TWIST1 controls cellular senescence and energy metabolism in mesenchymal stem cells

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Abstract

Mesenchymal stem cells (MSCs) are promising cells for regenerative medicine therapies because they can differentiate towards multiple cell lineages. However, the occurrence of cellular senescence and the acquiring of the senescence-associated secretory phenotype (SASP) limit their clinical use. Since the transcription factor TWIST1 influences expansion of MSCs, its role in regulating cellular senescence was investigated. The present study demonstrated that silencing of TWIST1 in MSCs increased the occurrence of senescence, characterised by a SASP profile different from irradiation-induced senescent MSCs. Knowing that senescence alters cellular metabolism, cellular bioenergetics was monitored by using the Seahorse XF apparatus. Both TWIST1-silencing-induced and irradiation-induced senescent MSCs had a higher oxygen consumption rate compared to control MSCs, while TWIST1-silencing-induced senescent MSCs had a low extracellular acidification rate compared to irradiation-induced senescent MSCs. Overall, data indicated how TWIST1 regulation influenced senescence in MSCs and that TWIST1 silencing-induced senescence was characterised by a specific SASP profile and metabolic state.

Original languageEnglish
Pages (from-to)401-414
Number of pages14
JournalEuropean cells & materials
Volume42
DOIs
Publication statusPublished - 25 Nov 2021

Bibliographical note

Acknowledgements:
The authors would like to thank Andrea Lolli for
advice on the TWIST1 silencing protocol, Eric
Farrell and Janneke Witte-Bouma for access to
their source of MSCs, Nicole Kops and Arielle
Molina Rakos for technical assistance with the
senescence-associated β-galactosidase staining
and quantification, Marius Wernig’s laboratory
(Stanford School of Medicine, Sandford, CA, USA)
for providing the GFP overexpression construct and
the lentiviral packaging constructs, the FACS sorting
facility at the Erasmus MC for support with the BD
LSRFortessa™ Cell Analyzer.
This research was financially supported by the
Dutch Arthritis Society (ReumaNederland; 16-1-201)
and by a TTW Perspectief grant from NWO (William
Hunter Revisited; P15-23). This study is part of the
Medical Delta RegMed4D program and the Erasmus
Postgraduate School Molecular Medicine.
The authors have no conflict of interest to declare.

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