Use of the Reversible Myogenic to Lipogenic Transdifferentiation Switch for the Design of Pre-clinical Drug Screening in Idiopathic Pulmonary Fibrosis

Arun Lingampally; Matthew R Jones; Shirisha Bagari; Chengshui Chen; Stefano Rivetti; Saverio Bellusci

doi:10.3389/fbioe.2020.569865

Use of the Reversible Myogenic to Lipogenic Transdifferentiation Switch for the Design of Pre-clinical Drug Screening in Idiopathic Pulmonary Fibrosis

Front Bioeng Biotechnol. 2020 Sep 15:8:569865. doi: 10.3389/fbioe.2020.569865. eCollection 2020.

Authors

Arun Lingampally^{1

2}, Matthew R Jones^{1

2}, Shirisha Bagari^{1

2}, Chengshui Chen¹, Stefano Rivetti^{1

2}, Saverio Bellusci^{1

2}

Affiliations

¹ Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
² Department of Pulmonary and Critical Care Medicine and Infectious Diseases, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Cardio-Pulmonary Institute, Justus-Liebig University Giessen, Giessen, Germany.

Abstract

Idiopathic Pulmonary Fibrosis (IPF) is an end-stage lung disease characterized by excessive extracellular matrix (ECM) deposition from activated myofibroblasts (MYFs) and tissue scarring. Eventually leading to stiffening of the lung, capable of assuming only limited gas exchange function. So far two drugs, pirfenidone [acting via TGF-β (transforming growth factor beta) inhibition] and nintedanib (a pan-tyrosine kinase receptor inhibitor) have been approved for IPF patients. They both act on the activated MYF by reducing the expression of fibrotic markers. Unfortunately, these drugs are only slowing down fibrosis formation and as such do not represent a cure for this lethal, devastating disease. We previously reported that activated MYF originate, at least in part, from lung fibroblast resident cells called lipofibroblasts (LIF). During resolution, these activated MYF can transdifferentiate into LIF. We propose that this reversible myogenic/lipogenic transdifferentiation switch paradigm can be used to screen for drugs capable of triggering the lipogenic differentiation of activated MYFs. Ideally, these drugs should also induce the reduction of pro-fibrotic markers alpha smooth muscle actin2 (ACTA2) and collagen 1A1 (COL1A1) in activated MYF and as such would represent important alternatives to the approved drugs. The goal of this review is to summarize the current knowledge and limitations of the current strategies aiming to carry out methodical pre-clinical drug screening in pertinent in vitro, ex vivo, and in vivo models of IPF. These models include (1) in vitro culture of primary fibroblasts from IPF patients, (2) ex vivo culture of precision cut lung slices from end-stage IPF lungs obtained from transplant patients, and (3) bleomycin-induced fibrosis mouse models in the context of lineage tracing of activated MYF during resolution. For all these assays, we propose the innovative use of lipogenic read outs for the LIFs.

Keywords: activated myofibroblast; aging; alveolar type 2 cells; idiopathic pulmonary fibrosis; in vitro models; lipofibroblast.

Publication types

Review