{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T00:16:37Z","timestamp":1791936997592,"version":"4.3.4"},"reference-count":62,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2026,1,4]],"date-time":"2026-01-04T00:00:00Z","timestamp":1767484800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,1,4]],"date-time":"2026-01-04T00:00:00Z","timestamp":1767484800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100013111","name":"Materials Research Science and Engineering Center, Harvard University","doi-asserted-by":"publisher","award":["DMR\u20102011754"],"award-info":[{"award-number":["DMR\u20102011754"]}],"id":[{"id":"10.13039\/100013111","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Adv Healthcare Materials"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    T\u2010cell\u2013based immunotherapies have revolutionized cancer treatment, yet their reliance on patient\u2010derived T\u2010cells limits scalability and accessibility. Engineering functional T\u2010cells de novo from human hematopoietic stem cells (HSCs) represents a promising alternative toward a renewable and customizable source of therapeutic lymphocytes. Successful HSC\u2010derived T\u2010cell generation requires recapitulation of key signaling and adhesion cues of the thymic microenvironment, particularly Notch1\u2013DLL\u20104 and \u03b14\u03b21\u2010integrin\u2013VCAM\u20101 interactions within ex vivo engineered thymic niche (ETN) systems. Notch1\u2010DLL\u20104 and \u03b14\u03b21\u2010integrin\u2010VCAM\u20101 interactions are known to respond to mechanical forces that regulate their bond dissociation behaviors and downstream signal transduction, yet manipulating the mechanosensitive features of these key receptor\u2010ligand interactions in thymopoiesis has been largely ignored in current ETN designs. Here, we demonstrate that human T\u2010cell development from cord blood\u2010derived CD34\n                    <jats:sup>+<\/jats:sup>\n                    HSCs is regulated via molecular cooperativity in notch1 and integrin\u2010mediated mechanotransduction. Mechanically confining interpenetrating network (IPN) hydrogel\u2010based 3D cell culture, comprised of collagen type I and alginate polysaccharides functionalized with DLL\u20104 and VCAM\u20101 is used as a model viscoelastic 3D ETN to manipulate human progenitor (pro)T\u2010cell differentiation. This ETN enables orthogonal control of the mechanical properties of the thymic niche, including storage modulus, and viscoelastic properties (e.g., stress relaxation kinetics). We identify that soft, viscous matrices that enhance activation of the notch1\u2010pathway, and subsequently notch1 intracellular domain (NICD) nuclear import, sustain the T\u2010cell development gene regulatory network during proT\u2010cell differentiation. Conversely, stiff, elastic matrices inhibit HSC commitment to the T\u2010lineage, and rather promotes Myeloid\u2010cell differentiation. Our observations indicate mechanical reciprocity in signaling pathways indispensable to thymopoiesis and highlight extracellular matrix mechanics as a variable in controlling hematopoietic stem cell fate decisions.\n                  <\/jats:p>","DOI":"10.1002\/adhm.202504316","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T06:41:42Z","timestamp":1767595302000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Human Progenitor T\u2010Cell Differentiation Regulated by the Mechanical Resistance of Thymus\u2010Mimetic Extracellular Matrices"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5500-619X","authenticated-orcid":false,"given":"Nicholas","family":"Jeffreys","sequence":"first","affiliation":[{"name":"John A. Paulson School of Engineering and Applied Sciences Harvard University  Cambridge Massachusetts USA"},{"name":"Wyss Institute for Biologically Inspired Engineering  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle T.","family":"Ruark","sequence":"additional","affiliation":[{"name":"John A. Paulson School of Engineering and Applied Sciences Harvard University  Cambridge Massachusetts USA"},{"name":"Wyss Institute for Biologically Inspired Engineering  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua M.","family":"Price","sequence":"additional","affiliation":[{"name":"John A. Paulson School of Engineering and Applied Sciences Harvard University  Cambridge Massachusetts USA"},{"name":"Wyss Institute for Biologically Inspired Engineering  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ella M.","family":"Serrano\u2010Wu","sequence":"additional","affiliation":[{"name":"John A. Paulson School of Engineering and Applied Sciences Harvard University  Cambridge Massachusetts USA"},{"name":"Wyss Institute for Biologically Inspired Engineering  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2944-7503","authenticated-orcid":false,"given":"Blake","family":"Hanan","sequence":"additional","affiliation":[{"name":"John A. Paulson School of Engineering and Applied Sciences Harvard University  Cambridge Massachusetts USA"},{"name":"Wyss Institute for Biologically Inspired Engineering  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1526-6656","authenticated-orcid":false,"given":"Andrew S.","family":"Khalil","sequence":"additional","affiliation":[{"name":"John A. Paulson School of Engineering and Applied Sciences Harvard University  Cambridge Massachusetts USA"},{"name":"Wyss Institute for Biologically Inspired Engineering  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4342-4105","authenticated-orcid":false,"given":"Wei\u2010Hung","family":"Jung","sequence":"additional","affiliation":[{"name":"John A. Paulson School of Engineering and Applied Sciences Harvard University  Cambridge Massachusetts USA"},{"name":"Wyss Institute for Biologically Inspired Engineering  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9269-3163","authenticated-orcid":false,"given":"Nuria","family":"Lafuente\u2010G\u00f3mez","sequence":"additional","affiliation":[{"name":"John A. Paulson School of Engineering and Applied Sciences Harvard University  Cambridge Massachusetts USA"},{"name":"Wyss Institute for Biologically Inspired Engineering  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2747-1200","authenticated-orcid":false,"given":"Christina M.","family":"Tringides","sequence":"additional","affiliation":[{"name":"John A. Paulson School of Engineering and Applied Sciences Harvard University  Cambridge Massachusetts USA"},{"name":"Wyss Institute for Biologically Inspired Engineering  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann","family":"Gao","sequence":"additional","affiliation":[{"name":"John A. Paulson School of Engineering and Applied Sciences Harvard University  Cambridge Massachusetts USA"},{"name":"Wyss Institute for Biologically Inspired Engineering  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2775-3478","authenticated-orcid":false,"given":"Joshua M.","family":"Brockman","sequence":"additional","affiliation":[{"name":"John A. Paulson School of Engineering and Applied Sciences Harvard University  Cambridge Massachusetts USA"},{"name":"Wyss Institute for Biologically Inspired Engineering  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7231-5902","authenticated-orcid":false,"given":"Andrew","family":"Lu","sequence":"additional","affiliation":[{"name":"John A. Paulson School of Engineering and Applied Sciences Harvard University  Cambridge Massachusetts USA"},{"name":"Wyss Institute for Biologically Inspired Engineering  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Izabela","family":"Zmirska","sequence":"additional","affiliation":[{"name":"John A. Paulson School of Engineering and Applied Sciences Harvard University  Cambridge Massachusetts USA"},{"name":"Wyss Institute for Biologically Inspired Engineering  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4009-879X","authenticated-orcid":false,"given":"Kyle H.","family":"Vining","sequence":"additional","affiliation":[{"name":"John A. Paulson School of Engineering and Applied Sciences Harvard University  Cambridge Massachusetts USA"},{"name":"Wyss Institute for Biologically Inspired Engineering  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3034-2445","authenticated-orcid":false,"given":"Junzhe","family":"Lou","sequence":"additional","affiliation":[{"name":"John A. Paulson School of Engineering and Applied Sciences Harvard University  Cambridge Massachusetts USA"},{"name":"Wyss Institute for Biologically Inspired Engineering  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1959-6794","authenticated-orcid":false,"given":"Kwasi","family":"Adu\u2010Berchie","sequence":"additional","affiliation":[{"name":"John A. Paulson School of Engineering and Applied Sciences Harvard University  Cambridge Massachusetts USA"},{"name":"Wyss Institute for Biologically Inspired Engineering  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyoon","family":"Kwon","sequence":"additional","affiliation":[{"name":"Wyss Institute for Biologically Inspired Engineering  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamza","family":"Ijaz","sequence":"additional","affiliation":[{"name":"Wyss Institute for Biologically Inspired Engineering  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0123-2127","authenticated-orcid":false,"given":"Azeem","family":"Sharda","sequence":"additional","affiliation":[{"name":"Department of Stem Cell and Regenerative Biology Harvard University  Cambridge Massachusetts USA"},{"name":"Harvard Stem Cell Institute  Cambridge Massachusetts USA"},{"name":"Center For Regenerative Medicine Massachusetts General Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9821-7133","authenticated-orcid":false,"given":"David T.","family":"Scadden","sequence":"additional","affiliation":[{"name":"Department of Stem Cell and Regenerative Biology Harvard University  Cambridge Massachusetts USA"},{"name":"Harvard Stem Cell Institute  Cambridge Massachusetts USA"},{"name":"Center For Regenerative Medicine Massachusetts General Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9406-773X","authenticated-orcid":false,"given":"David J.","family":"Mooney","sequence":"additional","affiliation":[{"name":"John A. Paulson School of Engineering and Applied Sciences Harvard University  Cambridge Massachusetts USA"},{"name":"Wyss Institute for Biologically Inspired Engineering  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,4]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature22395"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1089\/genbio.2023.0008"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20080134"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V89.7.2461"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxt027"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4258"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abn5522"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1177\/33.7.3891843"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/biotech11030027"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2016.11.054"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1089\/ten.tec.2022.0040"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580\u2010023\u201000583\u20101"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1089\/genbio.2024.0010"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1171643"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/cb400801m"},{"key":"e_1_2_9_17_1","first-page":"364","article-title":"Mechanotransduction in T Cell Development","volume":"9","author":"Rushdi M.","year":"2020","journal-title":"Differentiation and Function Cells"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010biophys\u2010101920\u2010082204"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2023.102244"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2013.11.012"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1231041"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf9739"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2015.05.004"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmat4489"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2017.108"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmat2732"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010020\u20102612\u20102"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.7684161"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.10.008"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41556\u2010022\u201000927\u20107"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1063\/5.0166848"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202200880"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.260442"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2018.10.013"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41563\u2010022\u201001293\u20103"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2015.01.048"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.progpolymsci.2011.06.003"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0142\u20109612(98)00107\u20100"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41570\u2010020\u20100205\u20100"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0036-1588682"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2012.01.003"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.113.23.4313"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010021\u201025245\u20108"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41536\u2010022\u201000210\u20101"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/wsbm.162"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1039\/D0BM01562H"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102018\u201002\u2010832998"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0808866106"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12915\u2010019\u20100625\u20109"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018\u2010024\u201005142\u20101"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1063\/5.0080480"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.48550\/arXiv.2307.07959"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00406\u201009"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2023.03.005"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2019.119665"},{"key":"e_1_2_9_56_1","first-page":"2015","article-title":"Dynamics of thymus Organogenesis and Colonization in Early human Development","volume":"140","author":"Farley A. M.","year":"2013","journal-title":"Dev Camb Engl"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200810002"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1611338113"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2010.03.005"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2016.10.002"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2015.09.004"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201502053"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2013.10.009"}],"container-title":["Advanced Healthcare Materials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/adhm.202504316","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/adhm.202504316","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/adhm.202504316","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T17:07:06Z","timestamp":1783012026000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/adhm.202504316"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,4]]},"references-count":62,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2026,3]]}},"alternative-id":["10.1002\/adhm.202504316"],"URL":"https:\/\/doi.org\/10.1002\/adhm.202504316","archive":["Portico"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2025.08.27.671384","asserted-by":"object"}]},"ISSN":["2192-2640","2192-2659"],"issn-type":[{"value":"2192-2640","type":"print"},{"value":"2192-2659","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,4]]},"assertion":[{"value":"2025-09-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-22","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-04","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e04316"}}