Function in the CNS depends not only on the correct generation of a variety of cell types during development, but also on the tight regulation of interactions between these cell types. Human induced pluripotent stem cell (hiPSC)-derived cellular models allow us, in an unprecedented way, the opportunity to not only generate a diversity of human cell types in vitro, but to also study how these interact both within and across CNS regions in a controlled manner. In the lab we are interested in neuron-glia interactions within the spinal cord, and interactions between cortical motor neurons and spinal neuronal networks.

Aberrations in cell-to-cell interactions within the spinal cord and motor system are likely to lead to disease. One such example, where susceptibility to disease is thought to be mediated in part through interaction of motor neurons with other cell types, is amyotrophic lateral sclerosis (ALS). In the lab we are particularly interested in studying 1) cortical hyperexcitability and glutamate excitotoxicity and 2) astrocyte dysfunction or toxicity in the context of motor neuron death in ALS and other motor neuron disorders within the ALS spectrum.

One of the backbones of our work is the use of hiPSC-derived models including 2D cultures, region-specific organoids or spheroids and physiologically-relevant organoid fusions we call assembloids (see image below of a cortico-motor assembloid). Human stem cell models are versatile and give us the opportunity to use patient-derived cells, or use genome engineering to study mutations of interest.

We also use a variety of functional imaging assays as readouts of connectivity and function. For example, we have implemented optogenetic techniques and the imaging of muscle contractions as well as calcium dynamics in assembloids, and we do this in combination with viral reporters and viral tracing techniques. See an example of optical stimulation of cortical spheroids coupled with muscle contraction in cortico-motor assembloids below.

Importantly, we continue to innovate and implement novel tools to study connectivity and neuronal function in our models.

Single cell transcriptomics, in combination with efforts to profile human primary tissues, has provided an unprecedented opportunity to interrogate the reproducibility and fidelity of human stem cell models and to gain novel insights into cellular and molecular phenotypes. In the lab we make use of some of these rapidly-evolving technologies, including single cell transcriptomics, spatial transcriptomics and single cell chromatin accessibility.