Therapeutic effect of cyclin‐dependent kinase 4/6 inhibitor on dermal fibrosis in murine models of systemic sclerosis

2021 ◽  
Author(s):  
Akio Yamamoto ◽  
Tetsuya Saito ◽  
Tadashi Hosoya ◽  
Kimito Kawahata ◽  
Yoshihide Asano ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Therapeutic Effect ◽  
Cyclin Dependent Kinase ◽  
Murine Models ◽  
Dermal Fibrosis

scholarly journals Blockade of PDGF Receptors by Crenolanib Has Therapeutic Effect in Patient Fibroblasts and in Preclinical Models of Systemic Sclerosis

2017 ◽  
Vol 137 (8) ◽  
pp. 1671-1681 ◽  
Author(s):  
Katsunari Makino ◽  
Tomoko Makino ◽  
Lukasz Stawski ◽  
Julio C. Mantero ◽  
Robert Lafyatis ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Therapeutic Effect ◽  
Preclinical Models

scholarly journals Epigenetic activation and memory at a TGFB2 enhancer in systemic sclerosis

2019 ◽  
Vol 11 (497) ◽  
pp. eaaw0790 ◽  
Author(s):  
Joseph Yusup Shin ◽  
James Daniel Beckett ◽  
Rustam Bagirzadeh ◽  
Tyler J. Creamer ◽  
Ami A. Shah ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Transcriptome Profiling ◽  
Chromatin Accessibility ◽  
Epigenetic Mechanism ◽  
Enhancer Activity ◽  
Dermal Fibrosis ◽  
Transforming Growth Factor Β2 ◽  
Skin Explants

In systemic sclerosis (SSc), previously healthy adults develop an inflammatory prodrome with subsequent progressive fibrosis of the skin and viscera. SSc has a weak signature for genetic contribution, and there are few pathogenic insights or targeted treatments for this condition. Here, chromatin accessibility and transcriptome profiling coupled with targeted epigenetic editing revealed constitutive activation of a previously unannotated transforming growth factor–β2 (TGFB2) enhancer maintained through epigenetic memory in SSc. The resulting autocrine TGFβ2 signaling enforced a profibrotic synthetic state in ex vivo fibroblasts from patients with SSc. Inhibition of NF-κB or BRD4 achieved sustained inhibition of TGFB2 enhancer activity, mitigated profibrotic gene expression, and reversed dermal fibrosis in patient skin explants. These findings suggest a potential epigenetic mechanism of fibrosis in SSc and inform a regulatory mechanism of TGFB2, a major profibrotic cytokine.

scholarly journals Allogeneic marrow transplantation in patients with severe systemic sclerosis: Resolution of dermal fibrosis

2006 ◽  
Vol 54 (6) ◽  
pp. 1982-1986 ◽  
Author(s):  
Richard A. Nash ◽  
Peter A. McSweeney ◽  
J. Lee Nelson ◽  
Mark Wener ◽  
George E. Georges ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Marrow Transplantation ◽  
Dermal Fibrosis ◽  
Allogeneic Marrow Transplantation ◽  
Allogeneic Marrow

scholarly journals Failed Degradation of JunB Contributes to Overproduction of Type I Collagen and Development of Dermal Fibrosis in Patients With Systemic Sclerosis

2014 ◽  
Vol 67 (1) ◽  
pp. 243-253 ◽  
Author(s):  
Markella Ponticos ◽  
Ioannis Papaioannou ◽  
Shiwen Xu ◽  
Alan M. Holmes ◽  
Korsa Khan ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Type I Collagen ◽  
Type I ◽  
Dermal Fibrosis

Experimental models of dermal fibrosis and systemic sclerosis

2013 ◽  
Vol 80 (1) ◽  
pp. 23-28 ◽  
Author(s):  
Jérôme Avouac ◽  
Muriel Elhai ◽  
Yannick Allanore
Keyword(s):  
Systemic Sclerosis ◽  
Experimental Models ◽  
Dermal Fibrosis

scholarly journals Decreased cathepsin V expression due to Fli1 deficiency contributes to the development of dermal fibrosis and proliferative vasculopathy in systemic sclerosis

Rheumatology ◽  
2013 ◽  
Vol 52 (5) ◽  
pp. 790-799 ◽  
Author(s):  
S. Noda ◽  
Y. Asano ◽  
T. Takahashi ◽  
K. Akamata ◽  
N. Aozasa ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Dermal Fibrosis ◽  
Cathepsin V

scholarly journals Lung Fibrosis Is Improved by Extracellular Vesicles from IFNγ-Primed Mesenchymal Stromal Cells in Murine Systemic Sclerosis

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2727
Author(s):  
Pauline Rozier ◽  
Marie Maumus ◽  
Alexandre Thibault Jacques Maria ◽  
Karine Toupet ◽  
Christian Jorgensen ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Therapeutic Effect ◽  
Extracellular Vesicles ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Lung Fibrosis ◽  
Large Size ◽  
Anti Inflammatory ◽  
High Doses ◽  
Skin Samples

Background: Systemic sclerosis (SSc) is a severe autoimmune disease for which mesenchymal stromal cells (MSCs)-based therapy was reported to reduce SSc-related symptoms in pre-clinical studies. Recently, extracellular vesicles released by MSCs (MSC-EVs) were shown to mediate most of their therapeutic effect. Here, we aimed at improving their efficacy by increasing the MSC-EV dose or by IFNγ-priming of MSCs. Methods: small size (ssEVs) and large size EVs (lsEVs) were recovered from murine MSCs that were pre-activated using 1 or 20 ng/mL of IFNγ. In the HOCl-induced model of SSc, mice were treated with EVs at day 21 and sacrificed at day 42. Lung and skin samples were collected for histological and molecular analyses. Results: increasing the dose of MSC-EVs did not add benefit to the dose previously reported to be efficient in SSc. By contrast, IFNγ pre-activation improved MSC-EVs-based treatment, essentially in the lungs. Low doses of IFNγ decreased the expression of fibrotic markers, while high doses improved remodeling and anti-inflammatory markers. IFNγ pre-activation upregulated iNos, IL1ra and Il6 in MSCs and ssEVs and the PGE2 protein in lsEVs. Conclusion: IFNγ-pre-activation improved the therapeutic effect of MSC-EVs preferentially in the lungs of SSc mice by modulating anti-inflammatory and anti-fibrotic markers.

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