Embryonic Stem Cell-Derived mmu-miR-291a-3p Inhibits Cellular Senescence in Human Dermal Fibroblasts Through the TGF-β Receptor 2 Pathway

Yun Ui Bae, Youlim Son, Chang Hyun Kim, Kwang Seok Kim, Se Hee Hyun, Hyun Goo Woo, Byul A. Jee, Jun Hyuk Choi, Hoon Ki Sung, Hyung Chul Choi, So Young Park, Ju Hyun Bae, Kyung Oh Doh, Jae Ryong Kim, Isabel Beerman, Joshua Hare

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Senescent cells accumulate in various tissues over time and contribute to tissue dysfunction and aging-associated phenotypes. Accumulating evidence suggests that cellular senescence can be inhibited through pharmacological intervention, as well as through treatment with soluble factors derived from embryonic stem cells (ESCs). In an attempt to investigate the anti-senescence factors secreted by ESCs, we analyzed mouse ESC-derived extracellular microRNAs in conditioned medium via microRNA array analysis. We selected mmu-miR-291a-3p as a putative anti-senescence factor via bioinformatics analysis. We validated its inhibitory effects on replicative, Adriamycin-induced, and ionizing radiation-induced senescence in human dermal fibroblasts. Treatment of senescent cells with mmu-miR-291a-3p decreased senescence-associated β-galactosidase activity, enhanced proliferative potential, and reduced mRNA and protein expression of TGF-β receptor 2, p53, and p21. mmu-miR-291a-3p in conditioned medium was enclosed in ESC-derived exosomes and exosomes purified from ESC conditioned medium inhibited cellular senescence. The inhibitory effects of mmu-miR-291a-3p were mediated through the TGF-β receptor 2 signaling pathway. Hsa-miR-371a-3p and hsa-miR-520e, the human homologs of mmu-miR-291a-3p, showed similar anti-senescence activity. Furthermore, mmu-miR-291a-3p accelerated the excisional skin wound healing process in aged mice. Our results indicate that the ESC-derived mmu-miR-291a-3p is a novel candidate agent that can be utilized for cell-free therapeutic intervention against aging and aging-related diseases.

Original languageEnglish (US)
Pages (from-to)1359-1367
Number of pages9
JournalJournals of Gerontology - Series A Biological Sciences and Medical Sciences
Volume74
Issue number9
DOIs
StatePublished - Aug 16 2019

Keywords

  • Anti-senescence
  • Cellular senescence
  • Embryonic stem cells
  • mmu-miR-291a-3p
  • TGF-β-receptor 2

ASJC Scopus subject areas

  • Aging
  • Geriatrics and Gerontology

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    Bae, Y. U., Son, Y., Kim, C. H., Kim, K. S., Hyun, S. H., Woo, H. G., Jee, B. A., Choi, J. H., Sung, H. K., Choi, H. C., Park, S. Y., Bae, J. H., Doh, K. O., Kim, J. R., Beerman, I., & Hare, J. (2019). Embryonic Stem Cell-Derived mmu-miR-291a-3p Inhibits Cellular Senescence in Human Dermal Fibroblasts Through the TGF-β Receptor 2 Pathway. Journals of Gerontology - Series A Biological Sciences and Medical Sciences, 74(9), 1359-1367. https://doi.org/10.1093/gerona/gly208