Idiopathic pulmonary fibrosis (IPF) is a devastating progressive fibrotic disease affecting the lungs and causing chronic respiratory failure. In IPF, adult alveolar type II stem cells (ATII) cannot trans-differentiate to alveolar type I cells (ATI), and therefore, represents a relevant target in the progression of lung fibrosis. There are only two FDA-approved drugs for the treatment of IPF, which can only ameliorate the disease, but a permanent cure is not yet available. In this work, we showed that human ATII cells isolated from IPF patients displayed impaired trans-differentiation in vitro. When transfected with miR-200c the ability of trans-differentiation was restored. The administration of miR-200c into mice lungs was performed using an aerosol delivery system, which resulted in an inhibited fibrosis in bleomycin-induced lung fibrosis mouse model. This data confirms miR-200c to be a powerful anti-fibrotic treatment in conditions of early onset fibrosis and when fibrosis was already established. We investigated if ATII differentiation could be rescued upon down-regulation of Flt1 a miR-200c target and highly expressed in endothelial cells. For this reason, we performed co-culture assays between endothelial cells from both Wild type (WT) and Cdh5 -ERT2-CreFlt1flox/flox mice, depleting Flt1 in endothelial cells, and ctrl and bleomycin ATII cells. We observed that the knock-out of Flt1 in endothelial cells prevented disease progression in a murine model of lung fibrosis, through releasing an increased amount of angiocrine factors, such as SerpinC1, Haptoglobin, Itih2 detected by mass spectrometry analysis of the secretome. This work importantly contributed to the discovery of a new potential IPF treatment, such as miR-200c, and to the underlying molecular mechanisms involved in both lung fibrosis and lung regeneration.

Idiopathic pulmonary fibrosis (IPF) is a devastating progressive fibrotic disease affecting the lungs and causing chronic respiratory failure. In IPF, adult alveolar type II stem cells (ATII) cannot trans-differentiate to alveolar type I cells (ATI), and therefore, represents a relevant target in the progression of lung fibrosis. There are only two FDA-approved drugs for the treatment of IPF, which can only ameliorate the disease, but a permanent cure is not yet available. In this work, we showed that human ATII cells isolated from IPF patients displayed impaired trans-differentiation in vitro. When transfected with miR-200c the ability of trans-differentiation was restored. The administration of miR-200c into mice lungs was performed using an aerosol delivery system, which resulted in an inhibited fibrosis in bleomycin-induced lung fibrosis mouse model. This data confirms miR-200c to be a powerful anti-fibrotic treatment in conditions of early onset fibrosis and when fibrosis was already established. We investigated if ATII differentiation could be rescued upon down-regulation of Flt1 a miR-200c target and highly expressed in endothelial cells. For this reason, we performed co-culture assays between endothelial cells from both Wild type (WT) and Cdh5 -ERT2-CreFlt1flox/flox mice, depleting Flt1 in endothelial cells, and ctrl and bleomycin ATII cells. We observed that the knock-out of Flt1 in endothelial cells prevented disease progression in a murine model of lung fibrosis, through releasing an increased amount of angiocrine factors, such as SerpinC1, Haptoglobin, Itih2 detected by mass spectrometry analysis of the secretome. This work importantly contributed to the discovery of a new potential IPF treatment, such as miR-200c, and to the underlying molecular mechanisms involved in both lung fibrosis and lung regeneration.

miR-200c prevents and reverts Lung fibrosis by down regulating Flt1 and promoting lung regeneration / Volpe, MARIA CONCETTA. - (2022 Mar 04).

miR-200c prevents and reverts Lung fibrosis by down regulating Flt1 and promoting lung regeneration

VOLPE, MARIA CONCETTA
2022-03-04

Abstract

Idiopathic pulmonary fibrosis (IPF) is a devastating progressive fibrotic disease affecting the lungs and causing chronic respiratory failure. In IPF, adult alveolar type II stem cells (ATII) cannot trans-differentiate to alveolar type I cells (ATI), and therefore, represents a relevant target in the progression of lung fibrosis. There are only two FDA-approved drugs for the treatment of IPF, which can only ameliorate the disease, but a permanent cure is not yet available. In this work, we showed that human ATII cells isolated from IPF patients displayed impaired trans-differentiation in vitro. When transfected with miR-200c the ability of trans-differentiation was restored. The administration of miR-200c into mice lungs was performed using an aerosol delivery system, which resulted in an inhibited fibrosis in bleomycin-induced lung fibrosis mouse model. This data confirms miR-200c to be a powerful anti-fibrotic treatment in conditions of early onset fibrosis and when fibrosis was already established. We investigated if ATII differentiation could be rescued upon down-regulation of Flt1 a miR-200c target and highly expressed in endothelial cells. For this reason, we performed co-culture assays between endothelial cells from both Wild type (WT) and Cdh5 -ERT2-CreFlt1flox/flox mice, depleting Flt1 in endothelial cells, and ctrl and bleomycin ATII cells. We observed that the knock-out of Flt1 in endothelial cells prevented disease progression in a murine model of lung fibrosis, through releasing an increased amount of angiocrine factors, such as SerpinC1, Haptoglobin, Itih2 detected by mass spectrometry analysis of the secretome. This work importantly contributed to the discovery of a new potential IPF treatment, such as miR-200c, and to the underlying molecular mechanisms involved in both lung fibrosis and lung regeneration.
4-mar-2022
CONFALONIERI, Marco
34
2020/2021
Settore MED/10 - Malattie dell'Apparato Respiratorio
Università degli Studi di Trieste
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Descrizione: PhD Thesis Maria Concetta Volpe
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11368/3014982
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