Neurons which developed from human embryonic stem cells (hESCs) in vitro can both send and receive nerve impulses when transplanted into the mouse brain, according to a report published today (November 21) in Proceedings of the National Academy of Sciences. The discovery provides some of the strongest evidence that hESC-derived neurons, which could be used to treat a variety of neurological disorders such as epilepsy, stroke, and Parkinson’s disease, can fully integrate and behave like regular neurons when transplanted into the brain.
Researchers used the powerful techniques of optogenetics to definitively demonstrate that hESC-derived neurons are capable of complete synaptic integration with a preexisting network both in vitro and in vivo, and can modulate the excitability of a network via synaptic output. To record the activity the researchers expressed light-sensitive ion channels from algae in hESC-derived neurons such that they incorporated into the membrane. In response to light, these channels sent a flood of ions surging into the cell triggering it to fire an action potential.
When the engineered neurons were co-cultured with mouse neurons or transplanted into mouse brains that were later prepared as slices, the team could simply flip on a light—an LED linked to a fiber optic cable placed a few millimeters from the cells—and look for activity from the mouse neurons. Sure enough, the mouse cells were receiving impulses from the hESC-derived neurons, and conversely, the human cells could receive impulses from the mouse neurons.
Study shows the integration of hESC-derived neurons occurred over a similar time course as of nascent dentate granule cells (DGCs) in mature hippocampus, where significantly greater presynaptic integration was observed after 6–8 week than at earlier time points. A similar time course is observed for the improvements in behavioral symptoms of neurodegeneration after stem cell transplantation, supporting the idea that synaptic integration is crucial for long-term outcomes of cell replacement in disease models. Significant effects of transplanted dopamine (DA) neurons on rotational behavior in Parkinson models are not typically observed at 4 week after transplantation but are observed after 6–8 wk, consistent with current findings for presynaptic innervations. In addition to the temporal correlation, hESC-derived neurons are capable of integrating synaptic currents to produce spiking, can make excitatory and inhibitory connections with mouse neurons, and pre- and postsynaptically integrate in vivo.
In vivo, the use of implantable light-stimulation devices will give researchers unprecedented real-time access to examine the physiological underpinnings of successful cell replacement for neurodegenerative disorders. For instance, whereas the forebrain glutamatergic or GABAergic neurons used in this study may be useful for treatment of frontotemporal dementia, ischemia, or epilepsy, optogenetics can be used to target a number of potentially therapeutic populations such as midbrain DA neurons and spinal motor neurons .
Researchers have shown previously that hESC-derived neurons transplanted into rat brains could modulate the animals’ behavior. Although this suggested functional integration but behavior does not have enough resolution to tell you what exactly is happening. The current study provides proof that is more definitive. For the first time researchers were able to show that, the cells can modulate the existing neurocircuitry. The current study can be the cornerstone upon which, future of stem cell therapeutics experiment will based upon.
Weick JP, Liu Y, & Zhang SC (2011). Human embryonic stem cell-derived neurons adopt and regulate the activity of an established neural network. Proceedings of the National Academy of Sciences of the United States of America, 108 (50), 20189-94 PMID: 22106298