Glowing Proteins Enable Stem Cell Stimulation for Stroke Recovery in Mice
Glowing Proteins Enable Stem Cell Stimulation for Stroke Recovery in Mice

Glowing Proteins Enable Stem Cell Stimulation for Stroke Recovery in Mice

A new method helps neural stem cells form synaptic connections, thereby restoring lost brain function.

Oct 1, 2019
Nicoletta Lanese

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The paper
S.P. Yu et al., “Optochemogenetic stimulation of transplanted iPS-NPCs enhances neuronal repair and functional recovery after ischemic stroke,” J Neurosci, 39:6571–94, 2019.  

Cell transplantation therapy offers a promising route to recovery after stroke, but the grafted cells face a harsh environment, with elevated levels of free radicals and proinflammatory cytokines, compromised blood supply, and degraded neural connectivity, says Shan Ping Yu, a neurology researcher at Emory University School of Medicine. He and his colleagues aimed to build a new tool to help stem cells integrate with host neural circuitry after implantation. 

A new technique, optochemogenetics, activates light-sensitive channels inside the brain with a drug-like compound administered through the nose. Once the compound, CTZ, has entered the brain, it interfaces with the protein Gaussia luciferase (GLuc) on modified ion channels—in this case a channelrhodopsin protein, VChR1. GLuc emits light, causing the VChR1 to open and allow sodium ions to flow inside the neuron, thus stimulating the cell.  WEB | PDF
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Scientists have long known that stimulating transplanted neural stem cells encourages them to differentiate into neurons and connect with nearby host cells. Many researchers turn to optogenetics to excite grafted stem cells, but because light travels poorly through dense tissue, the technique requires researchers to stick a laser into their subjects’ brains. So Yu and his coauthors turned instead to a type of enzyme that grants fireflies and jellyfish their glow: luciferase. “These proteins carry their own light, so they do not need a light source,” says Yu. 

The researchers injected neural progenitor cells that had been derived from induced pluripotent stem cells (iPSCs) into the brains of mouse models of stroke. The cells were genetically engineered to express a fusion protein called luminopsin 3 (LMO3), crafted from the bioluminescent enzyme Gaussia luciferase and the light-sensitive protein VChR1. LMO3 activates in response to either physical light or a molecule called CTZ, which can be delivered noninvasively through the nose into the brain tissue. The fusion protein can be hooked up to either excitatory or inhibitory channels in the neurons to either stimulate or tamp down the cells’ function. Yu and his colleagues dubbed the new technique “optochemogenetics.” 

The team treated a portion of the iPSC-injected mice with daily CTZ, while another group received light stimulation. Compared with cells grafted into mice that did not receive any stimulation, the cells in both groups of  treated animals formed more connections with neighboring neurons. Cells stimulated by CTZ or light also grew more-heavily-insulated axons, had increased rates of signal transmission between neurons, and better repaired damaged connections between the thalamus and cortex than cells that received no stimulation.    

A suite of behavioral tests revealed that treated mice had also regained lost sensorimotor function within a few weeks, showing significantly improved dexterity and heightened sensation in their paws and whiskers, among other parameters. “On some of the tasks, they can even recover to the normal [pre-stroke] level, so that’s a very exciting result,” says Yu. 

Promoting cell survival remains a central challenge in stem cell–based stroke treatment, says Marcel Daadi, a neuroscientist and medical researcher at the Texas Biomedical Research Institute who was not involved in the study. He adds that being able to stimulate stem cells through nasal administration of a drug was “a clever way to ensure wide distribution of the drug, and to be able to stimulate pretty much the totality of the grafted cells.” 

If the approach proves viable in people, it could find applications beyond stroke treatment, Daadi says—such as in helping to rebuild neural circuits damaged by Parkinson’s disease or traumatic brain injury.

Nicoletta Lanese is a former intern at The Scientist. Follow her on Twitter @NicolettaML.