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In vitro, isolated keratocytes adopt a stereotyped shape with a large fan\u2010shaped lamellipodium and a nearly spherical cell body. However, in their native in vivo environment, these cells adopt a significantly different shape during their rapid migration toward wounds. Within the epidermis, keratocytes experience two\u2010dimensional (2D) confinement between the outer epidermal cell layer and the basement membrane; these two deformable surfaces constrain keratocyte cell bodies to be flatter in vivo than in isolation. In vivo keratocytes also exhibit a relative elongation of the front\u2010to\u2010back axis and substantially more lamellipodial ruffling, as compared to isolated cells. We have explored the effects of 2D confinement, separated from other in vivo environmental cues, by overlaying isolated cells with an agarose hydrogel with occasional spacers, or with a ceiling made of polydimethylsiloxane (PDMS) elastomer. Under these conditions, isolated keratocytes more closely resemble the in vivo migratory shape phenotype, displaying a flatter apical\u2010basal axis and a longer front\u2010to\u2010back axis than unconfined keratocytes. We propose that 2D confinement contributes to multiple dimensions of in vivo keratocyte shape determination. Further analysis demonstrates that confinement causes a synchronous 20% decrease in both cell speed and volume. Interestingly, we were able to replicate the 20% decrease in speed using a sorbitol hypertonic shock to shrink the cell volume, which did not affect other aspects of cell shape. Collectively, our results suggest that environmentally imposed changes in cell volume may influence cell migration speed, potentially by perturbing physical properties of the cytoplasm.<\/jats:p>","DOI":"10.1002\/cm.21741","type":"journal-article","created":{"date-parts":[[2022,12,28]],"date-time":"2022-12-28T06:32:32Z","timestamp":1672209152000},"page":"34-51","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Confined keratocytes mimic in vivo migration and reveal volume\u2010speed relationship"],"prefix":"10.1002","volume":"80","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3487-0269","authenticated-orcid":false,"given":"Ellen C.","family":"Labuz","sequence":"first","affiliation":[{"name":"Biophysics Program Stanford University  Stanford California USA"},{"name":"Department of Biology and Howard Hughes Medical Institute University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Footer","sequence":"additional","affiliation":[{"name":"Department of Biology and Howard Hughes Medical Institute University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2334-2535","authenticated-orcid":false,"given":"Julie A.","family":"Theriot","sequence":"additional","affiliation":[{"name":"Department of Biology and Howard Hughes Medical Institute University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,1,10]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.109066"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.CUB.2013.02.047"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1083\/JCB.134.5.1209"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.49064"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1001059"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1207968109"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)67157-1"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.14440\/jbm.2014.36"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmbbm.2013.04.023"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200906139"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E18-05-0295"},{"issue":"2","key":"e_1_2_10_13_1","first-page":"70","article-title":"A brief survey of aquaporins and their implications for renal physiology","volume":"19","author":"Gade W.","year":"2006","journal-title":"Clinical Laboratory Science: Journal of the American Society for Medical Technology"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2021.11.024"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.74389"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201408049"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.ACTBIO.2018.03.016"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.2307\/1536726"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1705179114"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.091876"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.09376"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.21769\/BioProtoc.4260"},{"key":"e_1_2_10_23_1","doi-asserted-by":"crossref","unstructured":"Kennard A. 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