title: Ex vivo expansion of human outgrowth endothelial cells leads to IL-8-mediated replicative senescence and impaired vasoreparative function.
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, β-galactosidase activity, DNA damage, tumor 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 signaling pathways as major mechanistic components of the OEC senescence program. 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. This study also suggests that modulation of the senescence-associated secretory phenotype could be used to optimize OEC therapy.
authors: Centre for Vision and Vascular Science and.
authors: Reinhold J
authors: RJ
authors: Medina
authors: Christina L
authors: CL
authors: O'Neill
authors: T Michelle
authors: TM
authors: O'Doherty
authors: Sarah E J
authors: SE
authors: Chambers
authors: Jasenka
authors: J
authors: Guduric-Fuchs
authors: Jessica
authors: J
authors: Neisen
authors: David J
authors: DJ
authors: Waugh
authors: David A
authors: DA
authors: Simpson
authors: Alan W
authors: AW
authors: Stitt
mesh_terms: D000328:Adult; D000818:Animals; D064987:Cell- and Tissue-Based Therapy; D016922:Cellular Senescence / Q000502:physiology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism*; D005123:Eye / Q000098:blood supply; D005312:Fetal Blood / Q000166:cytology; D055785:Gene Knockdown Techniques; D006801:Humans; D016209:Interleukin-8 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007511:Ischemia / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D012038:Regeneration / Q000502:physiology; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D016209:Interleukin-8; D034741:RNA, Small Interfering
keywords: Angiogenesis; Cell therapy; Endothelial progenitor; IL8; Senescence