{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,8]],"date-time":"2025-11-08T23:05:52Z","timestamp":1762643152845,"version":"build-2065373602"},"reference-count":34,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,1,18]],"date-time":"2025-01-18T00:00:00Z","timestamp":1737158400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deutsche Forschungsgemeinschaft (DFG) through Excellence Cluster Cardiopulmonary System (ECCPS) to RH, DFG","award":["He1708-1"],"award-info":[{"award-number":["He1708-1"]}]},{"name":"German Ministry of Education and Research through \u201cMSC pro ISLE\u201d 01GN0952 to RH","award":["He1708-1"],"award-info":[{"award-number":["He1708-1"]}]},{"name":"Open Access Publishing Fund of Leipzig University","award":["He1708-1"],"award-info":[{"award-number":["He1708-1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Intravenously transplanted mesenchymal stromal cells (MSCs) have been shown to interact with endothelial cells and to migrate to tissues. However, intracellular signals regulating MSC migration are still incompletely understood. Here, we analyzed the role of Rap1 GTPase in the migration of human bone marrow-derived MSCs in vitro and in short-term homing in mice in vivo. MSCs expressed both Rap1A and Rap1B mRNAs, which were downregulated after treatment with siRNA against Rap1A and\/or B. In a flow chamber model with pre-established human umbilical vein endothelial cells (HUVECs), Rap1A\/B downregulated MSCs interacted for longer distances before arrest, indicating adhesion defects. CXCL12-induced adhesion of MSCs on immobilized Vascular Cell Adhesion Molecule (VCAM)-1 was also decreased after the downregulation of Rap1A, Rap1B, or both, as was CXCL12-induced transwell migration. In a competitive murine short-term homing model with i.v. co-injection of Rap1A+B siRNA-treated and control MSCs that were labeled with PKH 26 and PKH 67 fluorescent dyes, the Rap1A+B siRNA-treated MSCs were detected at increased frequencies in blood, liver, and spleen compared to control MSCs. Thus, Rap1 GTPase modulates the adhesion and migration of MSCs in vitro and may increase the bio-availability of i.v.-transplanted MSCs in tissues in a murine model.<\/jats:p>","DOI":"10.3390\/biology14010096","type":"journal-article","created":{"date-parts":[[2025,1,21]],"date-time":"2025-01-21T11:47:32Z","timestamp":1737460052000},"page":"96","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Rap1 Guanosine Triphosphate Hydrolase (GTPase) Regulates Shear Stress-Mediated Adhesion of Mesenchymal Stromal Cells"],"prefix":"10.3390","volume":"14","author":[{"given":"Melanie","family":"Giesen","sequence":"first","affiliation":[{"name":"Institute for Transfusion Medicine and Immune Hematology, German Red Cross Blood Donor Service, Clinics of the Goethe University Frankfurt (Main), 60528 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erika","family":"Fleck","sequence":"additional","affiliation":[{"name":"Institute for Transfusion Medicine and Immune Hematology, German Red Cross Blood Donor Service, Clinics of the Goethe University Frankfurt (Main), 60528 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J\u00fcrgen","family":"Scheele","sequence":"additional","affiliation":[{"name":"Department of Medicine I, Medical Center University of Freiburg and Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0377-7179","authenticated-orcid":false,"given":"Tanja Nicole","family":"Hartmann","sequence":"additional","affiliation":[{"name":"Department of Medicine I, Medical Center University of Freiburg and Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reinhard","family":"Henschler","sequence":"additional","affiliation":[{"name":"Institute for Transfusion Medicine, Medical Faculty, Leipzig University, 04103 Leipzig, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"779","DOI":"10.2174\/1574888X17666220823092202","article-title":"Review of the Published Literature Confirms the Safety of Intravenous Infusion of Mesenchymal Stem Cells","volume":"18","author":"Barmada","year":"2023","journal-title":"Curr. Stem Cell Res. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3938","DOI":"10.1182\/blood-2006-05-025098","article-title":"Mesenchymal stem cells display coordinated rolling and adhesion behavior on endothelial cells","volume":"108","author":"Ludwig","year":"2006","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.stem.2009.02.001","article-title":"Mesenchymal Stem Cell Homing: The Devil Is in the Details","volume":"4","author":"Karp","year":"2008","journal-title":"Cell Stem Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2472","DOI":"10.1002\/stem.1198","article-title":"Mesenchymal stem cells transmigrate between and directly through tumor necrosis factor-\u03b1-activated endothelial cells via both leukocyte-like and novel mechanisms","volume":"30","author":"Teo","year":"2012","journal-title":"Stem Cells"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1446","DOI":"10.1002\/stem.2614","article-title":"Concise Review: MSC Adhesion Cascade-Insights into Homing and Transendothelial Migration","volume":"35","author":"Nitzsche","year":"2017","journal-title":"Stem Cells"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Gao, Q., Xia, Y., Liu, L., Huang, L., Liu, Y., Zhang, X., Xu, K., Wei, J., Hu, Y., and Mu, Y. (2016). Galectin-3 Enhances Migration of Minature Pig Bone Marrow Mesenchymal Stem Cells Through Inhibition of RhoA-GTP Activity. Sci. Rep., 24.","DOI":"10.1038\/srep26577"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1111\/sji.12179","article-title":"Human umbilical cord blood-derived mesenchymal stromal cells display a novel interaction between P-selectin and galectin-1","volume":"80","author":"Suila","year":"2014","journal-title":"Scand J. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1007\/s10439-011-0461-8","article-title":"Glycoengineering of HCELL, the human bone marrow homing receptor: Sweetly programming cell migration","volume":"40","author":"Sackstein","year":"2012","journal-title":"Ann. Biomed. Eng."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/s12015-011-9293-z","article-title":"The role of chemokines in mesenchymal stem cell homing to myocardium","volume":"8","author":"Wu","year":"2012","journal-title":"Stem Cell Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.3109\/14653249.2011.602339","article-title":"Variability in chemokine-induced adhesion of human mesenchymal stromal cells","volume":"13","author":"Ciuculescu","year":"2011","journal-title":"Cytotherapy"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1007\/s00441-010-0994-4","article-title":"Integrin expression and integrin-mediated adhesion in vitro of human multipotent stromal cells (MSCs) to endothelial cells from various blood vessels","volume":"341","author":"Semon","year":"2010","journal-title":"Cell Tissue Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/S8756-3282(00)00424-5","article-title":"Integrin-mediated interactions between human bone marrow stromal precursor cells and the extracellular matrix","volume":"28","author":"Gronthos","year":"2001","journal-title":"Bone"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1089\/biores.2014.0055","article-title":"\u03b21 Integrins Mediate Attachment of Mesenchymal Stem Cells to Cartilage Lesions","volume":"4","author":"Zwolanek","year":"2015","journal-title":"Biores. Open Access"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1002\/stem.2924","article-title":"mDia1 and Cdc42 Regulate Activin B-Induced Migration of Bone Marrow-Derived Mesenchymal Stromal Cells","volume":"37","author":"Wang","year":"2019","journal-title":"Stem Cells"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"9358","DOI":"10.1074\/jbc.RA117.001113","article-title":"RhoA, Rac1, and Cdc42 differentially regulate \u03b1SMA and collagen I expression in mesenchymal stem cells","volume":"293","author":"Ge","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Melzer, M., Niebert, S., Heimann, M., Ullm, F., Pompe, T., Scheiner-Bobis, G., and Burk, J. (2024). Differential Smad2\/3 linker phosphorylation is a crosstalk mechanism of Rho\/ROCK and canonical TGF-\u03b23 signaling in tenogenic differentiation. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-60717-z"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"11455","DOI":"10.1038\/ncomms11455","article-title":"RhoA determines lineage fate of mesenchymal stem cells by modulating CTGF-VEGF complex in extracellular matrix","volume":"7","author":"Li","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3756","DOI":"10.1002\/jcp.24084","article-title":"Cooperation of Epac1\/Rap1\/Akt and PKA in prostaglandin E(2) -induced proliferation of human umbilical cord blood derived mesenchymal stem cells: Involvement of c-Myc and VEGF expression","volume":"227","author":"Jang","year":"2012","journal-title":"J. Cell Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"15007","DOI":"10.1038\/cddiscovery.2015.7","article-title":"Rap1-mediated nuclear factor-kappaB (NF-\u03baB) activity regulates the paracrine capacity of mesenchymal stem cells in heart repair following infarction","volume":"1","author":"Zhang","year":"2015","journal-title":"Cell Death Discov."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.3892\/mmr.2016.5398","article-title":"HMGB1 promotes cellular chemokine synthesis and potentiates mesenchymal stromal cell migration via Rap1 activation","volume":"14","author":"Lin","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13287-015-0271-2","article-title":"Biodistribution, migration and homing of systemically applied mesenchymal stem\/stromal cells","volume":"7","author":"Leibacher","year":"2016","journal-title":"Stem Cell Res. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1966","DOI":"10.1634\/stemcells.2007-0167","article-title":"Rho inhibition induces migration of mesenchymal stromal cells","volume":"25","author":"Jaganathan","year":"2007","journal-title":"Stem Cells"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1128\/MCB.26.2.643-653.2006","article-title":"Rap1A-deficient T and B cells show impaired integrin-mediated cell adhesion","volume":"26","author":"Duchniewicz","year":"2006","journal-title":"Mol. Cell. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.jcyt.2016.09.010","article-title":"Human mesenchymal stromal cells undergo apoptosis and fragmentation after intravenous application in immune-competent mice","volume":"19","author":"Leibacher","year":"2017","journal-title":"Cytotherapy"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1002\/stem.2264","article-title":"Epac Activation Regulates Human Mesenchymal Stem Cells Migration and Adhesion","volume":"34","author":"Yu","year":"2016","journal-title":"Stem Cells"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1038\/35073073","article-title":"Rap1 signaling: Adhering to new models. The small GTPase Rap1 is a potent activation signal for beta1, beta2, and beta3 integrins and enhances cellular adhesion in both immune and nonimmune cells","volume":"2","author":"Bos","year":"2001","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1083\/jcb.200311093","article-title":"Rap1 up-regulation and activation on plasma membrane regulates T cell adhesion","volume":"164","author":"Bivona","year":"2004","journal-title":"J. Cell Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1182\/blood-2009-03-211979","article-title":"Rap1 controls lymphocyte adhesion cascade and interstitial migration within lymph nodes in RAPL-dependent and -independent manners","volume":"115","author":"Ebisuno","year":"2010","journal-title":"Blood"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1182\/blood-2008-02-138438","article-title":"Role of the small GTPase Rap1 for integrin activity regulation in endothelial cells and angiogenesis","volume":"113","author":"Carmona","year":"2009","journal-title":"Blood"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1002\/stem.1848","article-title":"Intravital imaging of mesenchymal stem cell trafficking and association with platelets and neutrophils","volume":"33","author":"Teo","year":"2015","journal-title":"Stem Cells"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Masterson, C.H., Tabuchi, A., Hogan, G., Fitzpatrick, G., Kerrigan, S.W., Jerkic, M., Kuebler, W.M., Laffey, J.G., and Curley, G.F. (2021). Intra-vital imaging of mesenchymal stromal cell kinetics in the pulmonary vasculature during infection. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-83894-7"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1111\/j.1600-065X.2007.00536.x","article-title":"Integrin modulation and signaling in leukocyte adhesion and migration","volume":"218","author":"Alon","year":"2007","journal-title":"Immunol. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1089\/scd.2008.0253","article-title":"Pulmonary passage is a major obstacle for intravenous stem cell delivery: The pulmonary first-pass effect","volume":"18","author":"Fischer","year":"2009","journal-title":"Stem Cells Dev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1084\/jem.188.3.465","article-title":"Hematopoietic progenitor cell rolling in bone marrow microvessels: Parallel contributions by endothelial selectins and vascular cell adhesion molecule 1","volume":"188","author":"Mazo","year":"1998","journal-title":"J. Exp. Med."}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/14\/1\/96\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:31:25Z","timestamp":1759919485000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/14\/1\/96"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,18]]},"references-count":34,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["biology14010096"],"URL":"https:\/\/doi.org\/10.3390\/biology14010096","relation":{},"ISSN":["2079-7737"],"issn-type":[{"type":"electronic","value":"2079-7737"}],"subject":[],"published":{"date-parts":[[2025,1,18]]}}}