Embryonic stem cell-derived extracellular vesicles rejuvenate senescent cells and antagonize aging in mice

Lu Yu; Hang Wen; Chang Liu; Chen Wang; Huaxin Yu; Kaiyue Zhang; Qingsheng Han; Yue Liu; Zhongchao Han; Zongjin Li; Na Liu

doi:10.1016/j.bioactmat.2023.06.011

Embryonic stem cell-derived extracellular vesicles rejuvenate senescent cells and antagonize aging in mice

Bioact Mater. 2023 Jul 1:29:85-97. doi: 10.1016/j.bioactmat.2023.06.011. eCollection 2023 Nov.

Authors

Lu Yu¹, Hang Wen¹, Chang Liu¹, Chen Wang¹, Huaxin Yu¹, Kaiyue Zhang¹, Qingsheng Han¹, Yue Liu¹, Zhongchao Han², Zongjin Li¹, Na Liu^{1

3}

Affiliations

¹ School of Medicine, Nankai University, Tianjin, 300071, China.
² Institute of Stem Cells, Health-Biotech (Tianjin) Stem Cell Research Institute Co., Ltd, Tianjin, 301700, China.
³ Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences Nankai University, Tianjin, 300071, China.

Abstract

Aging is a degenerative process that leads to tissue dysfunction and death. Embryonic stem cells (ESCs) have great therapeutic potential for age-related diseases due to their capacity for self-renewal and plasticity. However, the use of ESCs in clinical treatment is limited by immune rejection, tumourigenicity and ethical issues. ESC-derived extracellular vesicles (EVs) may provide therapeutic effects that are comparable to those of ESCs while avoiding unwanted effects. Here, we fully evaluate the role of ESC-EVs in rejuvenation in vitro and in vivo. Using RNA sequencing (RNA-Seq) and microRNA sequencing (miRNA-Seq) screening, we found that miR-15b-5p and miR-290a-5p were highly enriched in ESC-EVs, and induced rejuvenation by silencing the Ccn2-mediated AKT/mTOR pathway. These results demonstrate that miR-15b-5p and miR-290a-5p function as potent activators of rejuvenation mediated by ESC-EVs. The rejuvenating effect of ESC-EVs was further investigated in vivo by injection into aged mice. The results showed that ESC-EVs successfully ameliorated the pathological age-related phenotypes and rescued the transcriptome profile of aged mice. Our findings demonstrate that ESC-EVs treatment can rejuvenate senescence both in vitro and in vivo and suggest the therapeutic potential of ESC-EVs as a novel cell-free alternative to ESCs for age-related diseases.