학술논문
Deconstructing heterogeneity of replicative senescence in human mesenchymal stem cells at single cell resolution.
Document Type
Academic Journal
Author
Taherian Fard A; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Australia.; Leeson HC; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Australia.; Aguado J; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Australia.; Pietrogrande G; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Australia.; Power D; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Australia.; Gómez-Inclán C; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Australia.; Zheng H; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Australia.; Nelson CB; Children's Medical Research Institute, University of Sydney, Westmead, Sydney, NSW, Australia.; Soheilmoghaddam F; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Australia.; School of Chemical Engineering, Faculty of Engineering, Architecture and Information Technology, The University of Queensland, St Lucia, Australia.; Glass N; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Australia.; Dharmaratne M; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Australia.; Watson ER; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Australia.; Lu J; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Australia.; Martin S; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Australia.; School of Biomedical Sciences, Faculty of Medicine, University of Queensland, St Lucia, QLD, Australia.; Pickett HA; Children's Medical Research Institute, University of Sydney, Westmead, Sydney, NSW, Australia.; Cooper-White J; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Australia.; School of Chemical Engineering, Faculty of Engineering, Architecture and Information Technology, The University of Queensland, St Lucia, Australia.; Wolvetang EJ; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Australia. e.wolvetang@uq.edu.au.; Mar JC; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Australia. jessica.mar@uq.edu.au.
Source
Publisher: Springer International Publishing Country of Publication: Switzerland NLM ID: 101686284 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2509-2723 (Electronic) Linking ISSN: 25092723 NLM ISO Abbreviation: Geroscience Subsets: MEDLINE
Subject
Language
English
Abstract
Following prolonged cell division, mesenchymal stem cells enter replicative senescence, a state of permanent cell cycle arrest that constrains the use of this cell type in regenerative medicine applications and that in vivo substantially contributes to organismal ageing. Multiple cellular processes such as telomere dysfunction, DNA damage and oncogene activation are implicated in promoting replicative senescence, but whether mesenchymal stem cells enter different pre-senescent and senescent states has remained unclear. To address this knowledge gap, we subjected serially passaged human ESC-derived mesenchymal stem cells (esMSCs) to single cell profiling and single cell RNA-sequencing during their progressive entry into replicative senescence. We found that esMSC transitioned through newly identified pre-senescent cell states before entering into three different senescent cell states. By deconstructing this heterogeneity and temporally ordering these pre-senescent and senescent esMSC subpopulations into developmental trajectories, we identified markers and predicted drivers of these cell states. Regulatory networks that capture connections between genes at each timepoint demonstrated a loss of connectivity, and specific genes altered their gene expression distributions as cells entered senescence. Collectively, this data reconciles previous observations that identified different senescence programs within an individual cell type and should enable the design of novel senotherapeutic regimes that can overcome in vitro MSC expansion constraints or that can perhaps slow organismal ageing.
(© 2023. Crown.)
(© 2023. Crown.)