Attenuation of Cellular Senescence and Improvement of Osteogenic Differentiation Capacity of Human Liver Stem Cells Using Specific Senomorphic and Senolytic Agents

Abstract

Expansion of adult stem cells in culture increases the percent of senescent cells, reduces their differentiation capacity and limits their clinical use. Here, we investigated whether treatment with certain senotherapeutic drugs would reduce the accumulation of senescent cells during expansion of human liver stem cells (HLSCs) while maintaining their differentiation capacity. Our results demonstrate that chronic treatment with the senomorphic XJB-5-131 or the senolytics cocktail D + Q reduced the number of senescent cells and significantly reduced the expression of senescence-associated genes and several inflammatory SASP factors in later passage HLSCs. Additionally, treatment with XJB-5-131 and D + Q improved the capacity of HLSCs to undergo osteogenic differentiation following extensive in vitro expansion. Overall, our data demonstrate that treatment with XJB-5-13 or D + Q results in a reduction in the percentage of replication-induced senescent HLSCs and likely other types of adult stem cells and improve the potential therapeutic use of later passage human stem cells. Graphical abstract

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