Work

Decreased miR-17-92 Cluster Correlates With the Senescent Features and Disrupted Oxidative Homeostasis, and the Impaired Therapeutic Efficacy of Adipose Tissue-derived Mesenchymal Stem Cells

Year: 2022

Type: preprint

Abstract: Background: Aging and replicative cellular senescence is associated with the reduced therapeutic potential of mesenchymal stem cells (MSCs) on variety of diseases. This study aimed to determine the mechanism in regulating MSC senescence and further explore a modification strategy to reverse the senescence-associated cell dysfunction for improving the therapeutic efficacy of MSCs on acute liver failure (ALF).Methods: Adipose tissue-derived MSCs from old-aged mice (oAMSCs) or young mice were intravenously administrated into the mice with lipopolysaccharide and D-galactosamine (LPS/GalN)-exposure and their effects were evaluated by serumbiochemical and liver histological analysis. SA-β-gal staining, expression analysis on p21, p16 and senescence-associated secretory phenotype markers, and reactive oxygen species (ROS) generation assay were used for determine the senescent features in aged AMSCs and replicative senescent AMSCs. MiRNA expression assay, small interfering RNA and miRNA transfection, and thioredoxin (TRX) activity assay were performed for further elucidate the mechanisms in AMSC senescence. MiRNA-modified AMSCs were used for determine whether cellular miR-17-92 cluster level can as an index to evaluate the therapeutic potential of AMSCs on ALF.Results: oAMSCs displayed senescent phenotypes and showed reduced therapeutic efficacy on LPS/GalN-induced ALF, as determined by reduced hepatic necrosis and serum liver function indicators, and inflammatory cytokine levels. Then we found that the miR-17-92 cluster, especially miR-17 and miR-20a, was obviously decreased in oAMSCs and replicative senescent AMSCs. The decreased miR-17-92 level was consistent with the declined oncogene c-Myc level during AMSC senescence and may mediate c-Myc stemness addiction. Further experiments revealed that miR-17-92 could modulate AMSC senescence by affecting the expression of classic senescence protein p21 and also the oxidative homeostasis in AMSCs through TXNIP-mediated TRX activity regulation. Furthermore, modification of AMSCs with the above two key miRNAs in miR-17-92 cluster could reverse the senescent features of oAMSCs and remodeling the therapeutic potential of senescent AMSCs on ALF.Conclusions: c-Myc-regulated miR-17-92 contributes to the increased p21 expression and dysregulated redox system during AMSC senescence. The cellular miR-17-92 cluster level can be used both as an index for evaluating and as a modification target for improving the therapeutic potential of AMSCs.

Source: Research Square

DOI: 10.21203/rs.3.rs-1333637/v1

Authors: Yelei Cen, Jinjin Qi, Liang Chen, Yanning Liu, Guohua Lou

Institutions: First Affiliated Hospital Zhejiang University, State Key Laboratory of Diagnosis and Treatment of Infectious Diseases, Zhejiang University

Language: English

Topic: Mesenchymal stem cell research

Subfield: Genetics

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funders: National Natural Science Foundation of China, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases