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Mesenchymal stromal/stem cells and their extracellular vesicles in liver diseases: insights on their immunomodulatory roles and clinical applications.

ABSTRACT: Liver disease is a leading cause of mortality and morbidity that is rising globally. Liver dysfunctions are classified into acute and chronic diseases. Various insults, including viral infections, alcohol or drug abuse, and metabolic overload, may cause chronic inflammation and fibrosis, leading to irreversible liver dysfunction. Up to now, liver transplantation could be the last resort for patients with end-stage liver disease. However, liver transplantation still faces unavoidable difficulties. Mesenchymal stromal/stem cells (MSCs) with their broad ranging anti-inflammatory and immunomodulatory properties can be effectively used for treating liver diseases but without the limitation that are associated with liver transplantation. In this review, we summarize and discuss recent advances in the characteristics of MSCs and the potential action mechanisms of MSCs-based cell therapies for liver diseases. We also draw attention to strategies to potentiate the therapeutic properties of MSCs through pre-treatments or gene modifications. Finally, we discuss progress toward clinical application of MSCs or their extracellular vesicles in liver diseases.

SUBMITTER: Huai Q

PROVIDER: S-EPMC10478279 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Mesenchymal stromal/stem cells and their extracellular vesicles in liver diseases: insights on their immunomodulatory roles and clinical applications.

Huai Qian Q Zhu Cheng C Zhang Xu X Dai Hanren H Li Xiaolei X Wang Hua H

Cell & bioscience 20230905 1

Liver disease is a leading cause of mortality and morbidity that is rising globally. Liver dysfunctions are classified into acute and chronic diseases. Various insults, including viral infections, alcohol or drug abuse, and metabolic overload, may cause chronic inflammation and fibrosis, leading to irreversible liver dysfunction. Up to now, liver transplantation could be the last resort for patients with end-stage liver disease. However, liver transplantation still faces unavoidable difficulties ...[more]

PMID: 37670393

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Project description:BackgroundThe paracrine effects of multipotent mesenchymal stromal cells (MSCs) are mediated by their secretome composed by soluble factors (i.e., cytokines, growth factors, hormones) and extracellular vesicles (EVs). EVs promote intercellular communication, and the EV cargoes [e.g., proteins, soluble factors, microRNAs (miRNAs), messenger RNA (mRNA), DNA] reflect the molecular and functional characteristics of their parental cells. MSC-derived EVs (MSC-EVs) are currently evaluated as subcellular therapeutics. A key function of the MSC secretome is its ability to promote immune tolerance (i.e., immunopotency), a property that is enhanced by priming approaches (e.g., cytokines, hypoxia, chemicals) and inversely correlates with the age of the MSC donors. We evaluated mechanisms underlying MSC vesiculation and the effects of inflammation and aging on this process.MethodsWe evaluated the effects of interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) on human adipose-derived MSC: (a) vesiculation (custom RT2 Profiler PCR Array), (b) EV profiles (Nanoparticle Tracking Analysis and Nanoparticle Flow Cytometry), (c) EV cargo (proteomic analysis and Western blot analysis), and (d) immunopotency (standard MSC:CD4 T cell proliferation inhibition assay). We confirmed the role of RAB27B on MSC vesiculation (RAB27B siRNA) and assessed its differential contribution to vesiculation in adult and pediatric MSCs (qPCR).ResultsCytokine priming upregulated RAB27B in adipose-derived MSCs increasing their secretion of exosome-like small EVs (sEVs; < 200 nm) containing two key mediators of immunopotency: A20 and TSG-6. These EVs inhibited T cell proliferation in a dose-dependent manner. RAB27B siRNA inhibited MSC vesiculation. Adipose-derived MSCs isolated from pediatric donors exhibited higher RAB27B expression and secreted more sEVs than adult MSCs.ConclusionsCytokine priming is a useful strategy to harvest anti-inflammatory MSC-sEVs for clinical applications. Of relevance, donor age should be considered in the selection of MSC-sEVs for clinical applications.

Dataset Information

Mesenchymal stromal/stem cells and their extracellular vesicles in liver diseases: insights on their immunomodulatory roles and clinical applications.

Publications

Mesenchymal stromal/stem cells and their extracellular vesicles in liver diseases: insights on their immunomodulatory roles and clinical applications.

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