Long-term cultured mesenchymal stem cells frequently develop genomic mutations but do not undergo malignant transformation
Open accessAbstract
Cultured human umbilical cord mesenchymal stem cells (hUC-MSCs) are being tested in several clinical trials and encouraging outcomes have been observed. To determine whether in vitro expansion influences the genomic stability of hUC-MSCs, we maintained nine hUC-MSC clones in long-term culture and comparatively analyzed them at early and late passages. All of the clones senesced in culture, exhibiting decreased telomerase activity and shortened telomeres. Two clones showed no DNA copy number variations (CNVs) at passage 30 (P30). Seven clones had ≥1 CNVs at P30 compared with P3, and one of these clones appeared trisomic chromosome 10 at the late passage. No tumor developed in immunodeficient mice injected with hUC-MSCs, regardless of whether the cells had CNVs at the late passage. mRNA-Seq analysis indicated that pathways of cell cycle control and DNA damage response were downregulated during in vitro culture in hUC-MSC clones that showed genomic instability, but the same pathways were upregulated in the clones with good genomic stability. These results demonstrated that hUC-MSCs can be cultured for many passages and attain a large number of cells, but most of the cultured hUC-MSCs develop genomic alterations. Although hUC-MSCs with genomic alterations do not undergo malignant transformation, periodic genomic monitoring and donor management focusing on genomic stability are recommended before these cells are used for clinical applications.
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Chromosomal abnormalities in culture-expanded MSCs appear to be linked to cell senescence due to extensive passaging, rather than tumorigenesis.
“Interestingly, chromosomal abnormalities in culture-expanded MSCs appear to be linked to cell senescence due to extensive passaging, rather than tumorigenesis [41,43,44].”
From Mesenchymal Stem/Stromal Cells: Immunomodulatory and Bone Regeneration Potential after Tumor Excision in Osteosarcoma Patients (2023) · cites this paper as [44]
The Abstract reports that all nine long-term-cultured hUC-MSC clones senesced, most developed genomic alterations, and none formed tumors in immunodeficient mice. This supports the contrast with observed tumorigenesis, but the paper does not establish that chromosomal abnormalities are specifically linked to senescence: clones without detected copy-number changes also senesced. The Discussion also cautions that potential tumorigenicity cannot be completely ruled out. (LLM, conf=0.82)
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- Authors
- Wang, Y., Zhang, Z., Chi, Y., Zhang, Q., Xu, F., Yang, Z., Meng, L., Yang, S., Yan, S., Mao, A., Zhang, J., Yang, Y., Wang, S., Cui, J., Liang, L., Ji, Y., Han, Z.-B., Fang, X., & Han, Z. C.
- Affiliations
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Chinese Academy of Sciences (CN)
- Corresponding author
- Han, Z-B
- Fang, X
- Han, Z C
- Venue
- Cell Death & Disease
- Published
- 2013-12-05
- Volume
- 4
- Issue
- 12
- Pages
- e950-e950
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC3877551
- OpenAlex
- W2050018625
- Cited by
- 185
- References
- 47
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 12 · 2023: 11 · 2022: 24 · 2021: 16 · 2020: 7 · 2019: 16 · 2018: 18 · 2017: 20 · 2016: 19 · 2015: 19 · 2014: 7
- FWCI
- 7.39
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Death and Disease (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81330015, 973 Program, 31371300, 2011CB964802)
- Chinese Academy of Sciences
- National Key Research and Development Program of China (2011CB964802, 2011AA020118, 2011CB964800)
- Topics
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Keywords
- mesenchymal stem cells, human umbilical cord mesenchymal stem cells, genomic instability, copy number variation, telomere shortening, telomerase activity, cellular senescence, malignant transformation, DNA damage response, cell cycle regulation, long-term culture
- MeSH terms
- Cells, Cultured, Humans, Mutation, Phylogeny, Telomere, DNA Copy Number Variations, Mesenchymal Stem Cells, Karyotype
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