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

Lun-Yin Chou; Chun-Te Ho; Shih-Chieh Hung

doi:10.3390/cells11203324

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

Cells. 2022 Oct 21;11(20):3324. doi: 10.3390/cells11203324.

Authors

Lun-Yin Chou¹, Chun-Te Ho¹, Shih-Chieh Hung^{1

2

3}

Affiliations

¹ Integrative Stem Cell Center, China Medical University Hospital, Taichung 404, Taiwan.
² Drug Development Center, Institute of Translational Medicine and New Drug Development, School of Medicine, China Medical University, Taichung 406, Taiwan.
³ Department of Orthopaedics, China Medical University Hospital, Taichung 404, Taiwan.

Abstract

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-1α and IL-8), and reduced clonogenic capacity and osteogenic differentiation when compared to early MSCs. Of note, paracrine effects of SASP-related IL-1α and IL-8 from late MSCs induced cellular senescence of early MSCs via an NF-κB-dependent manner. Moreover, cellular senescence of early MSCs was promoted by the synergistic action of IL-1α and IL-8. However, inhibition of NF-κB 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.

Keywords: IL-1α; IL-8; NF-κB; mesenchymal stromal cells; paracrine; senescence; senescence-associated secretory phenotype (SASP).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Humans
Interleukin-8 / metabolism
Mesenchymal Stem Cells* / metabolism
NF-kappa B* / metabolism
Osteogenesis
RNA, Small Interfering / metabolism

Substances

NF-kappa B
RNA, Small Interfering
Interleukin-8

Grants and funding

This work was financially supported by Minister of Science and Technology (MOST 111-2326-B-039 -001; 109-2321-B-039 -003), China Medical University (CMU110-Z-05) and China Medical University Hospital (DMR-108-BC-5; DMR-111-233). The funding sources were not involved in study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the article for publication.