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The successful in vitro cultivation of hair follicle organoids (HFOs) and the effective enhancement of HFOs sprouting rates are critical advancements in addressing this problem. While R\u2010spondin1 (RSPO1) demonstrates in vivo efficacy in activating quiescent follicular stem cells and enhancing hair density, its capacity to augment HFOs sprouting efficiency remains to be elucidated. In this study, we regulate the growth microenvironment of HFOs using RSPO1, enhancing the HFOs sprouting rate and exploring its mechanism. HFO\u2010induced dermal papilla cells (DPCs) induction was quantified via alkaline phosphatase (ALP) assay, with RSPO1\u2010mediated hair\u2010regenerative gene\/protein modulation assessed through triple\u2010method analysis (qPCR\/WB\/IF). Sequencing delineated RSPO1\u2010affected molecular pathways. Our study demonstrates that RSPO1 significantly promotes HFOs sprouting rate and upregulates the gene\/protein expression of DPCs. Furthermore, RSPO1 not only potentiates Wnt\/\u03b2\u2010catenin\u2010mediated organoid patterning but also coordinates a signaling triad involving PI3K\u2010Akt, Rap1 and NF\u2010\u03baB to drive synchronized hair follicle sprouting and stratified pilogenic differentiation. Our 3D organoid\u2010based expansion strategy enables definitive treatment of alopecia through in vitro hair follicle expansion, achieving functional hair neogenesis in patients with baldness.<\/jats:p>","DOI":"10.1002\/cbin.70045","type":"journal-article","created":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T08:45:25Z","timestamp":1749026725000},"page":"939-951","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["From Spheroid to Sprouting: Microenvironmental Modulation Boosts Hair Follicle Organoid Morphogenesis in 3D Culture"],"prefix":"10.1002","volume":"49","author":[{"given":"Ling","family":"Xiao","sequence":"first","affiliation":[{"name":"Department of Plastic Surgery, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital Third Military Medical University (Army Medical University) Chongqing 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