Novel Mechanism of the Pericyte-Myofibroblast Transition in Renal Interstitial Fibrosis: Core Fucosylation Regulation

Wang, Nan; Deng, Yiyao; Liu, Anqi; Shen, Nan; Wang, Weidong; Du, Xiangning; Tang, Qingzhu; Li, Shuangxin; Odeh, Zach; Wu, Ting; Lin, Hongli

doi:10.1038/s41598-017-17193-5

Cited by 49 publications

(53 citation statements)

References 47 publications

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“…Indeed, mesenchymal stem cells, which derive from bone marrow, are a known source of pericytes 32,33 . Myofibroblasts 34,35 and endothelial cells 36,37 can also differentiate into pericytes. Therefore, to improve anti-VEGF therapy, further analyses are required to understand the underlying mechanism of the recruitment of pericytes into the tumor microenvironment or the differentiation of other cell types into pericytes, and the role of FGF expression in pericytes.…”

Section: Discussionmentioning

confidence: 99%

Activated FGF2 signaling pathway in tumor vasculature is essential for acquired resistance to anti-VEGF therapy

Ichikawa

Miyano

Minoshima

et al. 2020

Sci Rep

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Anti-vascular endothelial growth factor (VEGF) therapy shows antitumor activity against various types of solid cancers. Several resistance mechanisms against anti-VEGF therapy have been elucidated; however, little is known about the mechanisms by which the acquired resistance arises. Here, we developed new anti-VEGF therapy-resistant models driven by chronic expression of the mouse VEGFR2 extracellular domain fused with the human IgG4 fragment crystallizable (Fc) region (VEGFR2-Fc). In the VEGFR2-Fc-expressing resistant tumors, we demonstrated that the FGFR2 signaling pathway was activated, and pericytes expressing high levels of FGF2 were co-localized with endothelial cells. Lenvatinib, a multiple tyrosine kinase inhibitor including VEGFR and FGFR inhibition, showed marked antitumor activity against VEGFR2-Fc-expressing resistant tumors accompanied with a decrease in the area of tumor vessels and suppression of phospho-FGFR2 in tumors. Our findings reveal the key role that intercellular FGF2 signaling between pericytes and endothelial cells plays in maintaining the tumor vasculature in anti-VEGF therapy-resistant tumors.Anti-vascular endothelial growth factor (VEGF) therapy, such as anti-VEGF antibody (Ab), anti-VEGFR2 Ab, and multiple tyrosine kinase inhibitors (TKIs) targeting VEGFR2, has been used to treat various types of solid cancers for over a decade. Despite massive efforts, the mechanisms of acquired resistance to anti-VEGF therapy are still not completely understood 1,2 .Other angiogenic factors such as fibroblast growth factors (FGFs) 3,4 , angiopoietins 5,6 , and platelet-derived growth factors (PDGFs) 7-9 have been reported to induce tumor angiogenesis as a single factor or in crosstalk with VEGF 10 . Upregulation of FGFs by chronic anti-VEGF therapy has been reported in the RIP1-Tag2 mouse (a pancreatic neuroendocrine tumor model) treated by DC101 (an anti-VEGFR2 Ab) 11 , and in a human head and neck squamous cell carcinoma xenograft tumor model treated by bevacizumab (an anti-VEGFA Ab) 12 . In a study of MCaIV syngeneic tumor models, cancer-associated fibroblasts and adipocytes expressed FGF2 and mediated resistance to anti-mouse VEGF Ab B20 13 . In addition, in the Y-MESO-14 (human malignant pleural mesothelioma cell line) xenograft tumor model, fibrocyte-like cells mediated the resistance to bevacizumab by producing FGF2 14 . In contrast, concurrent inhibition of VEGFR and FGFR by a chimeric dual decoy receptor enhanced antitumor activity in A549 (human lung cancer cell line) and Caki-1 (human renal cancer cell line) xenograft tumor models 15 . These results suggest that the FGF signaling pathway contributes to resistance to anti-VEGF therapy; however, it is largely unknown how the FGF signaling pathway becomes activated when tumors acquire resistance to anti-VEGF therapy. Recently, the role of the VEGF signaling pathway in cancer immunity has received increased attention because of the promising combination antitumor activity of anti-VEGF therapy with immune checkpoint inhibitors in pre-clinica...

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Section: Discussionmentioning

confidence: 99%

Activated FGF2 signaling pathway in tumor vasculature is essential for acquired resistance to anti-VEGF therapy

Ichikawa

Miyano

Minoshima

et al. 2020

Sci Rep

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“…Using genetic fate mapping, pericytes have been identified as a potential myofibroblast progenitor . It is hypothesized that signaling cascades, such as TGF‐B and PDGF, cause the detachment of pericytes from vessel walls and subsequent migration and acquisition of a fibroblast‐like phenotype . In a rat model of atherosclerosis, it has been demonstrated that pericytes show abundant lipidic vacuoles .…”

Section: Future Considerationsmentioning

confidence: 99%

Concise Review: The Regenerative Journey of Pericytes Toward Clinical Translation

et al. 2018

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Coronary artery disease (CAD) is the single leading cause of death worldwide. Advances in treatment and management have significantly improved patient outcomes. On the other hand, although mortality rates have decreased, more people are left with sequelae that require additional treatment and hospitalization. Moreover, patients with severe nonrevascularizable CAD remain with only the option of heart transplantation, which is limited by the shortage of suitable donors. In recent years, cell‐based regenerative therapy has emerged as a possible alternative treatment, with several regenerative medicinal products already in the clinical phase of development and others emerging as competitive preclinical solutions. Recent evidence indicates that pericytes, the mural cells of blood microvessels, represent a promising therapeutic candidate. Pericytes are abundant in the human body, play an active role in angiogenesis, vessel stabilization and blood flow regulation, and possess the capacity to differentiate into multiple cells of the mesenchymal lineage. Moreover, early studies suggest a robustness to hypoxic insult, making them uniquely equipped to withstand the ischemic microenvironment. This review summarizes the rationale behind pericyte‐based cell therapy and the progress that has been made toward its clinical application. We present the different sources of pericytes and the case for harvesting them from tissue leftovers of cardiovascular surgery. We also discuss the healing potential of pericytes in preclinical animal models of myocardial ischemia (MI) and current practices to upgrade the production protocol for translation to the clinic. Standardization of these procedures is of utmost importance, as lack of uniformity in cell manufacturing may influence clinical outcome. Stem Cells 2018;36:1295–1310

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“…These perivascular cells rich in PDGFRβ mainly provide support to the vasculature under physiological conditions. However, during a pathological insult in the kidney, they tend to migrate toward the renal interstitium and undergo transition into myofibroblasts positive for α-SMA (Wang et al, 2017). In the current model, mice intoxicated with AA had a significantly high number of pericyte/myofibroblast transitioned cells (positive for PDGFRβ/α-SMA), which was significantly reduced following MSC-EV treatment.…”

Section: Discussionmentioning

confidence: 71%

“…Another cell type known to play an important role in fibrosis is the pericyte. They have been identified as a major source of myofibroblasts in interstitial fibrosis (Wang et al, 2017). These perivascular cells rich in PDGFRβ mainly provide support to the vasculature under physiological conditions.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal Stem Cell Derived Extracellular Vesicles Ameliorate Kidney Injury in Aristolochic Acid Nephropathy

Kholia

Sanchez

Cedrino

et al. 2020

Front. Cell Dev. Biol.

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Limitations in the current therapeutic strategies for the prevention of progression of chronic kidney disease (CKD) to end stage renal disease has been a drawback to improving patient recovery. It is therefore imperative that a solution is found to alleviate this problem and improve the health and well-being of patients overall. Aristolochic acid (AA) induced nephropathy, a type of nephrotoxic CKD is characterised by cortical tubular injury, inflammation, leading to interstitial fibrosis. Extracellular vesicles derived from human bone marrow mesenchymal stem cells (MSC-EVs) display therapeutic properties in various disease models including kidney injury. In the current study, we intended to investigate the ability of MSC-EVs on ameliorating tubular injury and interstitial fibrosis in a mouse model of aristolochic acid nephropathy (AAN). The chronic model of AAN is comprised of an intraperitoneal injection of AA in NSG mice, followed by a three-day incubation period and then inoculation of MSC-EVs intravenously. This routine was performed on a weekly basis for four consecutive weeks, accompanied by the monitoring of body weight of all mice. Blood and tissue samples were collected post sacrifice. All animals administered with AA developed kidney injury and renal fibrosis. A gradual loss of body weight was observed, together with a deterioration in kidney function. Although no significant recovery was observed in weight loss following treatment with MSC-EVs, a significant reduction in: blood creatinine and blood urea nitrogen (BUN), tubular necrosis, and interstitial fibrosis was observed. In addition, infiltration of CD45 positive immune cells, fibroblasts, and pericytes which were elevated in the interstitium post AA induced injury, were also significantly reduced by MSC-EVs. Kidneys were also subjected to molecular analyses to evaluate the regulation of profibrotic genes. MSC-EVs significantly reduced AA induction of the pro-fibrotic genes α-Sma, Tgfb1 and Col1a1. A downregulation in pro-fibrotic genes was also observed in fibroblasts activated by AA injured mTECs in vitro. Furthermore, meta-analyses of miRNAs downregulated by MSC-EVs, such as miR21, revealed the regulation of multiple

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Novel Mechanism of the Pericyte-Myofibroblast Transition in Renal Interstitial Fibrosis: Core Fucosylation Regulation

Cited by 49 publications

References 47 publications

Activated FGF2 signaling pathway in tumor vasculature is essential for acquired resistance to anti-VEGF therapy

Activated FGF2 signaling pathway in tumor vasculature is essential for acquired resistance to anti-VEGF therapy

Concise Review: The Regenerative Journey of Pericytes Toward Clinical Translation

Mesenchymal Stem Cell Derived Extracellular Vesicles Ameliorate Kidney Injury in Aristolochic Acid Nephropathy

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