Transcriptional Programming of Human Mechanosensory Neuron Subtypes from Pluripotent Stem Cells

Efficient and homogeneous in vitro generation of peripheral sensory neurons may provide a framework for novel drug screening platforms and disease models of touch and pain. We discover that, by overexpressing NGN2 and BRN3A, human pluripotent stem cells can be transcriptionally programmed to differentiate into a surprisingly uniform culture of cold- and mechano-sensing neurons. Although such a neuronal subtype is not found in mice, we identify molecular evidence for its existence in human sensory ganglia. Combining NGN2 and BRN3A programming with neural crest patterning, we produce two additional populations of sensory neurons, including a specialized touch receptor neuron subtype. Finally, we apply this system to model a rare inherited sensory disorder of touch and proprioception caused by inactivating mutations in PIEZO2. Together, these findings establish an approach to specify distinct sensory neuron subtypes in vitro, underscoring the utility of stem cell technology to capture human-specific features of physiology and disease. [Display omitted] •NGN2-BRN3A expression in human stem cells induces homogeneous sensory neurons (iSNs)•Three kinds of iSNs can be produced, including subtypes co-expressing TRPM8 and PIEZO2•TRPM8 and PIEZO2 unexpectedly mark a subset of sensory neurons in humans, but not mice•iSNs from PIEZO2-deficient patients are insensitive to mechanical stimuli Nickolls et al. develop a method, using human stem cells, to generate specific types of sensory neurons that detect cold temperature and mechanical force. This approach uncovers a class of neuron found in humans, but not mice, and enables the modeling of a rare sensory disorder of touch and proprioception.