Stem cells and neural circuit engineering

Medical conditions that affect muscle function and/or its neuronal control represent some of the most common debilitating disorders, which are typically studied in rodent models in vivo. Current animal models of neuromuscular disease suffer from several limitations, such as high costs of transgenic animals and genetic differences between rodents and humans. We have developed a stem cell-based tissue culture model of neuromuscular circuitry to study nerve-muscle connectivity. The cellular components (motor neurons, astrocytes, and muscle) are derived separately from stem cells in vitro, magnetically purified and assembled in compartmentalized tissue culture devices that segregate the cell bodies of neural cells from muscle fibres, yet allow motor axons to fully differentiate and connect to their synaptic targets. Motor neurons are equipped with genetically encoded optogenetic actuators, enabling their selective activation without mechanical interference. We are initially focusing on modelling the cellular pathology of motor neuron disease in artificial neuromuscular circuits and hope to exploit the system for drug screening.

We are developing optogenetic neural grafts capable of linking an optoelectronic control system to host muscle. The long-term aim is to restore motor function and treat paralysis in patients suffering from spinal cord injury or neuromuscular disease with an implantable neural prosthesis. The idea is to use grafted optogenetic motor neurons derived from stem cells, embedded in a stem cell-derived glial scaffold, as a body-machine interface between an optoelectronic pacemaker device and recipient skeletal muscle. Due to the photosensitivity of the graft, muscle contractions can then be specifically triggered by light signals transmitted to the graft via implanted micro-LEDs. In a recent proof-of-principle study, my group and collaborators have shown that such peripherally implanted optogenetic motor neuron grafts can not only survive and extend axons to successfully re-innervate denervated muscles, but can also relay rhythmic contraction patterns from an artificial control system to skeletal muscle in vivo. While such a device, once fully developed, would not offer a cure for spinal cord injury or ALS, the quality of life for affected patients could be dramatically improved by restoring vital motor functions, such as breathing.