{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T03:28:17Z","timestamp":1786332497502,"version":"build-2736575974"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T00:00:00Z","timestamp":1778284800000},"content-version":"vor","delay-in-days":31,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004442","name":"National Science Centre, Poland","doi-asserted-by":"publisher","award":["2019\/33\/B\/NZ3\/02966"],"award-info":[{"award-number":["2019\/33\/B\/NZ3\/02966"]}],"id":[{"id":"10.13039\/501100004442","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Rodent and primate digit tips exhibit a remarkable regenerative capacity following amputation, driven by highly proliferative nail stem cells with active canonical Wnt signaling. Recently, a distinct, slow-cycling population of bi-functional nail proximal fold stem cells (NPFSCs) has been identified, contributing to both peri-nail epidermis and nail plate (NP). Here, we demonstrate that NPFSCs actively participate in nail growth, orchestrating digit regeneration, with bone morphogenetic protein (BMP) signaling serving as a key regulator. Inhibition of BMP resulted in an epidermalized NP-like structure with limited regeneration due to impaired Wnt pathway activation in the nail matrix cells. Conversely, BMP activation enhanced NPFSCs\u2019 involvement in the nail matrix and significantly promoted digit regeneration. We further revealed that enhanced BMP activity not only accelerated nail and bone regrowth but also extended the regenerative boundary proximally, enabling full regeneration after up to \u223c60% removal of the distal phalanx (P3). Moreover, in BMP gain-of-function models, extreme proximal amputation, removing the majority of the P3, still permitted partial NP regeneration despite the absence of bone reconstruction. Finally, we isolated and cultured lineage-traced NPFSCs and transplanted them into immunocompromised mice, where they integrated into the nail proximal fold and contributed to nail matrix progenitors during regeneration. Transplanted NPFSCs retained their regenerative capacity in vivo, highlighting their therapeutic potential. Collectively, our findings identify a pivotal role of BMP signaling in mediating NPFSC-driven digit regeneration, reveal BMP-Wnt cross-talk as essential to this process, and provide a framework for enhancing regenerative outcomes in previously non-regenerative contexts following traumatic amputation.<\/jats:p>","DOI":"10.1093\/stmcls\/sxag028","type":"journal-article","created":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T11:38:24Z","timestamp":1778067504000},"source":"Crossref","is-referenced-by-count":0,"title":["Nail proximal fold stem cells participate in nail growth, orchestrating enhanced digit regeneration via bone morphogenetic protein signaling activation"],"prefix":"10.1093","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2740-3059","authenticated-orcid":false,"given":"Anna","family":"Pulawska-Czub","sequence":"first","affiliation":[{"name":"Laboratory of Stem Cells, Development and Tissue Regeneration, Centre of New Technologies, University of Warsaw , Warsaw, 02-097,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicja","family":"Olczak-Cossu","sequence":"additional","affiliation":[{"name":"Laboratory of Stem Cells, Development and Tissue Regeneration, Centre of New Technologies, University of Warsaw , Warsaw, 02-097,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomasz D","family":"Pieczonka","sequence":"additional","affiliation":[{"name":"Laboratory of Stem Cells, Development and Tissue Regeneration, Centre of New Technologies, University of Warsaw , Warsaw, 02-097,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6319-8849","authenticated-orcid":false,"given":"Krzysztof","family":"Kobielak","sequence":"additional","affiliation":[{"name":"Laboratory of Stem Cells, Development and Tissue Regeneration, Centre of New Technologies, University of Warsaw , Warsaw, 02-097,","place":["Poland"]},{"name":"Faculty of Medicine, University of Warsaw , Warsaw, 02-089,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,4,8]]},"reference":[{"key":"2026080922381771600_sxag028-B1","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1126\/science.7100922","article-title":"Mice regrow the tips of their foretoes","volume":"217","author":"Borgens","year":"1982","journal-title":"Science (1979)."},{"key":"2026080922381771600_sxag028-B2","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1002\/jez.1402710212","article-title":"Bone regrowth in young mice stimulated by nail organ","volume":"271","author":"Zhao","year":"1995","journal-title":"J Exp Zool"},{"key":"2026080922381771600_sxag028-B3","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1111\/j.1440-169X.2007.00909.x","article-title":"Regeneration potency of mouse limbs","volume":"49","author":"Masaki","year":"2007","journal-title":"Dev Growth Differ"},{"key":"2026080922381771600_sxag028-B4","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1002\/ar.22660","article-title":"Comparative anatomy of mouse and human nail units","volume":"296","author":"Fleckman","year":"2013","journal-title":"Anat Rec (Hoboken)"},{"key":"2026080922381771600_sxag028-B5","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22062864","article-title":"The potential of nail mini-organ stem cells in skin, nail and digit tips regeneration","volume":"22","author":"Pulawska-Czub","year":"2021","journal-title":"Int J Mol Sci."},{"key":"2026080922381771600_sxag028-B6","volume-title":"Fitzpatrick\u2019s Dermatology","author":"Kobielak","year":"2019","edition":"9e"},{"key":"2026080922381771600_sxag028-B7","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/j.ydbio.2007.12.025","article-title":"Development and regeneration of the neonatal digit tip in mice","volume":"315","author":"Han","year":"2008","journal-title":"Dev Biol"},{"key":"2026080922381771600_sxag028-B8","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1038\/nature12214","article-title":"Wnt activation in nail epithelium couples nail growth to digit regeneration","volume":"499","author":"Takeo","year":"2013","journal-title":"Nature"},{"key":"2026080922381771600_sxag028-B9","doi-asserted-by":"publisher","first-page":"15114","DOI":"10.1073\/pnas.1318848111","article-title":"Bifunctional ectodermal stem cells around the nail display dual fate homeostasis and adaptive wounding response toward nail regeneration","volume":"111","author":"Leung","year":"2014","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026080922381771600_sxag028-B10","doi-asserted-by":"publisher","first-page":"9740","DOI":"10.1096\/fj.202000330R","article-title":"Transcriptomic analysis of bone and fibrous tissue morphogenesis during digit tip regeneration in the adult mouse","volume":"34","author":"Qu","year":"2020","journal-title":"Faseb J"},{"key":"2026080922381771600_sxag028-B11","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1016\/j.ydbio.2010.11.035","article-title":"Wound healing and blastema formation in regenerating digit tips of adult mice","volume":"350","author":"Fernando","year":"2011","journal-title":"Dev Biol"},{"key":"2026080922381771600_sxag028-B12","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1016\/j.devcel.2019.12.004","article-title":"Acquisition of a unique mesenchymal precursor-like blastema state underlies successful adult mammalian digit tip regeneration","volume":"52","author":"Storer","year":"2020","journal-title":"Dev Cell"},{"key":"2026080922381771600_sxag028-B13","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1111\/wrr.12856","article-title":"Proximal digit tip amputation initiates simultaneous blastema and transient fibrosis formation and results in partial regeneration","volume":"29","author":"Dawson","year":"2021","journal-title":"Wound Repair Regen"},{"key":"2026080922381771600_sxag028-B14","doi-asserted-by":"publisher","first-page":"111853","DOI":"10.1016\/j.celrep.2022.111853","article-title":"Nail-associated mesenchymal cells contribute to and are essential for dorsal digit tip regeneration","volume":"41","author":"Mahmud","year":"2022","journal-title":"Cell Rep"},{"key":"2026080922381771600_sxag028-B15","doi-asserted-by":"publisher","first-page":"13249","DOI":"10.1073\/pnas.1518874112","article-title":"Lgr6 marks nail stem cells and is required for digit tip regeneration","volume":"112","author":"Lehoczky","year":"2015","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026080922381771600_sxag028-B16","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1016\/j.ydbio.2017.08.007","article-title":"The blastema and epimorphic regeneration in mammals","volume":"433","author":"Seifert","year":"2018","journal-title":"Dev Biol"},{"key":"2026080922381771600_sxag028-B17","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1111\/wrr.12666","article-title":"Blastema formation and periosteal ossification in the regenerating adult mouse digit","volume":"26","author":"Dawson","year":"2018","journal-title":"Wound Repair Regen"},{"key":"2026080922381771600_sxag028-B18","doi-asserted-by":"publisher","first-page":"9720","DOI":"10.1038\/s41598-019-45521-4","article-title":"Bone growth as the main determinant of mouse digit tip regeneration after amputation","volume":"9","author":"Sensiate","year":"2019","journal-title":"Sci Rep."},{"key":"2026080922381771600_sxag028-B19","doi-asserted-by":"publisher","first-page":"3402","DOI":"10.3390\/ijms27083402","article-title":"Wnt signaling across adult skin Mini-Organs: Interfollicular epidermis, hair follicle, and nail\u2014implications for disease and regeneration","volume":"27","author":"Pulawska-Czub","year":"2026","journal-title":"Int J Mol Sci."},{"key":"2026080922381771600_sxag028-B20","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1002\/dvg.20744","article-title":"Msx2 and Foxn1 regulate nail homeostasis","volume":"49","author":"Cai","year":"2011","journal-title":"Genesis"},{"key":"2026080922381771600_sxag028-B21","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.ydbio.2013.07.020","article-title":"SDF-1\u03b1\/CXCR4 signaling mediates digit tip regeneration promoted by BMP-2","volume":"382","author":"Lee","year":"2013","journal-title":"Dev Biol"},{"key":"2026080922381771600_sxag028-B22","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/j.ydbio.2012.09.021","article-title":"BMP2 induces segment-specific skeletal regeneration from digit and limb amputations by establishing a new endochondral ossification center","volume":"372","author":"Yu","year":"2012","journal-title":"Dev Biol"},{"key":"2026080922381771600_sxag028-B23","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1242\/dev.042424","article-title":"BMP signaling induces digit regeneration in neonatal mice","volume":"137","author":"Yu","year":"2010","journal-title":"Development"},{"key":"2026080922381771600_sxag028-B24","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1002\/dvdy.23728","article-title":"Bone pattern formation in mouse limbs after amputation at the forearm level","volume":"241","author":"Ide","year":"2012","journal-title":"Dev Dyn."},{"key":"2026080922381771600_sxag028-B25","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1038\/nbt950","article-title":"Capturing and profiling adult hair follicle stem cells [in eng","volume":"22","author":"Morris","year":"2004","journal-title":"Nat Biotechnol"},{"key":"2026080922381771600_sxag028-B26","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1016\/j.cell.2006.07.036","article-title":"Tcf3 governs stem cell features and represses cell fate determination in skin","volume":"127","author":"Nguyen","year":"2006","journal-title":"Cell"},{"key":"2026080922381771600_sxag028-B27","doi-asserted-by":"publisher","first-page":"1351","DOI":"10.1073\/pnas.1121312110","article-title":"Competitive balance of intrabulge BMP\/wnt signaling reveals a robust gene network ruling stem cell homeostasis and cyclic activation","volume":"110","author":"Kandyba","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026080922381771600_sxag028-B28","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1083\/jcb.200309042","article-title":"Defining BMP functions in the hair follicle by conditional ablation of BMP receptor IA","volume":"163","author":"Kobielak","year":"2003","journal-title":"J Cell Biol"},{"key":"2026080922381771600_sxag028-B29","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1002\/gene.10038","article-title":"Generation of bmpr\/Alk3 conditional knockout mice","volume":"32","author":"Mishina","year":"2002","journal-title":"Genesis"},{"key":"2026080922381771600_sxag028-B30","doi-asserted-by":"publisher","first-page":"8551","DOI":"10.1073\/pnas.96.15.8551","article-title":"The magical touch: genome targeting in epidermal stem cells induced by tamoxifen application to mouse skin","volume":"96","author":"Vasioukhin","year":"1999","journal-title":". Proc Natl Acad Sci U S A"},{"key":"2026080922381771600_sxag028-B31","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1038\/nn.2467","article-title":"A robust and high-throughput cre reporting and characterization system for the whole mouse brain","volume":"13","author":"Madisen","year":"2010","journal-title":"Nat Neurosci"},{"key":"2026080922381771600_sxag028-B32","doi-asserted-by":"publisher","first-page":"752","DOI":"10.1006\/bbrc.1997.7124","article-title":"Regulation of cre recombinase activity by mutated estrogen receptor ligand-binding domains","volume":"237","author":"Feil","year":"1997","journal-title":"Biochem Biophys Res Commun"},{"key":"2026080922381771600_sxag028-B33","doi-asserted-by":"publisher","first-page":"2369","DOI":"10.1242\/dev.120.9.2369","article-title":"Programming gene expression in developing epidermis","volume":"120","author":"Byrne","year":"1994","journal-title":"Development"},{"key":"2026080922381771600_sxag028-B34","doi-asserted-by":"publisher","first-page":"10063","DOI":"10.1073\/pnas.0703004104","article-title":"Loss of a quiescent niche but not follicle stem cells in the absence of bone morphogenetic protein signaling","volume":"104","author":"Kobielak","year":"2007","journal-title":". Proc Natl Acad Sci U S A"},{"key":"2026080922381771600_sxag028-B35","doi-asserted-by":"publisher","first-page":"863","DOI":"10.1038\/s41551-020-0565-2","article-title":"High-throughput automated organoid culture via stem-cell aggregation in microcavity arrays","volume":"4","author":"Brandenberg","year":"2020","journal-title":"Nat Biomed Eng."},{"key":"2026080922381771600_sxag028-B36","doi-asserted-by":"publisher","first-page":"1355","DOI":"10.1016\/j.jid.2016.03.018","article-title":"Epithelium-derived wnt ligands are essential for maintenance of underlying digit bone","volume":"136","author":"Takeo","year":"2016","journal-title":"J Invest Dermatol"}],"container-title":["Stem Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/stmcls\/advance-article-pdf\/doi\/10.1093\/stmcls\/sxag028\/68257326\/sxag028.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/stmcls\/article-pdf\/44\/8\/sxag028\/68257326\/sxag028.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/stmcls\/article-pdf\/44\/8\/sxag028\/68257326\/sxag028.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T02:38:33Z","timestamp":1786329513000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/stmcls\/article\/doi\/10.1093\/stmcls\/sxag028\/8674740"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,8]]},"references-count":36,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,7,22]]}},"URL":"https:\/\/doi.org\/10.1093\/stmcls\/sxag028","relation":{},"ISSN":["1066-5099","1549-4918"],"issn-type":[{"value":"1066-5099","type":"print"},{"value":"1549-4918","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,8]]},"published":{"date-parts":[[2026,4,8]]},"article-number":"sxag028"}}