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Blocking antibodies against integrin-α3, -αM, and -αMβ2 de-differentiate myofibroblasts, and improve lung fibrosis and kidney fibrosis

ABSTRACT: Blocking antibodies against integrin-α3, -αM, and -αMβ2 de-differentiate myofibroblasts, and improve lung fibrosis and kidney fibrosis

PROVIDER: PRJNA1142900 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30075259.fastq.gz	Fastqsanger.gz
	SRR30075260.fastq.gz	Fastqsanger.gz
	SRR30075261.fastq.gz	Fastqsanger.gz
	SRR30075262.fastq.gz	Fastqsanger.gz
	SRR30075263.fastq.gz	Fastqsanger.gz

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Blocking antibodies against integrin-α3, -αM, and -αMβ2 de-differentiate myofibroblasts, and improve lung fibrosis and kidney fibrosis

Project description:Fibrosis is involved in 45% of deaths in the United States, and no treatment exists to reverse the progression of lung or kidney fibrosis. Myofibroblasts are key to the progression and maintenance of fibrosis. We investigated features of cell adhesion necessary for monocytes to differentiate into myofibroblasts, seeking to identify pathways key to myofibroblast differentiation. Blocking antibodies against integrins α3, αM, and αMβ2 de-differentiate myofibroblasts in vitro, lower the pro-fibrotic secretome of myofibroblasts, and treat lung fibrosis and inhibit kidney fibrosis in vivo. Decorin’s collagen-binding peptide can be used to direct functionalized blocking antibodies (against integrins-α3, -αM, -αMβ2) to both fibrotic lungs and fibrotic kidneys, reducing the dose of antibody necessary to treat fibrosis. This targeted immunotherapy blocking key integrins may be an effective therapeutic for the treatment of fibrosis.

2024-09-25 | GSE273713 | GEO

Blocking antibodies against integrin-α3, -αM, and -αMβ2 de-differentiate myofibroblasts, and improve lung fibrosis and kidney fibrosis.

Project description:Fibrosis is involved in 45% of deaths in the United States, and no treatment exists to reverse the progression of lung or kidney fibrosis. Myofibroblasts are key to the progression and maintenance of fibrosis. We investigated features of cell adhesion necessary for monocytes to differentiate into myofibroblasts, seeking to identify pathways key to myofibroblast differentiation. Blocking antibodies against integrins α3, αM, and αMβ2 de-differentiate myofibroblasts in vitro, lower the pro-fibrotic secretome of myofibroblasts, and treat lung fibrosis and inhibit kidney fibrosis in vivo. Decorin's collagen-binding peptide can be used to direct functionalized blocking antibodies (against integrins-α3, -αM, -αMβ2) to both fibrotic lungs and fibrotic kidneys, reducing the dose of antibody necessary to treat fibrosis. This targeted immunotherapy blocking key integrins may be an effective therapeutic for the treatment of fibrosis.

| S-EPMC11405753 | biostudies-literature

Integrin beta-1 (Itgb1) in profibrotic myofibroblasts

Project description:Fibrosis due to extracellular matrix (ECM) secretion from myofibroblasts complicates many chronic liver diseases causing scarring and organ failure. Integrin-dependent interaction with scar ECM promotes profibrotic features. This microarray study was performed to clarify the role of integrin beta-1 (Itgb1) in profibrotic myofibroblasts.

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Absence of integrin α3 modulates the integrin landscape of human keratinocytes

Project description:Integrins are among the most abundant cell surface receptors constituting the principal adhesion receptors for the extracellular matrix (ECM), providing a physical anchor for the cell and triggering multiple intracellular signalling events. Loss-of function mutations of the integrin α3 gene (ITGA3) have been recently disclosed in patients with interstitial lung disease, congenital nephrotic syndrome and junctional epidermolysis bullosa, a multiorgan disorder with fatal outcome. In these patients, the respiratory function is strongly impaired and the kidneys are variably affected, whereas skin fragility is rather mild, has a delayed onset after birth or remains unrecognized, suggesting that integrin α3 differently influences the development and homeostasis of these organs. Here we employed authentic human keratinocytes bearing a naturally occurring integrin α3 loss-of-function mutation as a prototype to characterize the molecular mechanisms launched by the constitutional absence of this integrin subunit. To validate our findings, we generated new cellular models, including an additional ILNEB patient cell line, ITGA3 rescued and knockdown cells. We show that keratinocytes lacking a functional α3 subunit have an activated cellular phenotype with a switch in the pattern of integrin α subunits on the cell surface. These assure spreading and adhesion of epidermal keratinocytes but also drive the migratory phenotype of these cells.

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Transcription profiling of human myofibroblasts isolated from patients with idiopathic pulmonary fibrosis

Project description:Idiopathic pulmonary fibrosis (IPF), a chronic progressive lung disease of unknown etiology, is characterized by the expansion of myofibroblasts and abnormal deposition of extracellular matrix in the lung parenchyma. To elucidate the molecular mechanisms that lead to IPF, we analyzed myofibroblasts established from patients with IPF by oligonucleotide microarrays. Gene expression profiles revealed a novel pathophysiologic function of myofibroblasts as a generator of reactive oxygen species, and a self-defense mechanism against oxidative stress of their own generating. Experiment Overall Design: We isolated two myofibroblast cell culture from patients with idiopathic pulmonary fibrosis. Embryonic pulmonary fibroblast was used for the reference.

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The Forkhead Box F1 Transcription Factor Inhibits Collagen Deposition and Accumulation of Myofibroblasts During Liver Fibrosis

Project description:Hepatic fibrosis is the common end stage to a variety of chronic liver injuries and is characterized by an excessive deposition of extracellular matrix (ECM), which disrupts the liver architecture and impairs liver function. The fibrous lesions are produced by myofibroblasts, which differentiate from hepatic stellate cells (HSC). The myofibroblasts transcriptional networks remain poorly characterized. Previous studies have shown that the Forkhead box F1 (FOXF1) transcription factor is expressed in HSCs and stimulates their activation during acute liver injury; however, the role of FOXF1 in the progression of hepatic fibrosis is unknown. In the present study, we generated αSMACreER;Foxf1fl/fl mice to conditionally inactivate Foxf1 in myofibroblasts during carbon tetrachloride-mediated liver fibrosis. Foxf1 deletion increased collagen depositions and disrupted liver architecture. Timp2 expression was significantly increased in Foxf1-deficient mice while MMP9 activity was reduced. RNA sequencing of purified liver myofibroblasts demonstrated that FOXF1 inhibits expression of pro-fibrotic genes, Col1α2, Col5α2, and Mmp2 in fibrotic livers and binds to active repressors located in promotors and introns of these genes. Overexpression of FOXF1 inhibits Col1a2, Col5a2, and MMP2 in primary murine HSCs in vitro. Altogether, FOXF1 prevents aberrant ECM depositions during hepatic fibrosis by repressing pro-fibrotic gene transcription in myofibroblasts and HSCs.

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SOX9 regulates NAV3 to control cytoskeletal and mechanical properties of profibrotic myofibroblasts during renal fibrosis

Project description:Fibrosis is a common pathway in the progression of chronic kidney disease. Extracellular matrix deposition from myofibroblasts causes scarring, tissue stiffness and organ failure. This submission studies the role of Sex determining region Y-box 9 (SOX9) in kidney fibrosis.

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A human integrin-α3 mutation confers major renal developmental defects.

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WWP2 MEDIATES THE METABOLIC REPROGRAMMING OF RENAL MYOFIBROBLASTS TO PROMOTE KIDNEY FIBROSIS [ChIP-Seq]

Project description:Renal fibrosis is a common pathological endpoint that is challenging to reverse in chronic kidney disease (CKD) independently of the underlying causes. Although myofibroblasts are mainly responsible for the accumulation of a fibrillar collagen-rich extracellular matrix (ECM), recent reports revealed their heterogeneity in proliferative and fibrotic activities, mirroring specific metabolic states that drive fibrosis. Here, we investigate the role of E3 ubiquitin-protein ligase WWP2 in the metabolic reprogramming of renal myofibroblasts in fibrosis. The tubulointerstitial expression of WWP2 contributes to the progression of fibrosis in CKD patients and in pre-clinical models of CKD. WWP2 deficiency leads to increased fatty acid oxidation, boosting mitochondrial respiration, promoting myofibroblast proliferation and arresting pro-fibrotic activation, thus ameliorating kidney fibrosis. Specifically, WWP2 suppresses the transcription of PGC-1α, which mediates the metabolic and proliferative changes in fibrotic myofibroblasts. Pharmacological intervention targeting PGC-1α reverses the pro-fibrotic effect of WWP2. These findings reveal a previously unappreciated WWP2-PGC-1α axis underlying the metabolic reprogramming of myofibroblasts during renal fibrosis, which could provide a new target for therapeutic intervention in CKD.

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WWP2 MEDIATES THE METABOLIC REPROGRAMMING OF RENAL MYOFIBROBLASTS TO PROMOTE KIDNEY FIBROSIS [scRNA-seq]

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