Long-term cultured mesenchymal stem cells frequently develop genomic mutations but do not undergo malignant transformation

Wang, Y.; Han, Zhi Bo; Zhang, Z.; Chi, Yuling; Yang, Zhouxin; Yang, Shaoguang; Sha, Yan; Mao, Aibin; Zhang, Jia-Ying; Xu, Fengming; Liang, Lihong; Zhang, Q.; Yang, Yadong; Wang, S.; Meng, Lingjun; Cui, Jiantao; Y, Ji; Fang, Xiangdong; Han, Zhongchao

doi:10.1016/j.jcyt.2014.01.279

Cited by 36 publications

(46 citation statements)

References 36 publications

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“…More recently, polyploid aberrant metaphases (loss of chromosomes 2, 3,5,6,7,8,9, and 16 in ∼ 70% of the cells) were found in 4 human dental pulp-derived MSC lines, in association with the presence of ring chromosomes ( table 2 ) [Duailibi et al, 2012]. Finally, data on chorionic villi-, human umbilical cord-and amniotic fluid-derived MSCs showed normal chromosome complements after 6-10 passages [Poloni et al, 2011;Wang et al, 2013;Ruan et al, 2014] or after 150 days of cryopreservation [Angelo et al, 2012].…”

Section: Mesenchymal Stromal Stem Cellsmentioning

confidence: 99%

Chromosomal Abnormalities in Embryonic and Somatic Stem Cells

Rebuzzini¹,

Zuccotti

Redi³

et al. 2015

Cytogenet Genome Res

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The potential use of stem cells (SCs) for tissue engineering, regenerative medicine, disease modeling, toxicological studies, drug delivery, and as in vitro model for the study of basic developmental processes implies large-scale in vitro culture. Here, after a brief description of the main techniques used for karyotype analysis, we will give a detailed overview of the chromosome abnormalities described in pluripotent (embryonic and induced pluripotent SCs) and somatic SCs, and the possible causes of their origin during culture.

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Section: Mesenchymal Stromal Stem Cellsmentioning

confidence: 99%

Chromosomal Abnormalities in Embryonic and Somatic Stem Cells

Rebuzzini¹,

Zuccotti

Redi³

et al. 2015

Cytogenet Genome Res

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“…Moreover, 162 different genes related to stemness were evaluated with quantitative real time Polymerase Chain Reaction (RT -PCR) after 7 passage showed similarity with 156 genes. In contrast reports of Wang et al [18] suggested that human umbilical cord derived mesenchymal stem cells cultured upto 30 passages to attain a large number of cells, developed genomic alterations which do not undergo malignant transformation.…”

Section: Introductionmentioning

confidence: 77%

A Novel Stem Cell Paradigm: Past Controversies, Present Challenges & Future Prospects

Vakodikar¹,

Thadani²,

Kshatriya³

2017

J Stem Cell Res Ther

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“…The use of hypoxia remains controversial; several studies have reported that hypoxia either compromised genomic stability or had no significant effect . In addition, spontaneous transformations of human MSCs during in vitro expansions have been reported, but these results were not confirmed by other studies and were finally retracted .…”

Section: Discussionmentioning

confidence: 93%

“…However, the in vitro expansion of MSCs presents some major challenges . Cultures are usually performed under 21% O 2 , a condition that does not reproduce the physiological context of the tissue niches and that promotes replicative stress, leading to genetic instability and senescence as well as a loss of viability or stem cell features .…”

Section: Introductionmentioning

confidence: 99%

Hypoxia Differentially Modulates the Genomic Stability of Clinical-Grade ADSCs and BM-MSCs in Long-Term Culture

et al. 2015

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Long-term cultures under hypoxic conditions have been demonstrated to maintain the phenotype of mesenchymal stromal/stem cells (MSCs) and to prevent the emergence of senescence. According to several studies, hypoxia has frequently been reported to drive genomic instability in cancer cells and in MSCs by hindering the DNA damage response and DNA repair. Thus, we evaluated the occurrence of DNA damage and repair events during the ex vivo expansion of clinical-grade adipose-derived stromal cells (ADSCs) and bone marrow (BM)-derived MSCs cultured with platelet lysate under 21% (normoxia) or 1% (hypoxia) O 2 conditions. Hypoxia did not impair cell survival after DNA damage, regardless of MSC origin. However, ADSCs, unlike BMMSCs, displayed altered cH2AX signaling and increased ubiquitylated cH2AX levels under hypoxic conditions, indicating an impaired resolution of DNA damage-induced foci. Moreover, hypoxia specifically promoted BM-MSC DNA integrity, with increased Ku80, TP53BP1, BRCA1, and RAD51 expression levels and more efficient nonhomologous end joining and homologous recombination repair. We further observed that hypoxia favored mtDNA stability and maintenance of differentiation potential after genotoxic stress. We conclude that long-term cultures under 1% O 2 were more suitable for BM-MSCs as suggested by improved genomic stability compared with ADSCs. STEM CELLS 2015;33:3608-3620 SIGNIFICANCE STATEMENTHuman mesenchymal stem cells (MSCs) feature differentiation capacities, immunomodulatory properties and therefore represent a great potential for medicine. In vitro culture allows their amplification for suitable clinical uses. Hypoxia seems relevant for the prevention of senescence and loss of MSC features. However, hypoxia is shown to promote cancer or DNA damage response (DDR) and repair failures. We demonstrate that long-term culture of MSCs with platelet lysate in hypoxia does not necessarily inhibit DDR and DNA repair. Here, bone marrowMSCs conserved or rather improved their DDR and DNA repair (NHEJ, HR), mtDNA stability in hypoxia compared to adipose-derived stem cells. Moreover, the ubiquitylation status of gH2AX between BM-MSCs and ADSCs might be responsible for changes in their DNA repair activities. Appropriate oxygen tension seems crucial to preserve the MSCs genomic stability according to their origins.

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Long-term cultured mesenchymal stem cells frequently develop genomic mutations but do not undergo malignant transformation

Cited by 36 publications

References 36 publications

Chromosomal Abnormalities in Embryonic and Somatic Stem Cells

Chromosomal Abnormalities in Embryonic and Somatic Stem Cells

A Novel Stem Cell Paradigm: Past Controversies, Present Challenges & Future Prospects

Hypoxia Differentially Modulates the Genomic Stability of Clinical-Grade ADSCs and BM-MSCs in Long-Term Culture

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