Dissecting the Role of Mesenchymal Stem Cells in Idiopathic Pulmonary Fibrosis: Cause or Solution.

Anna Valeria Samarelli,Linda Manicardi,Ilenia Mastrolia,Luca Tabbì,Irene Heijink,Daniel J Weiss,Roberto Tonelli,Stefania Cerri,Ivana Castaniere,Filippo Gozzi,Enrico Clini,Alessandro Marchioni,Giulia Bruzzi,Antonio Moretti,Riccardo Fantini,Chiara Nani,Dario Andrisani,Massimo Dominici,Aina Martin Medina

doi:10.3389/fphar.2021.692551

Abstract

Idiopathic pulmonary fibrosis (IPF) is one of the most aggressive forms of idiopathic interstitial pneumonias, characterized by chronic and progressive fibrosis subverting the lung’s architecture, pulmonary functional decline, progressive respiratory failure, and high mortality (median survival 3 years after diagnosis). Among the mechanisms associated with disease onset and progression, it has been hypothesized that IPF lungs might be affected either by a regenerative deficit of the alveolar epithelium or by a dysregulation of repair mechanisms in response to alveolar and vascular damage. This latter might be related to the progressive dysfunction and exhaustion of the resident stem cells together with a process of cellular and tissue senescence. The role of endogenous mesenchymal stromal/stem cells (MSCs) resident in the lung in the homeostasis of these mechanisms is still a matter of debate. Although endogenous MSCs may play a critical role in lung repair, they are also involved in cellular senescence and tissue ageing processes with loss of lung regenerative potential. In addition, MSCs have immunomodulatory properties and can secrete anti-fibrotic factors. Thus, MSCs obtained from other sources administered systemically or directly into the lung have been investigated for lung epithelial repair and have been explored as a potential therapy for the treatment of lung diseases including IPF. Given these multiple potential roles of MSCs, this review aims both at elucidating the role of resident lung MSCs in IPF pathogenesis and the role of administered MSCs from other sources for potential IPF therapies.

Highlights

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrosing lung disease of unknown cause that occurs primarily in older adults with a median survival of 3 years after diagnosis
Given the lessons learned from preclinical studies, further strategies can be developed in which exogenously administered mesenchymal stromal/ stem cells (MSCs) might contribute to prevent disease progression or might even revert established lung fibrosis, suppressing inflammation and supporting alveolar repair
Lung resident MSCs might contribute to IPF pathogenesis and progression as they might differentiate into myofibroblast following lung damage

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrosing lung disease of unknown cause that occurs primarily in older adults with a median survival of 3 years after diagnosis. According to more recent studies, the onset and progression of IPF is due to the aberrant damage and activation of alveolar epithelial cells (AECs) that lead to the secretion of profibrotic, coagulant, and inflammatory cytokines controlling the proliferation, activation and differentiation of fibroblasts into myofibroblasts and the consequent secretion and deposition of extracellular matrix (ECM) proteins (Selman and Pardo, 2020) These mechanisms translate into increased overall lung structural rigidity and thickening of the alveolarcapillary barrier with decline in alveolar gas exchange function. This includes a growing literature in which MSCsderived EVs can be as effective as the MSCs themselves in preclinical models of lung injuries (Cruz and Patricia, 2020; Harrell et al, 2019; Beer et al, 2017; Vizoso et al, 2017)

Objectives

Methods

Findings

Conclusion