Somatosensory neurons comprise a large variety of different subtypes, each specialized to detect and transduce specific sensory stimuli, such as mechanical force & tension, temperature, or the presence of chemical irritants. Previous studies using model organisms have yielded a coarse blueprint of the genetic programs required for the development of (general) sensory neuron lineages. However, the developmental pathways that assure precise and modality-specific sensory transduction mechanisms (for example such as those associated with cold vs. hot temperature detection) are largely unknown.
We are interested in developing differentiation strategies to generate different sensory neuronal subtypes using human pluripotent stem cells (hESCs and hiPSCs).
Our current differentiation procedure is based on a two-step process: in a first step neural crest-like cells, the in vivo progenitors of sensory neurons, are generated. These progenitors have the capacity to differentiate into the large and diverse plethora of sensory neurons.
In a second step these progenitors are further differentiated into sensory neurons by exposing them to a variety of different signaling molecules. Additionally, we virally express transcription factors known to drive differentiation of neural crest cells into discrete sensory lineages. Combining these two strategies, we have succeeded in generating human stem cell derived mechanoreceptive neurons showing characteristic hallmarks of low threshold “touch receptors”. More recently we have also been able to produce nociceptors, a heterogeneous group of sensory neurons responding to different painful stimuli (Figure 1).
Combined with a multidisciplinary approach including CRISPR/Cas9 genome editing, we are interested in using this new cellular model system to identify and characterize the signaling pathways and transcriptional programs that allow the generation of specific sensory neuron subtypes. Identified candidates will be assessed for their role in sensory neuron differentiation in vivo using model organisms.
We believe that this cellular “engineering” approach will yield new insight into sensory neuron differentiation that has escaped previous genetic studies using complex model organisms. Additionally, we compare the engineered sensory neurons not only to those found in model organisms but we also aim to address similarities and differences to human sensory neurons by employing human tissue samples.
Furthermore, we are also interested in exploring the molecular mechanisms underlying mechano-nociception.