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Skin\u2010derived precursors (SKPs) exhibit great potential as stem cell\u2010based therapies for hair regeneration; however, the proliferation and hair\u2010inducing capacity of SKPs gradually decrease during culturing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and Methods<\/jats:title><jats:p>We describe a 3D co\u2010culture system accompanied by kyoto encyclopaedia of genes and genomes and gene ontology enrichment analyses to determine the key factors and pathways that enhance SKP stemness and verified using alkaline phosphatase assays, Ki\u201067 staining, HF reconstitution, Western blot and immunofluorescence staining. The upregulated genes were confirmed utilizing corresponding recombinant protein or small\u2010interfering RNA silencing in vitro, as well as the evaluation of telogen\u2010to\u2010anagen transition and HF reconstitution in vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The 3D co\u2010culture system revealed that epidermal stem cells and adipose\u2010derived stem cells enhanced SKP proliferation and HF regeneration capacity by amphiregulin (AREG), with the promoted stemness allowing SKPs to gain an earlier telogen\u2010to\u2010anagen transition and high\u2010efficiency HF reconstitution. By contrast, inhibitors of the phosphoinositide 3\u2010kinase (PI3K) and mitogen\u2010activated protein kinase (MAPK) pathways downstream of AREG signalling resulted in diametrically opposite activities.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>By exploiting a 3D co\u2010culture model, we determined that AREG promoted SKP stemness by enhancing both proliferation and hair\u2010inducing capacity through the PI3K and MAPK pathways. These findings suggest AREG therapy as a potentially promising approach for treating alopecia.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cpr.13106","type":"journal-article","created":{"date-parts":[[2021,8,12]],"date-time":"2021-08-12T08:11:55Z","timestamp":1628755915000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Amphiregulin promotes hair regeneration of skin\u2010derived precursors via the PI3K and MAPK pathways"],"prefix":"10.1111","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3607-7141","authenticated-orcid":false,"given":"Qiumei","family":"Lu","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Sciences (Shenzhen) Sun Yat\u2010sen University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Gao","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences (Shenzhen) Sun Yat\u2010sen University Guangzhou 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