LncRNA GAS5 attenuates fibroblast activation through inhibiting Smad3 signaling

Abstract

Transforming Growth Factor β (TGF-β)-induced fibroblast activation is a key pathological event during tissue fibrosis. Long noncoding RNA (LncRNA) is a class of versatile gene regulators participating in various cellular and molecular processes. However, the function of lncRNA in fibroblast activation is still poorly understood. In this study, we identified growth arrest-specific transcript 5 (GAS5) as a novel regulator for TGF-β-induced fibroblast activation. GAS5 expression was downregulated in cultured fibroblasts by TGF-β and in resident fibroblasts isolated from bleomycin-treated skin tissues. Overexpression of GAS5 suppressed TGF-β-induced fibroblast to myofibroblast differentiation. Mechanistically, GAS5 directly bound Smad3 and promoted Smad3 bindin to PPM1A, a Smad3 dephosphatase, and thus accelerated Smad3 dephosphorylation in TGF-b-treated fibroblasts. GAS5 also inhibited fibroblast proliferation. Importantly, local delivery of GAS5 via adenoviral vector suppressed bleomycin-induced skin fibrosis in mice. Collectively, our data revealed that GAS5 suppresses fibroblast activation and fibrogenesis through inhibiting TGFβ /Smad3 signaling, which provides a rationale for developing an LncRNA-based therapy to treat fibrotic diseases. Results GAS5 expression was decreased in TGF-β-activated fibroblasts.TGF-β activated fibroblasts as shown by the induction of myofibroblast marker αSMA and Col1A in both 3T3 fibroblasts and primary cultured mouse skin fibroblasts (Fig 1A-1D). To test if GAS5 is involved in fibroblast activation, we first examined GAS5 expression in TGFβ-treated fibroblasts. 3T3 fibroblast cells were treated with vehicle, 1, 5, or 10 ng/ml TGF-β

Retrospective identification of intrinsic factors that mark pluripotency potential in rare somatic cells

“…The other primary gene expression signature of primed fibroblasts we observed was lower expression of several genes associated with activated fibroblasts (SPP1, SERPINE2, THBS1, TAGLN) (Hsia et al, 2016;Layton et al, 2020;Peyser et al, 2019;Sandberg et al, 2019), differentiation into myofibroblasts (MYL9, ACTA2, TPM2, POSTN) (Guerrero-Juarez et al, 2019;Hsia et al, 2016;Layton et al, 2020;Walker et al, 2019), and pathological fibrosis (GDF15, IGFBP7, GAS5) (L.-X. Liu et al, 2009;Radwanska et al, 2022;Tang et al, 2020) (Radwanska et al, 2022;Tang et al, 2020). This signature suggests that unactivated fibroblasts within the population are more likely to reprogram.…”

Silencing of long noncoding INHBA antisense RNA1 suppresses proliferation, migration, and extracellular matrix deposition in human hypertrophic scar fibroblasts via regulating microRNA-141-3p/myeloid cell leukemia 1 axis

“…As the key effector cells in the process of wound healing, fibroblasts exhibit excessive hypercellularity, increased migration and superabundant ECM accumulation during the formation of HS [23]. Dysfunction of lncRNAs may aggravate the progression of skin fibrosis [24,25]. Findings of this study demonstrated high level of INHBA-AS1 in hHSFs, and that INHBA-AS1 silencing exhibited efficiently the proliferation, migration and ECM synthesis in hHSFs via regulating miR-141-3p/ MCL1 axis.…”

LncRNA-COX2 inhibits Fibroblast Activation and Epidural Fibrosis by Targeting EGR1

“…There have been conflict and controversy about the role of LncRNAs in varieties of fibrogenesis. For example, some lncRNAs have been clarified to show anti-fibrosis effect in renal fibrosis [43], pulmonary fibrosis [44], skin fibrosis [45]. On the contrary, some lncRNAs are demonstrated to have pro-fibrosis characteristics in cardiac fibrosis [46], liver fibrosis [47], skeletal muscle fibrosis [48].…”