Culture expansion induces non-tumorigenic aneuploidy in adipose tissue-derived mesenchymal stromal cells |
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| Authors: | Marieke Roemeling-van Rhijn Annelies de Klein Hannie Douben Qiuwei Pan Luc J.W. van der Laan Jan N.M. Ijzermans Michiel G.H. Betjes Carla C. Baan Willem Weimar Martin J. Hoogduijn |
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| Affiliation: | 1. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands;2. Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands;3. Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, the Netherlands;4. Department of Surgery, Erasmus Medical Center, Rotterdam, the Netherlands;1. Blood Transfusion Center, Cell Engineering Laboratory, Botucatu Medical School, Universidade Estadual Paulista–UNESP, Botucatu, SP, Brazil;2. Department of Morphology, Extracellular Matrix Laboratory, Botucatu Biosciences Institute, Universidade Estadual Paulista–UNESP, Botucatu, SP, Brazil;3. Department of Urology, Botucatu Medical School, Universidade Estadual Paulista–UNESP, Botucatu, SP, Brazil;1. Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Austrian Cluster for Tissue Regeneration, Vienna, Austria;2. Red Cross Blood Transfusion Service of Upper Austria, Linz, Austria;3. Department of Biochemical Engineering, University of Applied Sciences Technikum Wien, Vienna, Austria;4. Miltenyi Biotech, Bergisch Gladbach, Germany;1. Embryonic Stem Cell Laboratories, Guy''s Assisted Conception Unit, Division of Women''s Health, King''s College School of Medicine, London, UK;2. St John''s Institute of Dermatology, Dermatology Research Laboratories, Guy''s Hospital, London, UK;3. Assisted Conception Unit, Guy''s and St Thomas'' Hospital Trust, London, UK;4. Cytogenetics Department, Guy''s and St Thomas'' Hospital Trust, London, UK;1. Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Kyoto, Japan;2. School of Biomedical Sciences, The University of Queensland, Brisbane, Australia;3. Commonwealth Scientific and Industrial Research Organization (CSIRO), Agriculture Flagship, St Lucia, QLD 4067, Australia;1. Department of Adult Stem Cell, Institute of Reproduction and Stem Cell Engineering, Central South University, Changsha, Hunan, China;2. Department of Adult Stem Cell, National Engineering and Research Center of Human Stem Cell, Changsha, Hunan, China |
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| Abstract: | Background aimsAdipose tissue-derived mesenchymal stromal cells (ASCs) are of interest as a cell therapeutic agent for immunologic and degenerative diseases. During in vitro expansion, ASCs may be at risk for genetic alterations, and genetic screening is a prerequisite. We examined the presence of aneuploidy in ASCs and its origin and development during culture and evaluated the implications of aneuploidy for therapeutic use of ASCs.MethodsAdipose tissue of healthy individuals was used for isolation and expansion of ASCs. Chromosome copy numbers were studied using fluorescence in situ hybridization analysis. Aneuploidy was studied in freshly isolated ASCs, in ASCs cultured for 0–16 passages and in senescent cultures. To evaluate the plasticity of ploidy, ASCs were cloned, and the variation of ploidy in the clones was examined. Tumorigenicity was studied by subcutaneous injection of aneuploid ASCs in immunodeficient NOD/SCID mice.ResultsNo aneuploidy was detected in freshly isolated ASCs. In low passages (passages 0–4), aneuploidy was detected in 3.4% of ASCs. Prolonged culture expansion of ASCs (passages 5–16) resulted in a significant increase of aneuploidy to 7.1%. With senescence, aneuploidy increased further to 19.8%. Aneuploidy was observed in clones of diploid ASCs, demonstrating the de novo development of aneuploidy. No transformation of ASCs was observed, and in contrast to cancer cell lines, aneuploid ASCs were incapable of tumor formation in immunodeficient mice.ConclusionsASC cultures contain a stable percentage of aneuploid cells. Aneuploidy was not a predecessor of transformation or tumor formation. This finding indicates that aneuploidy is culture-induced but unlikely to compromise clinical application of ASCs. |
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| Keywords: | adipose tissue aneuploidy clinical application mesenchymal stromal cell senescence transformation |
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