Integrated metabolomics and phosphoproteomics reveal the protective role of exosomes from human umbilical cord mesenchymal stem cells in naturally aging mouse livers

Aging (and ultimately death) is a certain process of life followed by all kinds of physical ailments, such as common metabolic disease and cancer. Even though these clinical characteristics are well described, the complex biomolecular networks contributing to the aging course are only initial to be explored [1]. Several common processes are found to cause or at least relate to aging, such as DNA damage and general metabolic dysfunction. To date, these pathways seem to be independent, but recent evidence shows that some of these pathways interact, as recently outstood by the connections between DNA damage, metabolic control and tumorigenesis, which is probably driven by posttranslational mechanisms, well known as phosphorylation [2].

Regardless of the mechanism, a common hallmark of aging-related disease is the involvement of metabolic systems in general. Across a diverse series of organs or tissues, the liver, being the primary location for metabolic activity, likely includes the most complex metabolic profiles and activities, particularly those related to liver aging [3]. The complex functions of the liver in molecular biosynthesis and metabolism are highly dependent on adequate protein phosphorylation due to its relatively low metabolic cost, fast and reversible features, and ability to deeply regulate the function of target proteins [4].

Although aging and senescence have been widely researched during the last few decades, there is a lack of available treatments. In recent years, exosomes derived from mesenchymal stem/stromal cells (MSC-exos) have been extensively used as therapeutic tools in basic studies and clinical trials. Exosomes with diameters of 40–150 nm are produced from the inside budding of the advanced endosomal membrane. Since they seem to exert similar therapeutic features to their parent cells and lack self-replicating abilities, dangers of abnormal differentiation, tumor generation, genetic instability, and cellular exclusion by the immune system, MSC-exos have been extensively researched in different types of animal models, including liver, cardiovascular, and immunological diseases [5]. It was previously observed that exosomes derived from human umbilical cord mesenchymal stem cells (hUCMSC-exos) delivered by silk fibroin hydrogel promoted blood perfusion in ischemic hindlimbs can be used to treat aging-induced vascular dysfunction [6]. Human placental MSC-derived exosomes (hPMSC-exos) exert protective effects against senescent cholangioids under oxidative stress-induced injury by delaying aging [7]. The adoption of MSC-exos in animal models of many liver diseases, such as liver fibrosis and cirrhosis, found that these interventions improved the process of the disease [8]. Although the biological properties of MSC-exos are well documented, there is little evidence of their effect on aging livers. Thus, it was hypothesized that hUCMSC-exos, with their potential antiaging effects, could ameliorate senescent states in aging livers mainly through metabolic reprogramming and genome stability, as examined by morphology, metabolomics and phosphoproteomics.

As aging is a multifaceted course, an antiaging intervention appears to be linked with multiple processes. The quantification of global phosphorylation among multiple samples is a powerful study tool to investigate altered signal transduction in aging. Mass spectrometry-based metabolomics and phosphoproteomics have become increasingly attractive techniques to find both differentially expressed metabolites and phosphorylated proteins in a complex mixture, and these tools have recently been applied to research aging states [9]. In this study, the morphology, metabolism and phosphoproteome were assessed using wild-type C57BL/6J aging mice, the most commonly adopted strain for aging research, to elucidate the effects of hUCMSC-exos and the molecular mechanisms on aging livers. The omics functional and integrated analyses were further performed to uncover the potential signaling pathways. Subsequently, immunohistochemical assay (IHC) and western blotting (WB) were used to verify the critical pathway.

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