{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T15:11:49Z","timestamp":1786115509636,"version":"build-2736575974"},"posted":{"date-parts":[[2026,8,3]]},"group-title":"Biophysics","reference-count":71,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R01AR074525"],"award-info":[{"award-number":["R01AR074525"]}],"id":[{"id":"https:\/\/ror.org\/006zn3t30","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Skin growth and remodeling underlies health, disease, and treatments such as tissue expansion (TE). The mechanotransduction pathways in dermal fibroblasts are increasingly well characterized, and tissue-level growth has been described phenomenologically, but coupling between cell-level signaling and tissue-level growth remains poorly understood. We develop a dermal fibroblast signaling network through extensive literature data curation, comprising 151 reactions among 96 nodes. The inputs are mechanical stretch and eight ligands (TGF\n                  <jats:italic>\u03b2<\/jats:italic>\n                  , PDGF, FGF, IL1, IL6, TNF\n                  <jats:italic>\u03b1<\/jats:italic>\n                  , AngII, ET1); outputs of interest span ECM-enzymes (proMMP1\/2\/9, MMP1\/2\/9), ECM proteins (CImRNA, collagen I, fibronectin), and fibroblast activity (\n                  <jats:italic>\u03b1<\/jats:italic>\n                  SMA, proliferation). Implemented as a logic-based ODE system, the network reproduces 82% of the calibration dataset and agrees with independent validation data. Sensitivity analysis reveals a tension-dependent regulation of signaling: at baseline tension, outputs are governed by many boosters (nodes that positively influence downstream targets) and one dominant brake, LATS1\/2, whereas at high tension control consolidates and new, tension-specific regulators such as integrin (ITGB1) emerge. Multiple pathway axes converge on a few central regulators, producing pronounced crosstalk, most notably between TGF\n                  <jats:italic>\u03b2<\/jats:italic>\n                  and mechanical tension. Finally, linking the collagen outputs to a tissue-level growth formulation yields a bidirectional mechanical\u2013biochemical coupling that reproduces tension-induced skin growth measured in a porcine TE model. This framework establishes a comprehensively calibrated dermal fibroblast signaling network coupled to tissue-level growth, opening opportunities for targeted TE interventions.\n                <\/jats:p>","DOI":"10.64898\/2026.07.31.742141","type":"posted-content","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T15:55:30Z","timestamp":1785772530000},"source":"Crossref","is-referenced-by-count":0,"title":["Coupling fibroblast mechanotransduction signaling to tissue growth in a multiscale model of skin expansion"],"prefix":"10.64898","author":[{"given":"Laura","family":"Nunez-Alvarez","sequence":"first","affiliation":[{"name":"Weldon School of Biomedical Engineering, Purdue University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna K.","family":"Ledwon","sequence":"additional","affiliation":[{"name":"Lurie Children\u2019s Hospital"},{"name":"Department of Plastic and Reconstructive Surgery, Northwestern School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parul","family":"Rai","sequence":"additional","affiliation":[{"name":"Lurie Children\u2019s Hospital"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn","family":"Reisner","sequence":"additional","affiliation":[{"name":"Lurie Children\u2019s Hospital"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianhong","family":"Han","sequence":"additional","affiliation":[{"name":"School of Mechanical Engineering, Purdue University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Solorio","sequence":"additional","affiliation":[{"name":"Weldon School of Biomedical Engineering, Purdue University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arun","family":"Gosain","sequence":"additional","affiliation":[{"name":"Lurie Children\u2019s Hospital"},{"name":"Department of Plastic and Reconstructive Surgery, Northwestern School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8531-0603","authenticated-orcid":false,"given":"Adrian","family":"Buganza Tepole","sequence":"additional","affiliation":[{"name":"Weldon School of Biomedical Engineering, Purdue University"},{"name":"School of Mechanical Engineering, Purdue University"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026080520000833000_2026.07.31.742141v1.1","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.amsu.2017.07.048","article-title":"Tissue expansion for breast reconstruction: methods and techniques","volume":"21","year":"2017","journal-title":"Annals of medicine and surgery"},{"key":"2026080520000833000_2026.07.31.742141v1.2","first-page":"7641","article-title":"Influence of mechanical stimulation on human dermal fibroblasts derived from different body sites","volume":"8","year":"2015","journal-title":"International Journal of Clinical and Experimental Medicine"},{"key":"2026080520000833000_2026.07.31.742141v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtbi.2011.12.022"},{"key":"2026080520000833000_2026.07.31.742141v1.4","doi-asserted-by":"crossref","first-page":"865983","DOI":"10.3389\/fcell.2022.865983","article-title":"Single-cell transcriptomics uncover key regulators of skin regeneration in human long-term mechanical stretch-mediated expansion therapy","volume":"10","year":"2022","journal-title":"Frontiers in Cell and Developmental Biology"},{"issue":"1","key":"2026080520000833000_2026.07.31.742141v1.5","doi-asserted-by":"crossref","first-page":"6876","DOI":"10.1038\/s41467-025-62270-3","article-title":"The mechanotransducer piezo1 coordinates metabolism and inflammation to promote skin growth","volume":"16","year":"2025","journal-title":"Nature communications"},{"key":"2026080520000833000_2026.07.31.742141v1.6","unstructured":"M. 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