Identification of miR-31-5p, miR-141-3p, miR-200c-3p, and GLT1 as human liver aging markers sensitive to donor-recipient age-mismatch in transplants

Abstract

SummaryTo understand why livers from aged donors are successfully used for transplants, we looked for markers of liver aging in 71 biopsies from donors aged 12–92 years before transplants and in 11 biopsies after transplants with high donor–recipient age‐mismatch. We also assessed liver function in 36 age‐mismatched recipients. The major findings were the following: (i) miR‐31‐5p, miR‐141‐3p, and miR‐200c‐3p increased with age, as assessed by microRNAs (miRs) and mRNA transcript profiling in 12 biopsies and results were validated by RT–qPCR in a total of 58 biopsies; (ii) telomere length measured by qPCR in 45 samples showed a significant age‐dependent shortage; (iii) a bioinformatic approach combining transcriptome and miRs data identified putative miRs targets, the most informative being GLT1, a glutamate transporter expressed in hepatocytes. GLT1 was demonstrated by luciferase assay to be a target of miR‐31‐5p and miR‐200c‐3p, and both its mRNA (RT–qPCR) and protein (immunohistochemistry) significantly decreased with age in liver biopsies and in hepatic centrilobular zone, respectively; (iv) miR‐31‐5p, miR‐141‐3p and miR‐200c‐3p expression was significantly affected by recipient age (older environment) as assessed in eleven cases of donor–recipient extreme age‐mismatch; (v) the analysis of recipients plasma by N‐glycans profiling, capable of assessing liver functions and biological age, showed that liver function recovered after transplants, independently of age‐mismatch, and recipients apparently ‘rejuvenated’ according to their glycomic age. In conclusion, we identified new markers of aging in human liver, their relevance in donor–recipient age‐mismatches in transplantation, and offered positive evidence for the use of organs from old donors.

MicroRNA Dysregulation Associated with Red Blood Cell Storage

“…However, evidence related to their role in other cell types could be an indication to understand their potential effect when increasing in RBCs. miR-31-5p is increased in aging endothelial cells isolated from umbilical cords, and it is considered as a human liver aging marker since it increases in livers of old age donors [37,38]. A recent study shows that miR-203a induces apoptosis in human scar fibroblasts [39].…”

MicroRNA‐31a‐5p from aging BMSCs links bone formation and resorption in the aged bone marrow microenvironment

“…In addition, miR‐31a‐5p has been reported to directly target bone relevant markers, such as RUNX2, OSX, and DKK1 (Baglio, Devescovi, Granchi, & Baldini, 2013; Deng, Wu et al., 2013; Gao et al., 2011; Lv et al., 2017). Furthermore, it has been reported that regulation of miR‐31a‐5p expression could be used to modulate senescence‐related pathological conditions such as cancer, and the aging process (Capri et al., 2017; Cho, Dimri, & Dimri, 2015), which highlights us the important role of miR‐31a‐5p in cellular senescence. Moreover, according to a previous study, miR‐31a‐5p controls osteoclast formation and facilitates IL‐2 production in T cells by targeting RhoA (Fan et al., 2012; Mizoguchi, Murakami, Saito, Miyasaka, & Kohsaka, 2013).…”

Serum miR‐182 is a predictive biomarker for dichotomization of risk of hepatocellular carcinoma in rats

“…36,39,40 In humans, miR-31 is associated with aging livers and is increased in tumors, correlating with cirrhosis. 28,41,42 significant elevation of this miRNA in sera observed less than 2 months after the AFB 1 dosing period and considerably before diagnosis (sacrifice). It is remarkable that this increase is maintained throughout the lifetimes of the animals during such a complex and multifactorial disease like cancer.…”

“…Rno‐miR‐31a‐5p is increased in plasma after liver injury and differs from its human homolog hsa‐miR‐31 by one nucleotide . In humans, miR‐31 is associated with aging livers and is increased in tumors, correlating with cirrhosis . Other miRNAs found upregulated in tumors, such as the miR‐200 family (eg rno‐miRs‐200b‐3p, 429, 141‐3p) and rno‐miR‐205 are known to play a role in angiogenesis and epithelial to mesenchymal transition in multiple cancers including HCC .…”