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Here, we studied transcriptome profiles of human nail units using polydactyly specimens. Single-cell RNAseq with 11,541 cells from 4 extra digits revealed nail-specific mesenchymal and epithelial cell populations, characterized by <jats:italic>RSPO4<\/jats:italic> (major gene in congenital anonychia) and <jats:italic>SPINK6<\/jats:italic>, respectively. In situ RNA hybridization demonstrated the localization of <jats:italic>RSPO4, MSX1 and WIF1<\/jats:italic> in onychofibroblasts suggesting the activation of WNT signaling. <jats:italic>BMP-5<\/jats:italic> was also expressed in onychofibroblasts implicating the contribution of BMP signaling. <jats:italic>SPINK6<\/jats:italic> expression distinguished the nail-specific keratinocytes from epidermal keratinocytes. <jats:italic>RSPO4<\/jats:italic><jats:sup><jats:italic>+<\/jats:italic><\/jats:sup> onychofibroblasts were distributed at close proximity with <jats:italic>LGR6<\/jats:italic><jats:sup>+<\/jats:sup> nail matrix, leading to WNT\/\u03b2-catenin activation. In addition, we demonstrated <jats:italic>RSPO4<\/jats:italic> was overexpressed in the fibroblasts of onychomatricoma and <jats:italic>LGR6<\/jats:italic> was highly expressed at the basal layer of the overlying epithelial component, suggesting that onychofibroblasts may play an important role in the pathogenesis of onychomatricoma.<\/jats:p>","DOI":"10.1038\/s42003-021-02223-w","type":"journal-article","created":{"date-parts":[[2021,6,7]],"date-time":"2021-06-07T10:06:06Z","timestamp":1623060366000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Single-cell RNA sequencing of human nail unit defines RSPO4 onychofibroblasts and SPINK6 nail epithelium"],"prefix":"10.1038","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4184-6702","authenticated-orcid":false,"given":"Hyun Je","family":"Kim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3974-1290","authenticated-orcid":false,"given":"Joon Ho","family":"Shim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6699-5202","authenticated-orcid":false,"given":"Ji-Hye","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1799-5860","authenticated-orcid":false,"given":"Hyun Tae","family":"Shin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong Sup","family":"Shim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7987-4437","authenticated-orcid":false,"given":"Kee-Taek","family":"Jang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4234-0380","authenticated-orcid":false,"given":"Woong-Yang","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0694-2499","authenticated-orcid":false,"given":"Kyung-Hoon","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9469-8654","authenticated-orcid":false,"given":"Eun Ji","family":"Kwon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyung-Suk","family":"Jang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5000-1675","authenticated-orcid":false,"given":"Hanseul","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong Hee","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-Mo","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0765-9812","authenticated-orcid":false,"given":"Dongyoun","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,6,7]]},"reference":[{"key":"2223_CR1","first-page":"257","volume":"27","author":"P Fleckman","year":"2001","unstructured":"Fleckman, P. & Allan, C. 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