Identification and characterization of dynamically regulated hepatitis-related genes in a concanavalin A-induced liver injury model

Chen, Anna; Wang, Yidong; Wu, Jiaqi; Tang, Dongfang; Zhu, Qianru; Lu, Anqian; Yang, Jin; Cai, Zhejun; Shi, Junping

doi:10.18632/aging.104089

Cited by 2 publications

(3 citation statements)

References 15 publications

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“…Corneal inflammation 157 Nerve Depression 158 Microglia Sleep deprivation 159 Immune cells Rheumatoid arthritis 25,37,60,121,[160][161][162][163] Synovium-Mesenchymal stromal cells and inflammatory cells Psoriasis 25,163,164 Macrophages Multiple sclerosis 150 Neurons Solid tumors 25,37,[165][166][167][168] Cancer cells, CAF, immune cells Intestinal segmented filamentous bacterial infection 25,46,61,169,170 Epithelial cells and macrophages Obesity and Insulin resistance [171][172][173] Adipocytes, epithelial cells, and macrophages Liver Injury and autoimmune hepatitis 174,175 Stromal cells and stellate cells Hepatic fibrogenesis 175…”

Section: Pathologies Type Of Cellsmentioning

confidence: 99%

Podoplanin Positive Cell-derived Extracellular Vesicles Contribute to Cardiac Amyloidosis After Myocardial Infarction

Cimini,

Hansmann,

Gonzalez

et al. 2024

Preprint

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BackgroundAmyloidosis is a major long-term complication of chronic disease; however, whether it represents one of the complications of post-myocardial infarction (MI) is yet to be fully understood.MethodsUsing wild-type and knocked-out MI mouse models and characterizing in vitro the exosomal communication between bone marrow-derived macrophages and activated mesenchymal stromal cells (MSC) isolated after MI, we investigated the mechanism behind Serum Amyloid A 3 (SAA3) protein overproduction in injured hearts.ResultsHere, we show that amyloidosis occurs after MI and that amyloid fibers are composed of macrophage-derived SAA3 monomers. SAA3 overproduction in macrophages is triggered by exosomal communication from a subset of activated MSC, which, in response to MI, acquire the expression of a platelet aggregation-inducing type I transmembrane glycoprotein named Podoplanin (PDPN). Cardiac MSCPDPN+communicate with and activate macrophages through their extracellular vesicles or exosomes. Specifically, MSCPDPN+derived exosomes (MSCPDPN+Exosomes) are enriched in SAA3 and exosomal SAA3 protein engages with Toll-like receptor 2 (TRL2) on macrophages, triggering an overproduction and impaired clearance of SAA3 proteins, resulting in aggregation of SAA3 monomers as rigid amyloid deposits in the extracellular space. The onset of amyloid fibers deposition alongside extra-cellular-matrix (ECM) proteins in the ischemic heart exacerbates the rigidity and stiffness of the scar, hindering the contractility of viable myocardium and overall impairing organ function. Using SAA3 and TLR2 deficient mouse models, we show that SAA3 delivered by MSCPDPN+exosomes promotes post-MI amyloidosis. Inhibition of SAA3 aggregation via administration of a retro-inverso D-peptide, specifically designed to bind SAA3 monomers, prevents the deposition of SAA3 amyloid fibrils, positively modulates the scar formation, and improves heart function post-MI.ConclusionOverall, our findings provide mechanistic insights into post-MI amyloidosis and suggest that SAA3 may be an attractive target for effective scar reversal after ischemic injury and a potential target in multiple diseases characterized by a similar pattern of inflammation and amyloid deposition.NOVELTY AND SIGNIFICANCEWhat is known?Accumulation of rigid amyloid structures in the left ventricular wall impairs ventricle contractility.After myocardial infarction cardiac Mesenchymal Stromal Cells (MSC) acquire Podoplanin (PDPN) to better interact with immune cells.Amyloid structures can accumulate in the heart after chronic inflammatory conditions.What information does this article contribute?Whether accumulation of cumbersome amyloid structures in the ischemic scar impairs left ventricle contractility, and scar reversal after myocardial infarction (MI) has never been investigated.The pathophysiological relevance of PDPN acquirement by MSC and the functional role of their secreted exosomes in the context of post-MI cardiac remodeling has not been investigated.Amyloid structures are present in the scar after ischemia and are composed of macrophage-derived Serum Amyloid A (SAA) 3 monomers, although mechanisms of SAA3 overproduction is not established.SUMMARY OF NOVELTY AND SIGNIFICANCEHere, we report that amyloidosis, a secondary phenomenon of an already preexisting and prolonged chronic inflammatory condition, occurs after MI and that amyloid structures are composed of macrophage-derived SAA3 monomers. Frequently studied cardiac amyloidosis are caused by aggregation of immunoglobulin light chains, transthyretin, fibrinogen, and apolipoprotein in a healthy heart as a consequence of systemic chronic inflammation leading to congestive heart failure with various types of arrhythmias and tissue stiffness. Although chronic MI is considered a systemic inflammatory condition, studies regarding the possible accumulation of amyloidogenic proteins after MI and the mechanisms involved in that process are yet to be reported. Here, we show that SAA3 overproduction in macrophages is triggered in a Toll-like Receptor 2 (TLR2)-p38MAP Kinase-dependent manner by exosomal communication from a subset of activated MSC, which, in response to MI, express a platelet aggregation-inducing type I transmembrane glycoprotein named Podoplanin. We provide the full mechanism of this phenomenon in murine models and confirm SAA3 amyloidosis in failing human heart samples. Moreover, we developed a retro-inverso D-peptide therapeutic approach, “DRI-R5S,” specifically designed to bind SAA3 monomers and prevent post-MI aggregation and deposition of SAA3 amyloid fibrils without interfering with the innate immune response.

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Section: Pathologies Type Of Cellsmentioning

confidence: 99%

Podoplanin Positive Cell-derived Extracellular Vesicles Contribute to Cardiac Amyloidosis After Myocardial Infarction

Cimini,

Hansmann,

Gonzalez

et al. 2024

Preprint

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“…Trendy is an R package that fits a set of segmented (piece-wise) regression models to high-throughput, ordered expression data, allowing to identify dynamic gene expression patterns over a time course and to determine the direction and point in time when changes in expression occur [ 46 ]. It is a recently developed methodology that has been so far applied in stem cell differentiation [ 48 ] and in hepatic disease progression [ 49 ] studies. Interestingly, the latter research also integrated Trendy with WGCNA to identify high-confidence genes involved in human autoimmune hepatitis (AIH) [ 49 ].…”

Section: Introductionmentioning

confidence: 99%

“…It is a recently developed methodology that has been so far applied in stem cell differentiation [ 48 ] and in hepatic disease progression [ 49 ] studies. Interestingly, the latter research also integrated Trendy with WGCNA to identify high-confidence genes involved in human autoimmune hepatitis (AIH) [ 49 ]. Conversely, WGCNA is a widely implemented systems biology approach not only used for constructing co-expression networks based on the pairwise correlations between genes, but also for detecting significant associations between these networks’ modules and a given trait of interest, and to identify important players in these associations [ 47 ].…”

Section: Introductionmentioning

confidence: 99%

Integration of segmented regression analysis with weighted gene correlation network analysis identifies genes whose expression is remodeled throughout physiological aging in mouse tissues

Ferreira

Francisco

Soares

et al. 2021

Aging

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Gene expression alterations occurring with aging have been described for a multitude of species, organs, and cell types. However, most of the underlying studies rely on static comparisons of mean gene expression levels between age groups and do not account for the dynamics of gene expression throughout the lifespan. These studies also tend to disregard the pairwise relationships between gene expression profiles, which may underlie commonly altered pathways and regulatory mechanisms with age. To overcome these limitations, we have combined segmented regression analysis with weighted gene correlation network analysis (WGCNA) to identify high-confidence signatures of aging in the brain, heart, liver, skeletal muscle, and pancreas of C57BL/6 mice in a publicly available RNA-Seq dataset (GSE132040). Functional enrichment analysis of the overlap of genes identified in both approaches showed that immune- and inflammation-related responses are prominently altered in the brain and the liver, while in the heart and the muscle, aging affects amino and fatty acid metabolism, and tissue regeneration, respectively, which reflects an age-related global loss of tissue function. We also explored sexual dimorphism in the aging mouse transcriptome and found the liver and the muscle to have the most pronounced gender differences in gene expression throughout the lifespan, particularly in proteostasis-related pathways. While the data showed little overlap among the age-dysregulated genes between tissues, aging triggered common biological processes in distinct tissues, which we highlight as important features of murine tissue physiological aging.

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Identification and characterization of dynamically regulated hepatitis-related genes in a concanavalin A-induced liver injury model

Cited by 2 publications

References 15 publications

Podoplanin Positive Cell-derived Extracellular Vesicles Contribute to Cardiac Amyloidosis After Myocardial Infarction

Podoplanin Positive Cell-derived Extracellular Vesicles Contribute to Cardiac Amyloidosis After Myocardial Infarction

Integration of segmented regression analysis with weighted gene correlation network analysis identifies genes whose expression is remodeled throughout physiological aging in mouse tissues

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