RT Journal Article
SR Electronic
T1 Deconstructing replicative senescence heterogeneity of human mesenchymal stem cells at single cell resolution reveals therapeutically targetable senescent cell sub-populations
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.01.24.476823
DO 10.1101/2022.01.24.476823
A1 Atefeh Taherian Fard
A1 Hannah Leeson
A1 Julio Aguado Perez
A1 Giovanni Pietrogrande
A1 Dominique Power
A1 Cecilia Liliana Gomez Inclan
A1 Huiwen Zheng
A1 Christopher Nelson
A1 Farhad Soheilmoghaddam
A1 Nick Glass
A1 Malindrie Dharmaratne
A1 Ebony R. Watson
A1 Jennifer Lu
A1 Sally Martin
A1 Hilda Pickett
A1 Justin Cooper-White
A1 Ernst Wolvetang
A1 Jessica C. Mar
YR 2022
UL http://biorxiv.org/content/early/2022/01/27/2022.01.24.476823.abstract
AB 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.Competing Interest StatementThe authors have declared no competing interest.