Mechanosensor YAP cooperates with TGF-β1 signaling to promote myofibroblast activation and matrix stiffening in a 3D model of human cardiac fibrosis

Ragazzini, Sara; Scocozza, Franca; Bernava, Giacomo; Auricchio, Ferdinando; Colombo, Gualtiero I.; Barbuto, Marianna; Conti, Michele; Pesce, Maurizio; Garoffolo, Gloria

doi:10.1016/j.actbio.2022.08.063

Cited by 17 publications

(14 citation statements)

References 44 publications

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“…Ergo, the HS pathway is a prime candidate to coordinate a strict level of hypertrophy that would facilitate improved heart function, while mitigating any negative consequences resulting from superfluous growth. Moreover, the HS pathway has also been shown to interact with the TGF‐β signaling pathway to activate fibroblasts, potentially resulting in increased myocardial fibrosis 112,113 . This is interesting as TGF‐β signaling was predicted to be downregulated in torpid Monito del Monte hearts.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the HS pathway has also been shown to interact with the TGF-β signaling pathway to activate fibroblasts, potentially resulting in increased myocardial fibrosis. 112,113 This is interesting as TGF-β signaling was predicted to be downregulated in torpid Monito del Monte hearts. However, the simultaneous upregulation of HS and downregulation of TGF-β signaling is likely explained by the need to strictly balance beneficial cardiac hypertrophy while limiting maladaptive fibrotic tissue deposition.…”

Section: Hs Pathwaymentioning

confidence: 95%

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Torpor‐responsive microRNAs in the heart of the Monito del monte, Dromiciops gliroides

et al. 2023

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The marsupial Monito del monte (Dromiciops gliroides) utilizes both daily and seasonal bouts of torpor to preserve energy and prolong survival during periods of cold and unpredictable food availability. Torpor involves changes in cellular metabolism, including specific changes to gene expression that is coordinated in part, by the posttranscriptional gene silencing activity of microRNAs (miRNA). Previously, differential miRNA expression has been identified in D. gliroides liver and skeletal muscle; however, miRNAs in the heart of Monito del monte remained unstudied. In this study, the expression of 82 miRNAs was assessed in the hearts of active and torpid D. gliroides, finding that 14 were significantly differentially expressed during torpor. These 14 miRNAs were then used in bioinformatic analyses to identify Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that were predicted to be most affected by these differentially expressed miRNAs. Overexpressed miRNAs were predicted to primarily regulate glycosaminoglycan biosynthesis, along with various signaling pathways such as Phosphoinositide‐3‐kinase/protein kinase B and transforming growth factor‐β. Similarly, signaling pathways including phosphatidylinositol and Hippo were predicted to be regulated by the underexpression of miRNAs during torpor. Together, these results suggest potential molecular adaptations that protect against irreversible tissue damage and enable continued cardiac and vascular function despite hypothermia and limited organ perfusion during torpor.

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Section: Discussionmentioning

confidence: 99%

Section: Hs Pathwaymentioning

confidence: 95%

Torpor‐responsive microRNAs in the heart of the Monito del monte, Dromiciops gliroides

et al. 2023

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“…Specific molds were designed and manufactured with a commercial 3D FDM printer (Creality 3D technology, China) to prepare samples for compressive and tensile tests. For the compressive test, cylindrical geometry with a diameter of 8 mm and height of 4 mm was used, as reported in [ 53 ]; for the tensile test, according to ASTM standard F2900-11 [ 54 ], dog-bone geometry was used. Next, hydrogels were poured inside the molds and crosslinked for 1 h to ensure proper crosslinking in the whole sample.…”

Section: Methodsmentioning

confidence: 99%

Silk Fibroin Bioink for 3D Printing in Tissue Regeneration: Controlled Release of MSC extracellular Vesicles

et al. 2023

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Sodium alginate (SA)-based hydrogels are often employed as bioink for three-dimensional (3D) scaffold bioprinting. They offer a suitable environment for cell proliferation and differentiation during tissue regeneration and also control the release of growth factors and mesenchymal stem cell secretome, which is useful for scaffold biointegration. However, such hydrogels show poor mechanical properties, fast-release kinetics, and low biological performance, hampering their successful clinical application. In this work, silk fibroin (SF), a protein with excellent biomechanical properties frequently used for controlled drug release, was blended with SA to obtain improved bioink and scaffold properties. Firstly, we produced a printable SA solution containing SF capable of the conformational change from Silk I (random coil) to Silk II (b-sheet): this transition is a fundamental condition to improve the scaffold’s mechanical properties. Then, the SA-SF blends’ printability and shape fidelity were demonstrated, and mechanical characterization of the printed hydrogels was performed: SF significantly increased compressive elastic modulus, while no influence on tensile response was detected. Finally, the release profile of Lyosecretome—a freeze-dried formulation of MSC-secretome containing extracellular vesicles (EV)—from scaffolds was determined: SF not only dramatically slowed the EV release rate, but also modified the kinetics and mechanism release with respect to the baseline of SA hydrogel. Overall, these results lay the foundation for the development of SA-SF bioinks with modulable mechanical and EV-release properties, and their application in 3D scaffold printing.

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“…19 In response to mechanical cues, YAP translocates from the cytoplasm into the nucleus, leading to transcription of proliferatory and fibrotic genes by binding with TEADs. [20][21][22] Further, YAP was shown to cooperate with TGFβ1 signals to promote matrix stiffening in a 3D model of human cardiac fibrosis, 23 suggesting that the TGFβ1/YAP axis is vital for remodeling, and that inhibiting this axis can offer protection against pathological remodeling.…”

Section: Introductionmentioning

confidence: 99%

Prostaglandin E₂ attenuates lung fibroblast differentiation via inactivation of yes‐associated protein signaling

Teegala,

Gudneppanavar,

Sabu Kattuman

et al. 2023

The FASEB Journal

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Prostaglandin E2 (PGE2) has been implicated in counteracting fibroblast differentiation by TGFβ1 during pulmonary fibrosis. However, the precise mechanism is not well understood. We show here that PGE2 via EP2R and EP4R inhibits the expression of mechanosensory molecules Lysyl Oxidase Like 2 (LOXL2), myocardin‐related transcription factor A (MRTF‐A), ECM proteins, plasminogen activation inhibitor 1 (PAI‐1), fibronectin (FN), α‐smooth muscle actin (α‐SMA), and redox sensor (nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4)) required for TGFβ1‐mediated fibroblast differentiation. We further demonstrate that PGE2 inhibits fibrotic signaling via Yes‐associated protein (YAP) but does so independently from its actions on SMAD phosphorylation and conserved cylindromatosis (CYLD; deubiquitinase) expression. Mechanistically, PGE2 phosphorylates/inactivates YAP downstream of EP2R/Gαs and restrains its translocation to the nucleus, thus inhibiting its interaction with TEA domain family members (TEADs) and transcription of fibrotic genes. Importantly, pharmacological or siRNA‐mediated inhibition of YAP significantly downregulates TGFβ1‐mediated fibrotic gene expression and myofibroblast formation. Notably, YAP expression is upregulated in the lungs of D. farinae‐treated wild type (WT) mice relative to saline‐treated WT mice. Our results unravel a unique role for PGE2‐YAP interactions in fibroblast differentiation, and that PGE2/YAP inhibition can be used as a novel therapeutic target in the treatment of pathological conditions associated with myofibroblasts like asthma.

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Mechanosensor YAP cooperates with TGF-β1 signaling to promote myofibroblast activation and matrix stiffening in a 3D model of human cardiac fibrosis

Cited by 17 publications

References 44 publications

Torpor‐responsive microRNAs in the heart of the Monito del monte, Dromiciops gliroides

Torpor‐responsive microRNAs in the heart of the Monito del monte, Dromiciops gliroides

Silk Fibroin Bioink for 3D Printing in Tissue Regeneration: Controlled Release of MSC extracellular Vesicles

Prostaglandin E₂ attenuates lung fibroblast differentiation via inactivation of yes‐associated protein signaling

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Mechanosensor YAP cooperates with TGF-β1 signaling to promote myofibroblast activation and matrix stiffening in a 3D model of human cardiac fibrosis

Cited by 17 publications

References 44 publications

Torpor‐responsive microRNAs in the heart of the Monito del monte, Dromiciops gliroides

Torpor‐responsive microRNAs in the heart of the Monito del monte, Dromiciops gliroides

Silk Fibroin Bioink for 3D Printing in Tissue Regeneration: Controlled Release of MSC extracellular Vesicles

Prostaglandin E2 attenuates lung fibroblast differentiation via inactivation of yes‐associated protein signaling

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Prostaglandin E₂ attenuates lung fibroblast differentiation via inactivation of yes‐associated protein signaling