BCL2 Regulates Differentiation of Intestinal Fibroblasts

Weder, Bruce; Mamie, Céline; Rogler, Gerhard; Clarke, Stephen H.; McRae, Bradford L.; Ruiz, Pedro A.; Hausmann, Martin

doi:10.1093/ibd/izy147

Cited by 19 publications

(13 citation statements)

References 59 publications

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“…Another signaling pathway, PI3K/AKT, regulates fibroblast proliferation and migration as well as collagen I production [43]. Activation of fibroblasts is also linked to the B-cell lymphoma 2 (Bcl2) family, which is involved in the induction of apoptosis, and Bcl2 antagonists partially prevent fibrogenesis in different fibrosis models [44], whereas its overexpression in fibroblasts promotes persistent fibrosis in the pulmonary fibrosis model [45]. Suppression of von Hippel-Lindau protein (VHL) in fibroblasts could protect them from profibrotic agents [46].…”

Section: Discussionmentioning

confidence: 99%

Secretome of Mesenchymal Stromal Cells Prevents Myofibroblasts Differentiation by Transferring Fibrosis-Associated microRNAs within Extracellular Vesicles

Basalova

Sagaradze

Arbatskiy

et al. 2020

Cells

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Fibroblasts differentiation into myofibroblasts is a central event of tissue fibrosis. Multipotent mesenchymal stromal cells (MSCs) secretome can interfere with fibrosis development; despite precise underlying mechanisms remain unclear. In this study, we tested the hypothesis that MSC secretome can affect fibroblast’ differentiation into myofibroblasts by delivering regulatory RNAs, including microRNAs to these cells. Using the model of transforming growth factor-beta (TGFbeta)-induced fibroblast differentiation into myofibroblasts, we tested the activity of human MSC secretome components, specifically extracellular vesicles (MSC-EV). We showed that MSC-EV down-regulated secretion of extracellular matrix proteins by fibroblasts as well as suppressed their contractility resulting in prevention as well as reversion of fibroblasts differentiation to myofibroblasts. High-throughput sequencing of RNAs extracted from MSC-EV has revealed many fibrosis-associated microRNAs. Fibroblast treatment with MSC-EV led to direct transfer of microRNAs, which resulted in the elevation of most prominent fibrosis-associated microRNAs, including microRNA-21 and microRNA-29c. Using MSC-EV transfection by antagomirs to these microRNAs we demonstrated their involvement in the suppression of fibroblast differentiation in our model. Taken together, MSC secretome can suppress fibrosis by prevention of fibroblast differentiation into myofibroblasts as well as induce de-differentiation of the latter by direct transfer of specific microRNAs.

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Section: Discussionmentioning

confidence: 99%

Secretome of Mesenchymal Stromal Cells Prevents Myofibroblasts Differentiation by Transferring Fibrosis-Associated microRNAs within Extracellular Vesicles

Basalova

Sagaradze

Arbatskiy

et al. 2020

Cells

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“…C188‐9 ameliorates the progression of pulmonary and skin fibrosis in mice exposed to bleomycin (Kasembeli et al , 2018; Pedroza et al , 2018). Likewise, Bcl2 is involved in tissue fibrosis (Safaeian et al , 2014; Weder et al , 2018). Thus, C188‐9 and venetoclax show promising anti‐fibrotic activity by targeting multiple pathways.…”

Section: Discussionmentioning

confidence: 99%

ER‐anchored CRTH2 antagonizes collagen biosynthesis and organ fibrosis via binding LARP6

et al. 2021

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Excessive deposition of extracellular matrix, mainly collagen protein, is the hallmark of organ fibrosis. The molecular mechanisms regulating fibrotic protein biosynthesis are unclear. Here, we find that chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2), a plasma membrane receptor for prostaglandin D2, is trafficked to the endoplasmic reticulum (ER) membrane in fibroblasts in a caveolin‐1‐dependent manner. ER‐anchored CRTH2 binds the collagen mRNA recognition motif of La ribonucleoprotein domain family member 6 (LARP6) and promotes the degradation of collagen mRNA in these cells. In line, CRTH2 deficiency increases collagen biosynthesis in fibroblasts and exacerbates injury‐induced organ fibrosis in mice, which can be rescued by LARP6 depletion. Administration of CRTH2 N‐terminal peptide reduces collagen production by binding to LARP6. Similar to CRTH2, bumetanide binds the LARP6 mRNA recognition motif, suppresses collagen biosynthesis, and alleviates bleomycin‐triggered pulmonary fibrosis in vivo. These findings reveal a novel anti‐fibrotic function of CRTH2 in the ER membrane via the interaction with LARP6, which may represent a therapeutic target for fibrotic diseases.

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“…Additionally, the apoptosis-suppressing protein BCL2 expression has been found scattered in both keloid and hypertrophic scar specimens, which together with the absence of p53 protein expression, could lead to cell proliferation and prolonged survival of cells in keloid-derived fibroblasts [ 25 ]. In addition, Bruce et al found that BCL2 antagonist administration partially prevented fibrogenesis in intestinal fibroblasts and reduced the expression of TGF-β-induced factors involved in the differentiation of myofibroblasts; therefore, BCL2 might be a potential treatment option against Crohn’s disease-associated fibrosis [ 26 ]. Jian et al revealed overexpression of miR-30a-5p induced keloid fibroblast apoptosis by targeting BCL2 [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

MiR-4328 inhibits proliferation, metastasis and induces apoptosis in keloid fibroblasts by targeting BCL2 expression

Tang¹,

Chen²,

Yu³

et al. 2020

Open Life Sciences

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Keloids are considered to be a type of benign tumor. MicroRNAs have been reported to be involved in the formation and growth of keloids. MicroRNA-4328 (miR-4328) was found to be abnormally expressed in keloids, while the role and the detailed molecular mechanism of miR-4328 in keloids remain unclear. The expression of miR-4328 and B-cell lymphoma 2 (BCL2) mRNA was detected by qRT-PCR. The proliferation, migration, invasion and apoptosis of keloid fibroblasts (KFs) was examined using Cell Counting Kit-8 assay, transwell assay or flow cytometry, respectively. Western blot was used to detect the level of proliferating cell nuclear antigen, cleaved-caspase 3, collagen I, collagen III and BCL2 protein. The interaction between miR-4328 and BCL2 was confirmed by luciferase reporter analyses. It was observed that miR-4328 was down-regulated in keloid tissues and fibroblasts, and miR-4328 restoration mediated the inhibition of proliferation, metastasis, collagen synthesis and the promotion of apoptosis in KFs. BCL2 was up-regulated in keloid tissues and fibroblasts, and BCL2 knockdown promoted the deterioration of KFs. In addition, BCL2 was confirmed to be a target of miR-4328, and the rescue experiment indicated that the inhibitory action of miR-4328 on keloid fibroblast progression was reversed by BCL2 overexpression. Thus, our results demonstrated that miR-4328 restrained the deterioration of KFs by targeting BCL2, which sheds new light on miR-4328 as a promising target for keloid development and therapeutic.

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BCL2 Regulates Differentiation of Intestinal Fibroblasts

Cited by 19 publications

References 59 publications

Secretome of Mesenchymal Stromal Cells Prevents Myofibroblasts Differentiation by Transferring Fibrosis-Associated microRNAs within Extracellular Vesicles

Secretome of Mesenchymal Stromal Cells Prevents Myofibroblasts Differentiation by Transferring Fibrosis-Associated microRNAs within Extracellular Vesicles

ER‐anchored CRTH2 antagonizes collagen biosynthesis and organ fibrosis via binding LARP6

MiR-4328 inhibits proliferation, metastasis and induces apoptosis in keloid fibroblasts by targeting BCL2 expression

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