{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T07:21:12Z","timestamp":1791098472877,"version":"4.1.0"},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2016,3,31]],"date-time":"2016-03-31T00:00:00Z","timestamp":1459382400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"European Union Seventh Framework Project CELL-PID and Deutsche Forschungsgemeinschaft","award":["FE568\/11-2"],"award-info":[{"award-number":["FE568\/11-2"]}]},{"name":"Cluster of Excellence REBIRTH","award":["Exc 62\/1"],"award-info":[{"award-number":["Exc 62\/1"]}]},{"name":"SFB","award":["738"],"award-info":[{"award-number":["738"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>Mesenchymal stem (or stromal) cells (MSCs) have been used in more than 400 clinical trials for the treatment of various diseases. The clinical benefit and reproducibility of results, however, remain extremely variable. During the in vitro expansion phase, which is necessary to achieve clinically relevant cell numbers, MSCs show signs of aging accompanied by different contributions of single clones to the mass culture. Here we used multicolor lentiviral barcode labeling to follow the clonal dynamics during in vitro MSC expansion from whole umbilical cord pieces (UCPs). The clonal composition was analyzed by a combination of flow cytometry, fluorescence microscopy, and deep sequencing. Starting with highly complex cell populations, we observed a massive reduction in diversity, transiently dominating populations, and a selection of single clones over time. Importantly, the first wave of clonal constriction already occurred in the early passages during MSC expansion. Consecutive MSC cultures from the same UCP implied the existence of more primitive, MSC culture-initiating cells. Our results show that microscopically homogenous MSC mass cultures consist of many subpopulations, which undergo clonal selection and have different capabilities. Among other factors, the clonal composition of the graft might have an impact on the functional properties of MSCs in experimental and clinical settings.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>Mesenchymal stem cells (MSCs) can easily be obtained from various adult or embryonal tissues and are frequently used in clinical trials. For their clinical application, MSCs have to be expanded in vitro. This unavoidable step influences the features of MSCs, so that clinical benefit and experimental results are often highly variable. Despite a homogenous appearance under the microscope, MSC cultures undergo massive clonal selection over time. Multicolor fluorescence labeling and deep sequencing were used to demonstrate the dynamic clonal composition of MSC cultures, which might ultimately explain the variable clinical performance of the cells.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.5966\/sctm.2015-0176","type":"journal-article","created":{"date-parts":[[2016,3,31]],"date-time":"2016-03-31T23:44:54Z","timestamp":1459467894000},"page":"591-601","source":"Crossref","is-referenced-by-count":90,"title":["Massive Clonal Selection and Transiently Contributing Clones During Expansion of Mesenchymal Stem Cell Cultures Revealed by Lentiviral RGB-Barcode Technology"],"prefix":"10.1093","volume":"5","author":[{"given":"Anton","family":"Selich","sequence":"first","affiliation":[{"name":"Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jannik","family":"Daudert","sequence":"additional","affiliation":[{"name":"Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Hass","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friederike","family":"Philipp","sequence":"additional","affiliation":[{"name":"Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany"},{"name":"Department of Pathology, Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constantin","family":"von Kaisenberg","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabi","family":"Paul","sequence":"additional","affiliation":[{"name":"Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin","family":"Cornils","sequence":"additional","affiliation":[{"name":"Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boris","family":"Fehse","sequence":"additional","affiliation":[{"name":"Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Rittinghausen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel","family":"Schambach","sequence":"additional","affiliation":[{"name":"Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany"},{"name":"Division of Hematology\/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Rothe","sequence":"additional","affiliation":[{"name":"Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,3,31]]},"reference":[{"key":"2021122705022945900_R1","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1097\/00007890-196803000-00009","article-title":"Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues","volume":"6","author":"Friedenstein","year":"1968","journal-title":"Transplantation"},{"key":"2021122705022945900_R2","doi-asserted-by":"crossref","first-page":"975871","DOI":"10.1155\/2012\/975871","article-title":"Markers for characterization of bone marrow multipotential stromal cells","volume":"2012","author":"Boxall","year":"2012","journal-title":"Stem Cells Int"},{"key":"2021122705022945900_R3","doi-asserted-by":"crossref","first-page":"1418","DOI":"10.1111\/trf.12421","article-title":"Mesenchymal stem or stromal cells: a review of clinical applications and manufacturing practices","volume":"54","author":"Sharma","year":"2014","journal-title":"Transfusion"},{"key":"2021122705022945900_R4","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.1089\/hum.2010.156","article-title":"Immunological aspects of allogeneic mesenchymal stem cell therapies","volume":"21","author":"Griffin","year":"2010","journal-title":"Hum Gene Ther"},{"key":"2021122705022945900_R5","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.jcyt.2014.04.002","article-title":"Standardization of Good Manufacturing Practice-compliant production of bone marrow-derived human mesenchymal stromal cells for immunotherapeutic applications","volume":"17","author":"Wuchter","year":"2015","journal-title":"Cytotherapy"},{"key":"2021122705022945900_R6","doi-asserted-by":"crossref","first-page":"196","DOI":"10.3390\/ph8020196","article-title":"Wharton's jelly-derived mesenchymal stromal cells as a promising cellular therapeutic strategy for the management of graft-versus-host disease","volume":"8","author":"McGuirk","year":"2015","journal-title":"Pharmaceuticals (Basel)"},{"key":"2021122705022945900_R7","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1002\/jcp.21940","article-title":"Regulation of stemness and stem cell niche of mesenchymal stem cells: Implications in tumorigenesis and metastasis","volume":"222","author":"Kuhn","year":"2010","journal-title":"J Cell Physiol"},{"key":"2021122705022945900_R8","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.stem.2014.11.004","article-title":"Perivascular Gli1+ progenitors are key contributors to injury-induced organ fibrosis","volume":"16","author":"Kramann","year":"2015","journal-title":"Cell Stem Cell"},{"key":"2021122705022945900_R9","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1080\/14653240600855905","article-title":"Minimal criteria for defining multipotent mesenchymal stromal cells. 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