Development and validation of a transcriptional signature for the assessment of fibrosis in organs

Wang, B; Chen, S; Qian, Hui; Chen, R; Zhang, X; Xuan, Jingxiu; Y, Liu; Shi, Guixiu

doi:10.1101/2020.03.14.20024141

Cited by 4 publications

(3 citation statements)

References 23 publications

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“…In addition, CML 2 was previously treated and therefore likewise excluded from further analyses (Supplementary Figure S3C). We could observe significant Frontiers in Pharmacology frontiersin.org changes in a defined fibrotic gene signature set, which was previously derived from the analysis of expression profiling datasets of human organs with fibrosis-related diseases (Wang et al, 2020) (Figure 4A). Furthermore, an altered expression profile was also observed in a defined gene set for hematopoiesis support (Figure 4B).…”

Section: Mscs Are Driven Towards a Fibrotic And Potentially Lsc-suppo...mentioning

confidence: 87%

Myelofibrosis at diagnosis is associated with the failure of treatment-free remission in CML patients

Jacobi,

Vieri,

Bütow

et al. 2023

Front. Pharmacol.

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The management of patients with chronic myeloid leukemia (CML) has been revolutionized by the introduction of tyrosine kinase inhibitors (TKIs), which induce deep molecular responses so that treatment can eventually be discontinued, leading to treatment-free remission (TFR) in a subset of patients. Unfortunately, leukemic stem cells (LSCs) often persist and a fraction of these can again expand in about half of patients that attempt TKI discontinuation. In this study, we show that presence of myelofibrosis (MF) at the time of diagnosis is a factor associating with TFR failure. Fibrotic transformation is governed by the action of several cytokines, and interestingly, some of them have also been described to support LSC persistence. At the cellular level, these could be produced by both malignant cells and by components of the bone marrow (BM) niche, including megakaryocytes (MKs) and mesenchymal stromal cells (MSCs). In our cohort of 57 patients, around 40% presented with MF at diagnosis and the number of blasts in the peripheral blood and BM was significantly elevated in patients with higher grade of MF. Employing a CML transgenic mouse model, we could observe higher levels of alpha-smooth muscle actin (α-SMA) in the BM when compared to control mice. Short-term treatment with the TKI nilotinib, efficiently reduced spleen weight and BCR::ABL1 mRNA levels, while α-SMA expression was only partially reduced. Interestingly, the number of MKs was increased in the spleen of CML mice and elevated in both BM and spleen upon nilotinib treatment. Analysis of human CML-vs healthy donor (HD)-derived MSCs showed an altered expression of gene signatures reflecting fibrosis as well as hematopoietic support, thus suggesting MSCs as a potential player in these two processes. Finally, in our cohort, 12 patients qualified for TKI discontinuation, and here we observed that all patients who failed TFR had BM fibrosis at diagnosis, whereas this was only the case in 25% of patients with achieved TFR, further supporting the link between fibrosis and LSC persistence.

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Section: Mscs Are Driven Towards a Fibrotic And Potentially Lsc-suppo...mentioning

confidence: 87%

Myelofibrosis at diagnosis is associated with the failure of treatment-free remission in CML patients

Jacobi,

Vieri,

Bütow

et al. 2023

Front. Pharmacol.

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“…Gene sets were acquired from Molecular Signatures Database (MSigDB) ( 36 ) (Hallmarks Inflammation Gene Set, GO_Osteoclast_differentiation), Aran et al ( 59 ) (M1/M2 signatures), and Wang et al ( 60 ) (fibrosis signature). For each gene, we translated the human gene set to mouse orthologs using the gorth function from the gprofiler2 package in R. For M1 and M2 analyses, only genes unique to one of the lists were used.…”

Section: Methodsmentioning

confidence: 99%

Pulmonary osteoclast-like cells in silica induced pulmonary fibrosis

Hasegawa,

Franks,

Tanaka

et al. 2024

Sci. Adv.

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The pathophysiology of silicosis is poorly understood, limiting development of therapies for those who have been exposed to the respirable particle. We explored mechanisms of silica-induced pulmonary fibrosis in human lung samples collected from patients with occupational exposure to silica and in a longitudinal mouse model of silicosis using multiple modalities including whole-lung single-cell RNA sequencing and histological, biochemical, and physiologic assessments. In addition to pulmonary inflammation and fibrosis, intratracheal silica challenge induced osteoclast-like differentiation of alveolar macrophages and recruited monocytes, driven by induction of the osteoclastogenic cytokine, receptor activator of nuclear factor κΒ ligand (RANKL) in pulmonary lymphocytes, and alveolar type II cells. Anti-RANKL monoclonal antibody treatment suppressed silica-induced osteoclast-like differentiation in the lung and attenuated pulmonary fibrosis. We conclude that silica induces differentiation of pulmonary osteoclast-like cells leading to progressive lung injury, likely due to sustained elaboration of bone-resorbing proteases and hydrochloric acid. Interrupting osteoclast-like differentiation may therefore constitute a promising avenue for moderating lung damage in silicosis.

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“…Gene sets were acquired from MSigDB ( 29 ) (Hallmarks Inflammation Gene Set, GO_Osteoclast_differentiation), Aran et al 2017 ( 64 ) (M1/M2 signatures), and Wang et al( 65 ) (Fibrosis signature). For each gene, we translated the human gene set to mouse orthologs using the gorth function from the gprofiler2 package in R. For M1 and M2 analyses, only genes unique to one of the lists was used.…”

Section: Methodsmentioning

confidence: 99%

Pulmonary osteoclast-like cells in silica induced pulmonary fibrosis

Hasegawa

Franks

Tanaka

et al. 2023

Preprint

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The pathophysiology of silicosis is poorly understood, limiting development of therapies for those who have been exposed to the respirable particle. We explored the mechanisms of silica-induced pulmonary fibrosis in a mouse model using multiple modalities including whole-lung single-nucleus RNA sequencing. These analyses revealed that in addition to pulmonary inflammation and fibrosis, intratracheal silica challenge induced osteoclast-like differentiation of alveolar macrophages and recruited monocytes, driven by induction of the osteoclastogenic cytokine, receptor activator of nuclear factor-κΒ ligand (RANKL) in pulmonary lymphocytes and alveolar type II cells. Furthermore, anti-RANKL monoclonal antibody treatment suppressed silica-induced osteoclast-like differentiation in the lung and attenuated silica-induced pulmonary fibrosis. We conclude that silica induces osteoclast-like differentiation of distinct recruited and tissue resident monocyte populations, leading to progressive lung injury, likely due to sustained elaboration of bone resorbing proteases and hydrochloric acid. Interrupting osteoclast-like differentiation may therefore constitute a promising avenue for moderating lung damage in silicosis.

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Development and validation of a transcriptional signature for the assessment of fibrosis in organs

Cited by 4 publications

References 23 publications

Myelofibrosis at diagnosis is associated with the failure of treatment-free remission in CML patients

Myelofibrosis at diagnosis is associated with the failure of treatment-free remission in CML patients

Pulmonary osteoclast-like cells in silica induced pulmonary fibrosis

Pulmonary osteoclast-like cells in silica induced pulmonary fibrosis

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