Ex Vivo Expansion of Human Outgrowth Endothelial Cells Leads to IL-8-Mediated Replicative Senescence and Impaired Vasoreparative Function

Reinhold J. Medina, Christina L. O'Neill, T. Michelle O'Doherty, Sarah E.J. Chambers, Jasenka Guduric-Fuchs, Jessica Neisen, David J. Waugh, David A. Simpson, Alan W. Stitt

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43 Citations (Scopus)
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Abstract

Harnessing outgrowth endothelial cells (OECs) for vasoreparative therapy and tissue-engineering requires efficient ex-vivo expansion. How such expansion impacts on OEC function is largely unknown. In this study, we show that OECs become permanently cell-cycle arrested after ex-vivo expansion, which is associated with enlarged cell size, ß-galactosidase activity, DNA damage, tumour suppressor pathway activation and significant transcriptome changes. These senescence hallmarks were coupled with low telomerase activity and telomere shortening, indicating replicative senescence. OEC senescence limited their regenerative potential by impairing vasoreparative properties in-vitro and in-vivo. Integrated transcriptome-proteome analysis identified inflammatory signalling pathways as major mechanistic components of the OEC senescence programme. In particular, IL8 was an important facilitator of this senescence; depletion of IL8 in OECs significantly extended ex-vivo lifespan, delayed replicative senescence and enhanced function. While the ability to expand OEC numbers prior to autologous or allogeneic therapy remains a useful property, their replicative senescence and associated impairment of vasorepair needs to be considered. The current study also suggests that modulation of the senescence-associated secretory phenotype (SASP) could be used to optimise OEC therapy.
Original languageEnglish
Pages (from-to)1657-1668
Number of pages12
JournalStem Cells
Volume31
Issue number8
DOIs
Publication statusPublished - Aug 2013

Keywords

  • Angiogenesis
  • Cell therapy
  • Endothelial progenitor
  • IL8
  • Senescence

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine

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