{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T03:05:01Z","timestamp":1740107101848,"version":"3.37.3"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2019,12,24]],"date-time":"2019-12-24T00:00:00Z","timestamp":1577145600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,12,24]],"date-time":"2019-12-24T00:00:00Z","timestamp":1577145600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"SciPharm","award":["FA641A0113"],"award-info":[{"award-number":["FA641A0113"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Mol Med"],"published-print":{"date-parts":[[2020,2]]},"abstract":"<jats:sec>\n                <jats:title>Abstract<\/jats:title>\n                <jats:p>The cell dose in umbilical cord blood units is a major determinant for the outcome of hematopoietic cell transplantation. Prostaglandin analogs and dipeptidylpeptidase-4 (DPP4\/CD26)-inhibitors enhance the ability of hematopoietic stem cells (HSCs) to reconstitute hematopoiesis. Here we explored the synergism between treprostinil, a stable prostaglandin agonist, and the DPP4\/CD26-inhibitor vildagliptin. The combination of treprostinil and forskolin caused a modest but statistically significant increase in the surface levels of DPP4\/CD26 on hematopoietic stem and progenitor cells (HSPCs) derived from murine bone and human cord blood. Their migration towards stromal cell-derived factor-1 (SDF-1\/CXCL12) was enhanced, if they were pretreated with treprostinil and forskolin, and further augmented by vildagliptin. Administration of vildagliptin rescued 25% of lethally irradiated recipient mice injected with a limiting number of untreated HSPCs, but 90 to 100% of recipients injected with HSPCs preincubated with treprostinil and forskolin. The efficacy of vildagliptin surpassed that of treprostinil (60% rescue). Surprisingly, concomitant administration of vildagliptin and treprostinil resulted in poor survival of recipients indicating mutual antagonism, which was recapitulated when homing of and colony formation by HSPCs were assessed. These observations of regimen-dependent synergism and antagonism of treprostinil and vildagliptin are of translational relevance for the design of clinical trials.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Key messages<\/jats:title>\n                <jats:p><jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Pretreatment with treprostinil increases surface levels of DPP4\/CD26 in HSPCs.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Vildagliptin enhances in vitro migration of pretreated HSPCs.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Vildagliptin enhances in vivo homing and engraftment of pretreated HSPCs.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Unexpected mutual antagonism in vivo by concomitant administration of vildagliptin and treprostinil.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list><\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00109-019-01869-8","type":"journal-article","created":{"date-parts":[[2019,12,24]],"date-time":"2019-12-24T07:30:21Z","timestamp":1577172621000},"page":"233-243","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Regimen-dependent synergism and antagonism of treprostinil and vildagliptin in hematopoietic cell transplantation"],"prefix":"10.1007","volume":"98","author":[{"given":"Eva","family":"Zebedin-Brandl","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madeleine","family":"Themanns","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zahra","family":"Kazemi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shahrooz","family":"Nasrollahi-Shirazi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marion","family":"Mussbacher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Heyes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katrin","family":"Meissl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michaela","family":"Prchal-Murphy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wolfgang","family":"Strohmaier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guenther","family":"Krumpl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9398-1765","authenticated-orcid":false,"given":"Michael","family":"Freissmuth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,12,24]]},"reference":[{"key":"1869_CR1","doi-asserted-by":"publisher","first-page":"470","DOI":"10.3389\/fimmu.2016.00470","volume":"7","author":"MK Juric","year":"2016","unstructured":"Juric MK, Ghimire S, Ogonek J, Weissinger EM, Holler E, van Rood JJ, Oudshoorn M, Dickinson A, Greinix HT (2016) Milestones of hematopoietic stem cell transplantation - from first human studies to current developments. 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Front Immunol 9:1387","journal-title":"Front Immunol"}],"container-title":["Journal of Molecular Medicine"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s00109-019-01869-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1007\/s00109-019-01869-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s00109-019-01869-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,12,23]],"date-time":"2020-12-23T00:19:24Z","timestamp":1608682764000},"score":1,"resource":{"primary":{"URL":"http:\/\/link.springer.com\/10.1007\/s00109-019-01869-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,24]]},"references-count":27,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2020,2]]}},"alternative-id":["1869"],"URL":"https:\/\/doi.org\/10.1007\/s00109-019-01869-8","relation":{},"ISSN":["0946-2716","1432-1440"],"issn-type":[{"type":"print","value":"0946-2716"},{"type":"electronic","value":"1432-1440"}],"subject":[],"published":{"date-parts":[[2019,12,24]]},"assertion":[{"value":"21 June 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 November 2019","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 December 2019","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 December 2019","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Human umbilical cord blood samples were obtained at the General Hospital Vienna (AKH), University Clinic of Gynaecology and Obstetrics, Department of Obstetrics and Fetomaternal Medicine, W\u00e4hringer G\u00fcrtel 18-20, 1090 Vienna, Austria. The protocol was approved by the local ethics committee of the Medical University of Vienna (EC number 1553\/2014) and conducted according to the Declaration of Helsinki (1969, including current revisions) of the World Medical Association. Written informed consent to donate umbilical cord blood was obtained of the study participants.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"The animal study protocols were reviewed by the animal ethics committee of the Veterinary University of Vienna, approved by the Austrian Ministry of Science and Research under licenses BMWFW-68.205\/0103-WF\/V\/3b\/2015 and BMWFW-68.205\/0047-V\/3b\/2018 and conducted according to the guidelines of FELASA and ARRIVE.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"WS is a consultant to SciPharm; all other authors declare that they have no conflict of interest.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}