Optical Control of Muscle Function by Transplantation of Stem Cell–Derived Motor Neurons in Mice

Abstract

Damage to the central nervous system caused by traumatic injury or neurological disorders can lead to permanent loss of voluntary motor function and muscle paralysis. Here, we describe an approach that circumvents central motor circuit pathology to restore specific skeletal muscle function. We generated murine embryonic stem cell-derived motor neurons that express the light-sensitive ion channel channelrhodopsin-2, which we then engrafted into partially denervated branches of the sciatic nerve of adult mice. These engrafted motor neurons not only reinnervated lower hind-limb muscles but also enabled their function to be restored in a controllable manner using optogenetic stimulation. This synthesis of regenerative medicine and optogenetics may be a successful strategy to restore muscle function after traumatic injury or disease.

Restoring motor function using optogenetics and neural engraftment

“…Importantly, this study also demonstrated that motor units activated by optical stimulation are recruited in normal physiological order, with smaller, fatigue-resistant motor units being recruited at lower optical stimulus intensities and larger fatigable motor units only being activated at higher intensities [26]. The same physiological recruitment of ChR2 expressing motor units and prevention of muscle fatigue was also verified in our recent study [3], discussed below. Theoretical modelling of the orderly recruitment of motor units in peripheral optogenetic neural stimulation (PONS) suggests that the reduced internodal distance in small diameter myelinated motor axons is an essential parameter underlying this phenomenon [27].…”

“…Strategies targeting the peripheral rather than central nervous system [19] may circumvent the challenges described above and this approach has been used to restore specific motor functions in animal models [3].…”

“…Although important experimental information has been learned from the use of optogenetics in transgenic mice, this is not a viable translational strategy for humans. Indeed, in a recent study, we developed a combinatorial strategy that utilizes the advantages of both stem cell-derived neural engraftment into denervated peripheral motor nerves and optogenetic control of motor neuron function, as a translationally relevant approach to restoring lost muscle function in mice following nerve injury [3]. In this study, we transplanted mouse ESC-derived motor neurons, modified to express ChR2 as well as the neurotrophic factor GDNF, into a denervated peripheral nerve of adult mice, and showed that not only were these grafted motor neurons able to survive in this peripheral environment, but to also extend axons to reinnervate specific target muscles in the hindlimb.…”

“…Therefore alternative strategies are being sought to repair neural circuits that mediate motor control and to artificially restore function to specific muscle groups to enable essential motor tasks. This review will focus on recent advances towards the application of these approaches to restore motor function, with a particular focus on the use of stem cell-derived neuronal replacement strategies [3], optogenetic control of motor function and the potential future translational application of these approaches.…”

Leveraging Optogenetic-Based Neurovascular Circuit Characterization for Repair

“…Optogenetics thus allows for the noninvasive activation or inhibition of specific cells with light, a method that can be leveraged to combat a wide range of neurological conditions. Already, the potential of optogenetic techniques has been demonstrated in sciatic nerve injury [2], Parkinson's disease [3], epilepsy [4], depression [5,6], and retinal degeneration [7,8]. In this work, we describe a new method of using optogenetic techniques to study retinal circuit interactions between neurons and vascular cells, and show how this general approach can be potentially applied to treat neurological diseases.…”