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Two major subclasses of mechanosensory neurons reside within the dorsal root ganglia; proprioceptor neurons (PN) that innervate muscle tissue and low threshold mechanoreceptor neurons (LTMR) that innervate skin. To date, the specific cellular neurophysiology of PN and LTMR subclasses are primarily defined by animal models due to the limited availability of human neural tissue. Here an efficient approach is described for generating PN and LTMR from human pluripotent stem cells (hPSC) by inducing co\u2010expression of NGN2\/RUNX3 or NGN2\/SHOX2 in hPSC\u2010derived neural crest, respectively. Molecular and functional mechanosensory profiles are validated in both populations. Of significance, functional interrogation of induced mechanosensory subtypes reveals their distinct responses to mechanical stimuli. Induced proprioceptor neurons produce scaled responses to increasing mechanical stimuli that can sustain repetition and result in action potential firing. In contrast, induced LTMRs desensitize upon repeated mechanical stimuli and display a lower mechanical threshold for action potential firing. Furthermore, both subtypes predominantly rely on PIEZO2 for mechanosensory function. These findings highlight the unique mechanically sensitive profiles and excitability properties that may distinguish human mechanosensory subtypes, distinct from the presence of end\u2010organs.<\/jats:p>","DOI":"10.1002\/advs.202512413","type":"journal-article","created":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T17:41:16Z","timestamp":1765302076000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Induced Proprioceptor and Low\u2010Threshold Mechanoreceptor Neurons Derived from Human Pluripotent Stem Cells Exhibit Distinct Functional Mechanosensory Properties"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7700-3486","authenticated-orcid":false,"given":"Amy J.","family":"Hulme","sequence":"first","affiliation":[{"name":"Molecular Horizons University of Wollongong  Wollongong NSW 2522 Australia"},{"name":"School of Medical Indigenous and Health Sciences University of 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University of Wollongong  Wollongong NSW 2522 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Guo","sequence":"additional","affiliation":[{"name":"Victor Chang Cardiac Research Institute  Darlinghurst NSW 2010 Australia"},{"name":"School of Clinical Medicine St Vincent's Healthcare Clinical Campus University of New South Wales  Darlinghurst NSW 2010 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominic","family":"Kaul","sequence":"additional","affiliation":[{"name":"Molecular Horizons University of Wollongong  Wollongong NSW 2522 Australia"},{"name":"Illawarra Health and Medical Research Institute  Wollongong NSW 2522 Australia"},{"name":"School of Chemistry and Molecular Biosciences University of Wollongong  Wollongong NSW 2522 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marnie","family":"Maddock","sequence":"additional","affiliation":[{"name":"Molecular Horizons University of 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