New Insights into Hippo/YAP Signaling in Fibrotic Diseases

Mia, Masum M.; Singh, Manvendra K.

doi:10.3390/cells11132065

Cited by 42 publications

(31 citation statements)

References 115 publications

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“…As LOXL4 appears not to contribute to lung fibroblast activation directly (figs. S3 to S5), we speculate that LOXL4 and its dependent pathological collagen cross-linking may promote myofibroblast activation via indirect stimulation of profibrotic signaling pathways such as yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) and TGFβ signaling in vivo ( 50 – 55 ).…”

Section: Resultsmentioning

confidence: 99%

LOXL4, but not LOXL2, is the critical determinant of pathological collagen cross-linking and fibrosis in the lung

Ma¹,

Li²,

Wong³

et al. 2023

Sci. Adv.

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Idiopathic pulmonary fibrosis is a progressive fibrotic disease characterized by excessive deposition of (myo)fibroblast produced collagen fibrils in alveolar areas of the lung. Lysyl oxidases (LOXs) have been proposed to be the central enzymes that catalyze the cross-linking of collagen fibers. Here, we report that, while its expression is increased in fibrotic lungs, genetic ablation of LOXL2 only leads to a modest reduction of pathological collagen cross-linking but not fibrosis in the lung. On the other hand, loss of another LOX family member, LOXL4, markedly disrupts pathological collagen cross-linking and fibrosis in the lung. Furthermore, knockout of both Loxl2 and Loxl4 does not offer any additive antifibrotic effects when compared to Loxl4 deletion only, as LOXL4 deficiency decreases the expression of other LOX family members including Loxl2 . On the basis of these results, we propose that LOXL4 is the main LOX activity underlying pathological collagen cross-linking and lung fibrosis.

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Section: Resultsmentioning

confidence: 99%

LOXL4, but not LOXL2, is the critical determinant of pathological collagen cross-linking and fibrosis in the lung

Ma¹,

Li²,

Wong³

et al. 2023

Sci. Adv.

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“…We speculate that CFs may be different between the LA and RA, which has been reported in human hearts on the basis of single-nucleus transcriptomics data 25,26 . Because the Hippo pathway in CFs plays a key role in organ fibrosis 27,2829 , understanding the key differences between LA and RA CFs that affect Hippo pathway should provide insight into fibroblast biology and treatment designs for fibrotic diseases.…”

Section: Discussionmentioning

confidence: 99%

Hippo-deficient cardiac fibroblasts differentiate into osteochondroprogenitors

Tsai,

Kim,

et al. 2023

Preprint

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Cardiac fibrosis, a common pathophysiology associated with various heart diseases, occurs from the excess deposition of extracellular matrix (ECM)1. Cardiac fibroblasts (CFs) are the primary cells that produce, degrade, and remodel ECM during homeostasis and tissue repair2. Upon injury, CFs gain plasticity to differentiate into myofibroblasts3and adipocyte-like4,5and osteoblast-like6cells, promoting fibrosis and impairing heart function7. How CFs maintain their cell state during homeostasis and adapt plasticity upon injury are not well defined. Recent studies have shown that Hippo signalling in CFs regulates cardiac fibrosis and inflammation8–11. Here, we used single-nucleus RNA sequencing (snRNA-seq) and spatially resolved transcriptomic profiling (ST) to investigate how the cell state was altered in the absence of Hippo signaling and how Hippo-deficient CFs interact with macrophages during cardiac fibrosis. We found that Hippo-deficient CFs differentiate into osteochondroprogenitors (OCPs), suggesting that Hippo restricts CF plasticity. Furthermore, Hippo-deficient CFs colocalized with macrophages, suggesting their intercellular communications. Indeed, we identified several ligand-receptor pairs between the Hippo-deficient CFs and macrophages. Blocking the Hippo-deficient CF-induced CSF1 signaling abolished macrophage expansion. Interestingly, blocking macrophage expansion also reduced OCP differentiation of Hippo-deficient CFs, indicating that macrophages promote CF plasticity.

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“…[13][14][15] Yet anti-inflammatory functions may also eventuate in kidney fibrosis, whereby chronic kidney disease manifests as an excessive accumulation of extracellular matrix, resulting in renal dysfunction and disruption of normal architecture. 16 Therefore, anti-inflammatory repair mechanisms need to be fine-tuned to achieve the required level of damage repair without unwarranted scarring. This balance might be achieved through carefully orchestrated activation of different types of antiinflammatory mechanisms.…”

Section: Inflammation In Kidney Diseasesmentioning

confidence: 99%

TSG-6 (Tumor Necrosis Factor-α-Stimulated Gene/Protein-6): An Emerging Remedy for Renal Inflammation

et al. 2023

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The inflammatory response is a major pathological feature in most kidney diseases and often evokes compensatory mechanisms. Recent evidence suggests that TSG-6 (tumor necrosis factor-α-stimulated gene/protein-6) plays a pivotal role in anti-inflammation in various renal diseases, including immune-mediated and nonimmune-mediated renal diseases. TSG-6 has a diverse repertoire of anti-inflammatory functions: it potentiates antiplasmin activity of IαI (inter-α-inhibitor) by binding to its light chain, crosslinks hyaluronan to promote its binding to cell surface receptor CD44, and thereby regulate the migration and adhesion of lymphocytes, inhibits chemokine-stimulated transendothelial migration of neutrophils by directly interacting with the glycosaminoglycan binding site of CXCL-8 (CXC motif chemokine ligand), and upregulates COX-2 (cyclooxygenase) to produce anti-inflammatory metabolites. Hopefully, further developments can target this anti-inflammatory molecule to the kidney and harness its remedial properties. This review provides an overview of the emerging role of TSG-6 in blunting renal inflammation.

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New Insights into Hippo/YAP Signaling in Fibrotic Diseases

Cited by 42 publications

References 115 publications

LOXL4, but not LOXL2, is the critical determinant of pathological collagen cross-linking and fibrosis in the lung

LOXL4, but not LOXL2, is the critical determinant of pathological collagen cross-linking and fibrosis in the lung

Hippo-deficient cardiac fibroblasts differentiate into osteochondroprogenitors

TSG-6 (Tumor Necrosis Factor-α-Stimulated Gene/Protein-6): An Emerging Remedy for Renal Inflammation

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