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Urolithin A Alleviates Doxorubicin-Induced Senescence in Mesenchymal Stem Cells
Alexander Kalinin1,2, Ekaterina Zubkova1, Mikhail Menshikov1
1National Medical Research Centre of Cardiology Named After Academician E.I. Chazov, Moscow 121552, Russia.
Abstract:
The accumulation of senescent cells, characterized by a pro-inflammatory secretory phenotype (SASP), metabolic dysfunction, and irreversible cell cycle arrest, is a driving force behind numerous age-related pathologies and directly undermines the therapeutic potential of mesenchymal stem cells (MSCs). In this study, we explore the senotherapeutic potential of urolithin A, a renowned antioxidant compound, in human adipose-derived MSCs (AD-hMSCs). Our findings reveal that urolithin A is non-cytotoxic to senescent AD-hMSCs and significantly suppresses the SASP by reducing the secretion of key pro-inflammatory mediators, including MCP1, PAI2, and IL1B. In addition, it was demonstrated that urolithin A was capable of reversing the decline in H3K9me3 levels induced by Doxorubicin treatment, restoring them to levels observed in untreated cells. The results of this study suggest that urolithin A functions as a senomorphic agent, capable of modulating cellular senescence. Moreover, its combination with senolytic therapies has the potential to yield novel and effective treatment strategies for regenerative medicine.
Insights
Urolithin A, an antioxidant, effectively reduces the pro-inflammatory SASP in senescent mesenchymal stem cells (MSCs) without causing toxicity. This senomorphic agent shows promise for regenerative medicine, especially when combined with senolytic therapies.
Area of Science:
- Cellular senescence
- Regenerative medicine
- Molecular biology
Background:
- Cellular senescence, marked by SASP, drives age-related diseases and impairs MSC therapy.
- Senescent cells exhibit metabolic dysfunction and irreversible cell cycle arrest.
- Mesenchymal stem cells (MSCs) are crucial for regenerative medicine but are affected by senescence.
Purpose of the Study:
- To investigate the senotherapeutic potential of urolithin A in human adipose-derived MSCs (AD-MSCs).
- To assess urolithin A's effects on the senescence-associated secretory phenotype (SASP) and epigenetic modifications in senescent AD-MSCs.
Main Methods:
- Treatment of senescent AD-MSCs with urolithin A.
- Measurement of pro-inflammatory mediator secretion (MCP1, PAI2, IL1B).
- Analysis of H3K9me3 levels following Doxorubicin treatment and urolithin A intervention.
Main Results:
- Urolithin A demonstrated non-cytotoxicity in senescent AD-MSCs.
- Urolithin A significantly suppressed the SASP by reducing key pro-inflammatory cytokine secretion.
- Urolithin A reversed Doxorubicin-induced H3K9me3 decline, restoring normal levels.
Conclusions:
- Urolithin A acts as a senomorphic agent, modulating cellular senescence.
- Urolithin A holds potential for regenerative medicine, particularly in combination with senolytic therapies.
- Targeting cellular senescence with agents like urolithin A offers novel therapeutic strategies.
