# The Secretome of Human Trophoblast Stem Cells Attenuates Senescence‐Associated Traits

## TL;DR

Human trophoblast stem cell secretions reduce harmful traits of aging cells, suggesting potential for anti-aging therapies.

## Contribution

Demonstrates that hTSC-derived secretome and EVs suppress SASP and DNA damage in senescent cells.

## Key findings

- hTSC-CM and EVs significantly reduced SASP factor mRNAs and secretions like CXCL1, IL8, and GDF15.
- hTSC-EVs suppressed DNA damage and inflammatory signaling via reduced NF-κB activity.
- Proteomic analysis showed enrichment in proteins related to cell adhesion and ECM remodeling.

## Abstract

Senescent cells display indefinite growth arrest and a pro‐inflammatory, senescence‐associated secretory phenotype (SASP). As the accumulation of senescent cells in tissues with age plays detrimental roles in age‐related pathologies, there is much interest in finding therapeutic strategies to eliminate them or suppress the SASP. In this study, we investigated the impact of the secretome and extracellular vesicles (EVs) derived from human trophoblast stem cells (hTSCs) on senescent human fibroblasts. We found that the hTSC conditioned medium (hTSC‐CM), and in particular the EVs (hTSC‐EVs), significantly reduced the levels of mRNAs encoding SASP factors and the secretion of SASP factors including CXCL1, IL8, and GDF15. Proteomic analysis of hTSC‐CM and EVs indicated an enrichment in proteins involved in cell adhesion, tissue repair, and remodeling of the extracellular matrix (ECM). Furthermore, incubation of senescent cells with hTSC‐EVs attenuated DNA damage and inflammatory signaling, at least in part by suppressing the function of NF‐κB, a major transcriptional regulator of the SASP program. Our findings underscore the value of hTSC‐CM and EVs therein in therapeutic approaches directed at senescent cells.

Human trophoblast stem cell‐derived secretome/conditioned medium (hTSC‐CM) and the extracellular vesicles (EVs) therein suppress DNA damage and NF‐κB activation in senescent fibroblasts, in turn reducing the production of senescence‐associated secretory phenotype (SASP) factors. This study highlights hTSC‐CM and EVs as potential senotherapeutic agents.