Generation of hiPSC-derived low threshold mechanoreceptors containing axonal termini resembling bulbous sensory nerve endings and expressing Piezo1 and Piezo2

Stem Cell Res. 2021 Oct:56:102535. doi: 10.1016/j.scr.2021.102535. Epub 2021 Sep 11.


Somatosensory low threshold mechanoreceptors (LTMRs) sense innocuous mechanical forces, largely through specialized axon termini termed sensory nerve endings, where the mechanotransduction process initiates upon activation of mechanotransducers. In humans, a subset of sensory nerve endings is enlarged, forming bulb-like expansions, termed bulbous nerve endings. There is no in vitro human model to study these neuronal endings. Piezo2 is the main mechanotransducer found in LTMRs. Recent evidence shows that Piezo1, the other mechanotransducer considered absent in dorsal root ganglia (DRG), is expressed at low level in somatosensory neurons. We established a differentiation protocol to generate, from iPSC-derived neuronal precursor cells, human LTMR recapitulating bulbous sensory nerve endings and heterogeneous expression of Piezo1 and Piezo2. The derived neurons express LTMR-specific genes, convert mechanical stimuli into electrical signals and have specialized axon termini that morphologically resemble bulbous nerve endings. Piezo2 is concentrated within these enlarged axon termini. Some derived neurons express low level Piezo1, and a subset co-express both channels. Thus, we generated a unique, iPSCs-derived human model that can be used to investigate the physiology of bulbous sensory nerve endings, and the role of Piezo1 and 2 during mechanosensation.

Keywords: Bulbous sensory nerve ending; Human induced pluripotent stem cells; Low threshold mechanoreceptors; Piezo1, Piezo2; Small molecule-derived neural precursor cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Induced Pluripotent Stem Cells* / metabolism
  • Ion Channels / genetics
  • Ion Channels / metabolism
  • Mechanoreceptors / metabolism
  • Mechanotransduction, Cellular
  • Nerve Endings / metabolism
  • Sensory Receptor Cells / metabolism


  • Ion Channels
  • PIEZO1 protein, human
  • PIEZO2 protein, human