Deletion of delta-like 1 homologue accelerates fibroblast–myofibroblast differentiation and induces myocardial fibrosis

Rodriguez, Patricia Q.; Sassi, Yassine; Troncone, Luca; Bénard, Ludovic; Ishikawa, Kiyotake; Gordon, Ronald E.; Lamas, Santiago; Laborda, Jorge; Hajjar, Roger J.; Lebeche, Djamel

doi:10.1093/eurheartj/ehy188

Cited by 77 publications

(70 citation statements)

References 27 publications

(48 reference statements)

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“…In the adult bone marrow DLK1 mRNA expression is detected by PCR, but with a clear inter-donor variation [32]. Previous studies have shown, that DLK1 is largely absent in the human heart [19], but a very recent study suggests that DLK1 is expressed in adult cardiomyocytes and fibroblasts [33]. This may however be debatable as we have unpublished data demonstrating that DLK1 is only expressed in cells residing in the adult peri-/epicardium, and not within the myocardium itself.…”

Section: Mesodermal Tissuesmentioning

confidence: 97%

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The imprinted gene Delta like non-canonical Notch ligand 1 (Dlk1) is conserved in mammals, and serves a growth modulatory role during tissue development and regeneration through Notch dependent and independent mechanisms

Traustadóttir

Lagoni

Ankerstjerne

et al. 2019

Cytokine & Growth Factor Reviews

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Section: Mesodermal Tissuesmentioning

confidence: 97%

“…Pancreas [19,26,28,29] ------------------Prostate [30,31] Liver [19,26,137] Lung [19] Mesoderm Bone [19,32] --------Heart (unpublished, [33])…”

Section: Pre-natalmentioning

confidence: 99%

The imprinted gene Delta like non-canonical Notch ligand 1 (Dlk1) is conserved in mammals, and serves a growth modulatory role during tissue development and regeneration through Notch dependent and independent mechanisms

Traustadóttir

Lagoni

Ankerstjerne

et al. 2019

Cytokine & Growth Factor Reviews

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show abstract

“…Moreover, several other miRNAs that were in higher abundance in CMC db/db -derived EVs have been shown to have beneficial actions. For example, the levels of miR-15a, mi339–5p, and mi-370 were higher in EVs derived from CMC db/db cells, and these are thought to be involved in tissue regeneration or fibrosis [37, 51, 53]. That these in vitro measures of cell competence do not equate to in vivo efficacy is an important outcome of this study that merits further investigation.…”

Section: Discussionmentioning

confidence: 97%

Cardiac mesenchymal cells from diabetic mice are ineffective for cell therapy-mediated myocardial repair

et al. 2018

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Although cell therapy improves cardiac function after myocardial infarction, highly variable results and limited understanding of the underlying mechanisms preclude its clinical translation. Because many heart failure patients are diabetic, we examined how diabetic conditions affect the characteristics of cardiac mesenchymal cells (CMC) and their ability to promote myocardial repair in mice. To examine how diabetes affects CMC function, we isolated CMCs from non-diabetic C57BL/6J (CMCWT) or diabetic B6.BKS(D)-Leprdb/J (CMCdb/db) mice. When CMCs were grown in 17.5 mM glucose, CMCdb/db cells showed > twofold higher glycolytic activity and a threefold higher expression of Pfkfb3 compared with CMCWT cells; however, culture of CMCdb/db cells in 5.5 mM glucose led to metabolic remodeling characterized by normalization of metabolism, a higher NAD+/NADH ratio, and a sixfold upregulation of Sirt1. These changes were associated with altered extracellular vesicle miRNA content as well as proliferation and cytotoxicity parameters comparable to CMCWT cells. To test whether this metabolic improvement of CMCdb/db cells renders them suitable for cell therapy, we cultured CMCWT or CMCdb/db cells in 5.5 mM glucose and then injected them into infarcted hearts of non-diabetic mice (CMCWT, n = 17; CMCdb/db, n = 13; Veh, n = 14). Hemodynamic measurements performed 35 days after transplantation showed that, despite normalization of their properties in vitro, and unlike CMCWT cells, CMCdb/db cells did not improve load-dependent and -independent parameters of left ventricular function. These results suggest that diabetes adversely affects the reparative capacity of CMCs and that modulating CMC characteristics via culture in lower glucose does not render them efficacious for cell therapy.

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“…TGF-β1 is a powerful chemokine for monocytes and broblasts [30]. As well as, it can increase the proliferation ability of broblasts, promote their secretion of extracellular matrix such as collagen and bronectin [31]. TGF-β1 can induce broblasts phenotype Transformation to myo broblasts phenotype, characterized by high synthesis of α-SMA, causing matrix contraction and participating in accelerating the extracellular matrix deposition [32].…”

Section: Discussionmentioning

confidence: 99%

Mycophenolate mofetil reduces epidural fibrosis by regulating TGF-β1/Smad2/3 axis to repress the proliferation, migration and differentiation of fibroblasts

Zhu¹,

Zhang²,

Zhang³

et al. 2020

Preprint

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Background Excessive fibroblasts proliferation is believed as a major reason in the process of epidural fibrosis, which is known as a troublesome complication of lumbar laminectomy clinically. Mycophenolate mofetil (MMF) is a kind of immunosuppressant, previous studies had shown that it has the function of preventing fibrosis, but the role and mechanism are still unclear. In this study, we determined the repressed effect of MMF on fibroblasts proliferation, migration and differentiation in surgical-induced epidural fibrosis and the underlying mechanism. Methods In vitro, the impacts of MMF on cell viability were measured by cell counting kit-8 (CCK-8) assay and the fibroblasts proliferation rates were determined by using EdU incorporation, cell cycle assays and western blot. Additionally, the impacts of MMF on fibroblasts migration and differentiation were analyzed by cell wound scratch assay, transwell assay, immunofluorescence analysis and western blot. In vivo, we built epidural fibrosis models in rats and locally applied MMF. Histological and immunohistochemical staining were used to determine the effect of MMF on reducing epidural fibrosis and fibroblasts functions. Results CCK-8 assay demonstrated that MMF repressed fibroblasts proliferation in a time- and a dose-dependent manner. EdU incorporation assay and cell cycle analysis proved the inhibition effect of MMF on the proliferation of fibroblasts. Cell wound scratch assay, transwell assay and immunofluorescence proved the inhibition effect of MMF on the migration and differentiation of fibroblasts. Western blotting analysis proved that MMF inhibited the expression of TGF-β1, p-Smad2 and p-Smad3. The expression of proliferation proteins, migration proteins and differentiation proteins were downregulated. In addition, histological and immunohistochemical stain showed that MMF reduces epidural fibrosis by repressing the proliferation, migration and differentiation of fibroblasts. Conclusion MMF could inhibit the proliferation, migration and differentiation of fibroblasts, it reduced surgical-induced epidural fibrosis as well. TGF-β1/Smad2/3 axis may be the latent mechanism in MMF reduced epidural fibrosis. It might provide a new notion for mitigating surgery-induced epidural fibrosis.

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Deletion of delta-like 1 homologue accelerates fibroblast–myofibroblast differentiation and induces myocardial fibrosis

Cited by 77 publications

References 27 publications

The imprinted gene Delta like non-canonical Notch ligand 1 (Dlk1) is conserved in mammals, and serves a growth modulatory role during tissue development and regeneration through Notch dependent and independent mechanisms

The imprinted gene Delta like non-canonical Notch ligand 1 (Dlk1) is conserved in mammals, and serves a growth modulatory role during tissue development and regeneration through Notch dependent and independent mechanisms

Cardiac mesenchymal cells from diabetic mice are ineffective for cell therapy-mediated myocardial repair

Mycophenolate mofetil reduces epidural fibrosis by regulating TGF-β1/Smad2/3 axis to repress the proliferation, migration and differentiation of fibroblasts

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