4.6 Article

Paracrine Senescence of Mesenchymal Stromal Cells Involves Inflammatory Cytokines and the NF-κB Pathway

期刊

CELLS
卷 11, 期 20, 页码 -

出版社

MDPI
DOI: 10.3390/ce11s11203324

关键词

mesenchymal stromal cells; paracrine; IL-1 alpha; IL-8; NF-kappa B; senescence; senescence-associated secretory phenotype (SASP)

资金

  1. Minister of Science and Technology [MOST 1112326-B-039 -001, 109-2321-B-039 -003]
  2. China Medical University [CMU110-Z-05]
  3. China Medical University Hospital [DMR-108-BC-5, DMR-111-233]

向作者/读者索取更多资源

This study reveals that late MSCs display senescence features and that proinflammatory cytokines from late MSCs contribute to the cellular senescence of early MSCs via paracrine signaling, ultimately impairing their functionality.
It has been known that senescence-associated secretory phenotype (SASP) triggers senescence of the surrounding normal cells. However, SASP signaling regarding mesenchymal stromal cell aging remains to be fully elucidated. Therefore, the present study aimed to clarify the molecular mechanism of late (passage) MSC-induced paracrine SASP-mediated senescence of early (passage) MSCs during ex vivo expansion. Here, we conducted an extensive characterization of senescence features in bone-marrow (BM)-derived MSCs from healthy human donors. Late MSCs displayed an enlarged senescent-like morphology, induced SASP-related proinflammatory cytokines (IL-1 alpha and IL-8), and reduced clonogenic capacity and osteogenic differentiation when compared to early MSCs. Of note, paracrine effects of SASP-related IL-1 alpha and IL-8 from late MSCs induced cellular senescence of early MSCs via an NF-kappa B-dependent manner. Moreover, cellular senescence of early MSCs was promoted by the synergistic action of IL-1 alpha and IL-8. However, inhibition of NF-kappa B by shRNA transfection or using inhibitors in early MSCs blocked early MSCs cellular senescence caused by paracrine SASP of late MSCs. In conclusion, these findings reveal that late MSCs display features of senescence and that, during ex vivo expansion, SASP-related proinflammatory cytokines contribute to activate a cellular senescence program in early MSCs that may ultimately impair their functionality.

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