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

Area of Science:

• Cell Biology
• Stem Cell Biology
• Aging Research

Background:

• Senescence-associated secretory phenotype (SASP) is known to induce senescence in neighboring cells.
• The specific mechanisms of SASP signaling in mesenchymal stromal cell (MSC) aging require further investigation.
• Understanding MSC aging during ex vivo expansion is crucial for regenerative medicine applications.

Purpose of the Study:

• To elucidate the molecular mechanisms by which late-passage MSCs induce senescence in early-passage MSCs through paracrine SASP.
• To characterize senescence features in human bone marrow-derived MSCs at different passage numbers.
• To investigate the role of specific SASP factors and signaling pathways in MSC senescence.

Main Methods:

• Extensive characterization of senescence features in human bone marrow-derived MSCs.
• Analysis of SASP-related proinflammatory cytokines (IL-1α and IL-8) in late-passage MSCs.
• Investigating the effect of paracrine SASP from late MSCs on early MSCs, including NF-κB pathway modulation.

Main Results:

• Late-passage MSCs showed enlarged morphology, increased IL-1α and IL-8, and reduced differentiation capacity compared to early-passage MSCs.
• Paracrine IL-1α and IL-8 from late MSCs induced senescence in early MSCs via an NF-κB-dependent pathway.
• Synergistic action of IL-1α and IL-8 promoted early MSC senescence, which was blocked by NF-κB inhibition.

Conclusions:

• Late-passage MSCs exhibit senescence characteristics and a SASP.
• Ex vivo expansion of MSCs involves paracrine SASP-mediated senescence of early-passage MSCs.
• This senescence process, driven by IL-1α and IL-8 via NF-κB, can impair MSC functionality.