PreprintCited by 3Telomeres, Telomerase, and SenescenceMesenchymal stem cell researchGenetics, Aging, and Longevity in Model Organisms

Deconstructing replicative senescence heterogeneity of human mesenchymal stem cells at single cell resolution reveals therapeutically targetable senescent cell sub-populations

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Fard, Atefeh Taherian, Leeson, Hannah, Perez, Julio Aguado, Pietrogrande, Giovanni, Power, Dominique, Inclan, Cecilia Liliana Gomez, Zheng, Huiwen, Nelson, Christopher +10 more·2022·bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Cellular senescence is characterised by a state of permanent cell cycle arrest. It is accompanied by often variable release of the so-called senescence-associated secretory phenotype (SASP) factors, and occurs in response to a variety of triggers such as persistent DNA damage, telomere dysfunction, or oncogene activation. While cellular senescence is a recognised driver of organismal ageing, the extent of heterogeneity within and between different senescent cell populations remains largely unclear. Elucidating the drivers and extent of variability in cellular senescence states is important for discovering novel targeted seno-therapeutics and for overcoming cell expansion constraints in the cell therapy industry. Here we combine cell biological and single cell RNA-sequencing approaches to investigate heterogeneity of replicative senescence in human ESC-derived mesenchymal stem cells (esMSCs) as MSCs are the cell type of choice for the majority of current stem cell therapies and senescence of MSC is a recognized driver of organismal ageing. Our data identify three senescent subpopulations in the senescing esMSC population that differ in SASP, oncogene expression, and escape from senescence. Uncovering and defining this heterogeneity of senescence states in cultured human esMSCs allowed us to identify potential drug targets that may delay the emergence of senescent MSCs in vitro and perhaps in vivo in the future.

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Authors
Fard, A. T., Leeson, H., Perez, J. A., Pietrogrande, G., Power, D., Inclan, C. L. G., Zheng, H., Nelson, C., Soheilmoghaddam, F., Glass, N., Dharmaratne, M., Watson, E. R., Lu, J., Martin, S., Pickett, H., Cooper-White, J., Wolvetang, E., & Mar, J. C.
Affiliations
  • The University of Queensland (AU)
  • The University of Sydney (AU)
Corresponding author
  • Wolvetang, Ernst
  • Mar, Jessica C.
Venue
bioRxiv (Cold Spring Harbor Laboratory)
Publisher
openRxiv
Published
2022-01-27
OpenAlex
W4225077734
Cited by
3
References
92
Citations by year
2025: 1 · 2024: 1 · 2023: 1
Type
posted content
Language
en
Open access
Locations
bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
replicative senescence, mesenchymal stem cells, senescence-associated secretory phenotype, senescence escape, oncogene expression, aging

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