{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T16:43:19Z","timestamp":1791045799745,"version":"4.1.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T00:00:00Z","timestamp":1751241600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Mesenchymal stem cells (MSCs) participate in the dynamic remodeling of the extracellular matrix during wound healing, natural bleeding processes or cancer progression. Pericellular proteolysis is a key mechanism mediating the aforementioned processes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim<\/jats:title><jats:p>This study primarily aimed to define mechanistic pathways of plasmin formation and its consequences on MSC phenotype and functioning. We have also investigated the regulatory mechanisms mediated by PAI-1 and the ability of MSCs to shed microvesicles bearing the proteolytic machinery.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Human MSCs were derived from bone marrow or umbilical cord donors. Cells thus obtained were seeded in multi-well plates and treated with different concentrations of plasminogen and pro-urokinase in the presence or absence of variable amounts of tranexamic acid. We measured MVs formation and phenotypical changes occurring on MSCs. The amount of plasmin formed was quantified by western blot along with the plasmin activity detected by photometry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We demonstrate that vesiculation is the early response of plasmin formation at the membrane of MSCs followed by cell retraction and detachment. We measured the effect of TXA on plasmin formation and its consequences on cell behavior. Our findings provide the first demonstration that TXA efficiently inhibits MSC-driven plasmin generation by competitively blocking plasminogen binding to the uPA\u2022uPAR complex at the cell plasma membrane.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>We propose that plasmin formation on MSCs may be involved in pathological processes such as endometrial hemorrhage (metrorrhagia and Post-Partum Hemorrhage), autoimmune and ischaemic diseases, as well as cancer. By advancing our understanding of these mechanisms, we open new avenues for the development of biomarkers and targeted treatments.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmed.2025.1570395","type":"journal-article","created":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T05:26:08Z","timestamp":1751261168000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Tranexamic acid impairs plasmin generation on human mesenchymal stem cells and derived membrane microvesicles, halting pericellular proteolysis"],"prefix":"10.3389","volume":"12","author":[{"given":"Ramy","family":"Abou Rjeily","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Mrad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatiha Z.","family":"El-Ghazouani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florence","family":"Toti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey","family":"Cras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Angles-Cano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,30]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/1478-811X-9-12","article-title":"Different populations and sources of human mesenchymal stem cells (MSC): a comparison of adult and neonatal tissue-derived MSC","volume":"9","author":"Hass","year":"2011","journal-title":"Cell Commun Signal"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1159\/000215579","article-title":"Secretion of fibrinolytic enzymes facilitates human mesenchymal stem cell invasion into fibrin clots","volume":"191","author":"Neuss","year":"2010","journal-title":"Cells Tissues Organs"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1634\/stemcells.2008-0520","article-title":"Improved autograft survival of mesenchymal stromal cells by plasminogen activator inhibitor 1 inhibition","volume":"27","author":"Copland","year":"2009","journal-title":"Stem Cells"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"972","DOI":"10.1002\/jor.20819","article-title":"Activated platelets increase fibrinolysis of mesenchymal progenitor cells","volume":"27","author":"Agis","year":"2009","journal-title":"J Orthop Res"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1406","DOI":"10.1634\/stemcells.2008-0141","article-title":"Urokinase plasminogen activator and urokinase plasminogen activator receptor mediate human stem cell tropism to malignant solid tumors","volume":"26","author":"Gutova","year":"2008","journal-title":"Stem Cells"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"818616","DOI":"10.3389\/fcell.2022.818616","article-title":"Modulation of cellular function by the Urokinase receptor signalling: a mechanistic view","volume":"10","author":"Alfano","year":"2022","journal-title":"Front Cell Dev Biol"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1016\/j.yexcr.2010.01.013","article-title":"Mesenchymal cells stimulate capillary morphogenesis via distinct proteolytic mechanisms","volume":"316","author":"Ghajar","year":"2010","journal-title":"Exp Cell Res"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2012\/141806","article-title":"So many plasminogen receptors: why?","volume":"2012","author":"Plow","year":"2012","journal-title":"J Biomed Biotechnol"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1772","DOI":"10.3390\/biom11121772","article-title":"The ANXA2\/S100A10 complex-regulation of the oncogenic plasminogen receptor","volume":"11","author":"Bharadwaj","year":"2021","journal-title":"Biomol Ther"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"5984","DOI":"10.3390\/ijms23115984","article-title":"Plasminogen binding and activation at the mesothelial cell surface promotes invasion through a collagen matrix","volume":"23","author":"Ditzig","year":"2022","journal-title":"Int J Mol Sci"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"7630","DOI":"10.1021\/bi00244a035","article-title":"Characterization of the binding of plasminogen to fibrin surfaces: the role of carboxy-terminal lysines","volume":"30","author":"Fleury","year":"1991","journal-title":"Biochemistry"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1111\/j.1432-1033.1973.tb02880.x","article-title":"Activation of human plasminogen by an insoluble derivative of urokinase. 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