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Mesenchymal Stromal Cells Overexpressing Farnesoid X Receptor Exert Cardioprotective Effects Against Acute Ischemic Heart Injury by Binding Endogenous Bile Acids.

ABSTRACT: Bile acid metabolites have been increasingly recognized as pleiotropic signaling molecules that regulate cardiovascular functions, but their role in mesenchymal stromal cells (MSC)-based therapy has never been investigated. It is found that overexpression of farnesoid X receptor (FXR), a main receptor for bile acids, improves the retention and cardioprotection of adipose tissue-derived MSC (ADSC) administered by intramyocardial injection in mice with myocardial infarction (MI), which shows enhanced antiapoptotic, proangiogenic, and antifibrotic effects. RNA sequencing, LC-MS/MS, and loss-of-function studies reveal that FXR overexpression promotes ADSC paracrine angiogenesis via Angptl4. FXR overexpression improves ADSC survival in vivo but fails in vitro. By performing bile acid-targeted metabolomics using ischemic heart tissue, 19 bile acids are identified. Among them, cholic acid and deoxycholic acid significantly increase Angptl4 secretion from ADSC overexpressing FXR and further improve their proangiogenic capability. Moreover, ADSC overexpressing FXR shows significantly lower apoptosis by upregulating Nqo-1 expression only in the presence of FXR ligands. Retinoid X receptor α is identified as a coactivator of FXR. It is first demonstrated that there is a bile acid pool in the myocardial microenvironment. Targeting the bile acid-FXR axis may be a novel strategy for improving the curative effect of MSC-based therapy for MI.

SUBMITTER: Xia Y

PROVIDER: S-EPMC9404394 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Mesenchymal Stromal Cells Overexpressing Farnesoid X Receptor Exert Cardioprotective Effects Against Acute Ischemic Heart Injury by Binding Endogenous Bile Acids.

Xia Yunlong Y Xu Xinyue X Guo Yongzhen Y Lin Chen C Xu Xiaoming X Zhang Fuyang F Fan Miaomiao M Qi Tingting T Li Congye C Hu Guangyu G Peng Lu L Wang Shan S Zhang Ling L Hai Chunxu C Liu Rui R Yan Wenjun W Tao Ling L

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20220703 24

Bile acid metabolites have been increasingly recognized as pleiotropic signaling molecules that regulate cardiovascular functions, but their role in mesenchymal stromal cells (MSC)-based therapy has never been investigated. It is found that overexpression of farnesoid X receptor (FXR), a main receptor for bile acids, improves the retention and cardioprotection of adipose tissue-derived MSC (ADSC) administered by intramyocardial injection in mice with myocardial infarction (MI), which shows enhan ...[more]

PMID: 35780502

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Project description:Background aimsSkeletal muscle regeneration after severe damage is reliant on local stem cell proliferation and differentiation, processes that are tightly regulated by macrophages. Peripheral artery disease is a globally prevalent cardiovascular disease affecting millions of people. Progression of the disease leads to intermittent claudication, subsequent critical limb ischemia and muscle injury. Tissue-derived and ex vivo-expanded mesenchymal stromal cells (MSCs) for skeletal muscle regeneration have been studied, but pre-clinical and clinical results have not been consistent. As a result, the potential therapeutic efficacy and associated repair mechanisms of MSCs remain unclear. Numerous studies have demonstrated the vulnerability of delivered MSCs, with a precipitous drop in cell viability upon transplantation. This has prompted investigation into the therapeutic benefit of apoptotic cells, microvesicles, exosomes and soluble signals that are released upon cell death.MethodsIn this study, we characterized various components produced by MSCs after cell death induction under different conditions. We discovered anti-inflammatory and pro-regenerative effects produced by cell components following a freeze and thaw (F&T) process on macrophage polarization in vitro. We further investigated the underlying mechanisms of macrophage polarization by those components resulting from severe cell death induction.ResultsWe found potent therapeutic effects from F&T-induced cell debris are dependent on the externalization of phosphatidylserine on the plasma membrane. In contrast, effects from the supernatant of F&T-induced cell death primarily depends on the released protein content. We then applied the F&T-induced cell supernatant to an animal model of peripheral artery disease to treat muscle injury caused by severe ischemia. Treatment with the F&T supernatant but not the vulnerable MSCs resulted in significantly improved recovery of muscle function, blood flow and morphology and inflammation resolution in the affected muscles 2 weeks after injury.ConclusionsThis study validates the therapeutic potential of F&T-induced supernatant obviating the need for a viable population from vulnerable MSCs to treat injury, thus providing a roadmap for cell-free therapeutic approaches for tissue regeneration.

Dataset Information

Mesenchymal Stromal Cells Overexpressing Farnesoid X Receptor Exert Cardioprotective Effects Against Acute Ischemic Heart Injury by Binding Endogenous Bile Acids.

Publications

Mesenchymal Stromal Cells Overexpressing Farnesoid X Receptor Exert Cardioprotective Effects Against Acute Ischemic Heart Injury by Binding Endogenous Bile Acids.

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