Mesenchymal Stem Cells Induce a Fibrolytic Phenotype By Regulating mmu-miR-6769b-5p Expression in Macrophages

Nishi, Maiko; Matsumoto, Toshihiko; Fujisawa, Koichi; Suehiro, Yutaka; Takami, Taro; Yamamoto, Naoki; Yamasaki, Takahiro; Sakaida, Isao

doi:10.1089/scd.2020.0123

Cited by 6 publications

(8 citation statements)

References 36 publications

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“…Mechanistically, the therapeutic effect was attributed to exosome-mediated activation of Wnt/β-catenin as shown by reduced hepatic production of PPARγ , Wnt3a, Wnt10b , β-catenin , WISP1 , cyclin D1 , αSMA , and collagen I [ 273 ]. In studies relating to BM-MSC-augmented post-liver transplant regeneration, LPS-stimulated macrophages produced enhanced levels of fibrolytic MMPs when the cells were co-cultured with BM-MSC; this was associated with the action of miR-6769b-5p, which inhibited ATF4 expression and was the most enriched miR in EVs from the co-culture supernatant, highlighting potential anti-fibrotic actions of EV miR-6769-5p [ 274 ].…”

Section: Hepatic Fibrosismentioning

confidence: 99%

Extracellular Vesicles in Organ Fibrosis: Mechanisms, Therapies, and Diagnostics

Brigstock

2021

Cells

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Fibrosis is the unrelenting deposition of excessively large amounts of insoluble interstitial collagen due to profound matrigenic activities of wound-associated myofibroblasts during chronic injury in diverse tissues and organs. It is a highly debilitating pathology that affects millions of people globally and leads to decreased function of vital organs and increased risk of cancer and end-stage organ disease. Extracellular vesicles (EVs) produced within the chronic wound environment have emerged as important vehicles for conveying pro-fibrotic signals between many of the cell types involved in driving the fibrotic response. On the other hand, EVs from sources such as stem cells, uninjured parenchymal cells, and circulation have in vitro and in vivo anti-fibrotic activities that have provided novel and much-needed therapeutic options. Finally, EVs in body fluids of fibrotic individuals contain cargo components that may have utility as fibrosis biomarkers, which could circumvent current obstacles to fibrosis measurement in the clinic, allowing fibrosis stage, progression, or regression to be determined in a manner that is accurate, safe, minimally-invasive, and conducive to repetitive testing. This review highlights the rapid and recent progress in our understanding of EV-mediated fibrotic pathogenesis, anti-fibrotic therapy, and fibrosis staging in the lung, kidney, heart, liver, pancreas, and skin.

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Section: Hepatic Fibrosismentioning

confidence: 99%

Extracellular Vesicles in Organ Fibrosis: Mechanisms, Therapies, and Diagnostics

Brigstock

2021

Cells

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“…In this article, we describe macrophages from distinct organs that serve similar functions to express ECM degradation-related genes to promote the resolution of fibrosis as fibrolytic macrophages, and their characteristics are described in Table 1 . [ 38 ] (Table 1 ) Fibrolytic macrophages express a variety of proteins involved in ECM degradation, including secretory proteases, phagocytic receptors and enzymes critical for the intracellular digestion of phagocytosed ECM fragments [ 39 ]. Fibrolytic macrophages can express several proteolytic enzymes.…”

Section: Introductionmentioning

confidence: 99%

“…Recruitment and transformation of monocytes from peripheral blood create another source of fibrolytic macrophages. In both murine liver and kidney fibrosis, Ly6C hi (Gr1 hi ) monocytes in peripheral blood were recruited to sites of injury or inflammation [ 39 , 54 ]. After phagocytosing cell debris, Ly6C hi monocytes transformed into Ly6C lo monocytes, which further differentiated into Ly6C lo fibrolytic macrophages through the regulation of CX3CR1 expression [ 39 ].…”

Section: Introductionmentioning

confidence: 99%

“…In both murine liver and kidney fibrosis, Ly6C hi (Gr1 hi ) monocytes in peripheral blood were recruited to sites of injury or inflammation [ 39 , 54 ]. After phagocytosing cell debris, Ly6C hi monocytes transformed into Ly6C lo monocytes, which further differentiated into Ly6C lo fibrolytic macrophages through the regulation of CX3CR1 expression [ 39 ]. In addition to monocyte recruitment from peripheral blood, fibrolytic macrophages also originate from macrophages recruited from adjacent areas.…”

Section: Introductionmentioning

confidence: 99%

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New insights into fibrosis from the ECM degradation perspective: the macrophage-MMP-ECM interaction

et al. 2022

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Fibrosis is a pathological feature of a variety of chronic inflammatory diseases that can affect almost all organs, which can cause severe consequences and even lead to death. Fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM) due to disruption of the balance between ECM production and degradation. Although overabundance of ECM proteins has long been the focus of studies on fibrosis, another facet of the problem—impaired degradation of the ECM—is gaining increasing attention. Matrix metalloproteinase (MMP) and the tissue inhibitor of metalloproteinase (TIMP) system is the main molecular system contributing to ECM degradation, and macrophages are the major regulators of ECM. However, the relationship among macrophages, the MMP/TIMP system and the ECM is not fully understood in the context of fibrosis. Here, we discuss in detail the role played by the ECM in the development of fibrosis and highlight the macrophage-MMP-ECM interaction that is involved in fibrogenesis and may be a potential therapeutic target for fibrosis.

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“…Among these miRNAs, 5 have already been studied. The up-regulation of miR-6769b-5p in bone marrow-derived macrophages led to a fibrolytic phenotype, where was up-regulated while inflammatory mediator expression was decreased by the suppression of ATF4 expression, which suggested that the miR-6769b-5p/ATF4 axis may be a potential therapeutic target for chronic liver disease (41). MiR-1249-5p was involved in the regulation of bone metabolism (42,43), which can positively regulate osteogenic differentiation of adiposederived stem cells via targeting PDX1 through the PI3K/ Akt signaling pathway (43).…”

Section: Qrt-pcr Validation Of Hsa_circ_0005265 In Both Synovium and Ipfpmentioning

confidence: 99%

RNA sequencing reveals the circular RNA expression profiles of the infrapatellar fat pad/synovium unit

Jiang¹,

Lu²,

Chen³

et al. 2021

Ann Transl Med

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Background: The infrapatellar fat pad (IPFP) and synovium are reported to act as a functional unit, with emerging roles in the pathophysiology of knee osteoarthritis (KOA). Circular RNAs (circRNAs) are involved in the pathogenesis of KOA, especially in cartilage homeostasis regulation. Nevertheless, the regulatory mechanisms of circRNAs in the KOA IPFP/synovium unit remain to be elucidated. Therefore, the current study aimed to investigate alterations in the expression of circRNAs and predict their functions in the KOA IPFP/synovium unit using bioinformatics analysis.Methods: In brief, 6 synovium and IPFP specimens were collected, in which 3 from patients with KOA and 3 from controls. Then, circRNA sequencing was conducted on 2 KOA synovium and IPFP specimens as well as 1 control to investigate the expression profiles of circRNAs. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome signaling pathway analyses were employed to predict the functions of the differentially expressed circRNAs. Based on the miRNA sponge theory, we constructed a circRNA-miRNA network to predict the molecular regulatory mechanism of these circRNAs. Venn analysis was performed to confirm the circRNAs and miRNAs expressed in both synovium and IPFP. Realtime quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was also used to validate the expression levels of circRNAs that were co-expressed in both synovium and IPFP.Results: A total of 65 and 72 circRNAs were differentially expressed in KOA synovium and IPFP, respectively (fold change ≥2, P<0.05). After obtaining the parental genes of differentially expressed circRNAs, the top 10 enrichment GO entries, KEGG pathways, and Reactome pathways were annotated. Furthermore, hsa_circ_0005265 was found to be down-regulated in both synovium and IPFP, which was validated by qRT-PCR. The circRNA-miRNA network was created to annotate the probable regulatory mechanisms of the differentially expressed circRNAs, which consequently confirmed 2 target miRNAs (hsa-miR-6769b-5p and hsa-miR-1249-5p) associated with hsa_circ_0005265 in both synovium and IPFP.Conclusions: Our outcomes bring us closer to understanding the potential mechanism of the IPFP/ synovium unit in the progression of KOA and finding new molecular targets for KOA therapy.

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Mesenchymal Stem Cells Induce a Fibrolytic Phenotype By Regulating mmu-miR-6769b-5p Expression in Macrophages

Cited by 6 publications

References 36 publications

Extracellular Vesicles in Organ Fibrosis: Mechanisms, Therapies, and Diagnostics

Extracellular Vesicles in Organ Fibrosis: Mechanisms, Therapies, and Diagnostics

New insights into fibrosis from the ECM degradation perspective: the macrophage-MMP-ECM interaction

RNA sequencing reveals the circular RNA expression profiles of the infrapatellar fat pad/synovium unit

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