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.

The oncogenic landscape of the idiopathic pulmonary fibrosis: a narrative review

“…According to this definition, the most clinical implications regard clearly cancer, but the recent progresses in the knowledge of molecular mechanisms responsible of IPF with the evidence of biologic similarities between IPF and malignant proliferation give a strong rationale for the investigation and development of cell therapeutic strategies and tissue engineering to impair fibrotic damages. MSCs feature the pluripotent capacity of and their ability to differentiate to important lineages that can modulate on immunity, impair inflammatory reactions, and promote epithelial tissue repair (247); the clinical application of MSC therapy has been shown to be feasible and safe in humans with IPF (www.clinicaltrial.gov) and several data have been already published (248)(249)(250)(251)(252). A schematic representation of the application of MSCs in lung fibrosis is reported in Figure 3.…”

Mesenchymal Stem/Stromal Cells in Progressive Fibrogenic Involvement and Anti-Fibrosis Therapeutic Properties

“…Importantly, IPF lung derived MSCs were able to alter the expression of genes related to inflammation and oxidative stress on the NHLF, a fibroblast lung cell line, after co-culture. Indeed, specific lung-resident MSCs also play a potential role in the regulation of tissue homeostasis ( Sveiven and Nordgren, 2020 ; Samarelli et al, 2021 ) through their unique immunomodulatory and secretary capacity to provide appropriate tissue-specific niches. MSCs can in part contribute to the recruitment of fibrotic mesenchymal cells (fibroblasts, myofibroblasts and SMCs) through differentiation of MSCs.…”

Fibrotic Idiopathic Interstitial Lung Disease: The Molecular and Cellular Key Players

“…Specifically, pre-clinical studies show that the administration of MSCs leads to the downregulation of TGF-β signaling, reducing the extent of fibrotic lesions and lung collagen content [97]. To date, the MSC administration has been studied in the Phase I trial assessing their safety [98], while there are issues and concerns concerning their therapeutic role that still need to be clarified [99].…”