptor with HA. Transient disruption of the retinal outer limiting membrane, combined with HAMC delivery, results in significantly improved rod survival and visual function. HAMC also improves the distribution, viability, and functional repair of neural stem and progenitor cells (NSCs). The HAMC delivery system improves cell transplantation efficacy in two CNS models, suggesting broad applicability.

Topics: Animals; Blindness; Cell Survival; Hyaluronan Receptors; Hyaluronic Acid; Hydrogel, Polyethylene Glycol Dimethacrylate; Immunohistochemistry; Methylcellulose; Mice; Mice, Inbred C57BL; Mice, Knockout; Real-Time Polymerase Chain Reaction; Retina; Retinal Rod Photoreceptor Cells; Rhodopsin; Stem Cell Transplantation; Stem Cells; Stroke