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

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.

Keywords: cell based therapy; exosomes; extracellular matrix; idiopathic pulmonary fibrosis; mesenchymal stem cells.

FIGURE 1

Different response from the epithelium to lung injury in normal and IPF lung. In normal lung, the depletion of alveolar epithelial cells 1 (AECI) that play a pivotal role in gas exchange with the adjacent blood vessels after injuries, is compensated/replenished by/upon the differentiation of alveolar epithelial cells 2 (AECII) in AECI, restoring the alveolar epithelium. In lung epithelium of IPF patients, the regeneration of AECI by AECII progenitors is compromised, leading to impaired alveolar re-epithelialization. Together with the aberrant repair mechanisms the AECs start to secrete pro-fibrotic mediators that through different molecular pathway and down-stream effectors lead to fibroblast migration, proliferation, activation and differentiation into myofibroblasts with deposition of exaggerated ECM that drastically compromise the lung biomechanics properties.

FIGURE 2

Onset and progression of IPF: the myofibroblast in focus. According to the first hypothesis, the activation of alveolar epithelial cells (AECs) leads to the secretion of pro-fibrotic molecules, coagulant and cytokines that activate several cells from different sources: the resident fibroblast, the resident mesenchymal stromal/stem cells, the epithelial cells that undergo to the epithelial mesenchymal transition, the pericytes and the endothelial cells progenitors. These different cell types in IPF lungs may differentiate into myofibroblasts with the consequent secretion and deposition of extracellular matrix proteins followed by an overall lung structural rigidity and decline of alveolar function. According to the most recent publications (Etc 2019; Xie et al., 2016), interstitial lung fibroblasts, pericytes, lipofibroblasts, mesothelial cells and LR-MSCs, whose roles within the alveolar lung niche are list in the legend within the figure, give rise to the myofibroblast population representing the key cells for the onset and progression of fibrosis.

FIGURE 3

Paracrine effects of MSCs in lung disease. Since the MSCs derived EVs play pivotal roles in different pathways that are common in lung disease, several works describe the effect of their administration for lung diseases treatment. In general, the MSCs derived EVs display antifibrotic, antiapoptotic, anti-inflammatory effects and counteract fibrosis with different mechanisms where they can either enhance (green head-arrow) or down-regulate (red head-arrow) growth factors and cytokines secretion as well as functional activity in lungs (e.g., collagen deposition, mitochondria transfer, etc) as summarized in the cartoon.