The Role of Mesenchymal Stem Cells in Radiation-Induced Lung Fibrosis

Abstract

Radiation therapy is one of the most important treatment modalities for thoracic tumors. Despite significant advances in radiation techniques, radiation-induced lung injury (RILI) still occurs in up to 30% of patients undergoing thoracic radiotherapy, and therefore remains the main dose-limiting obstacle. RILI is a potentially lethal clinical complication of radiotherapy that has 2 main stages: an acute stage defined as radiation pneumonitis, and a late stage defined as radiation-induced lung fibrosis. Patients who develop lung fibrosis have a reduced quality of life with progressive and irreversible organ malfunction. Currently, the most effective intervention for the treatment of lung fibrosis is lung transplantation, but the lack of available lungs and transplantation-related complications severely limits the success of this procedure. Over the last few decades, advances have been reported in the use of mesenchymal stem cells (MSCs) for lung tissue repair and regeneration. MSCs not only replace damaged lung epithelial cells but also promote tissue repair through the secretion of anti-inflammatory and anti-fibrotic factors. Here, we present an overview of MSC-based therapy for radiation-induced lung fibrosis, focusing in particular on the molecular mechanisms involved and describing the most recent preclinical and clinical studies carried out in the field.

Keywords: lung fibrosis; mesenchymal stem cells (MSCs); radiotherapy; regenerative medicine; thoracic cancer.

Figure 1

Alterations in normal wound healing processes promote the development of pulmonary fibrosis. (A) After radiation injury epithelial cells release inflammatory mediators, triggering platelet aggregation and inflammatory cell recruitment and activation. (B) Pro-fibrotic and inflammatory cytokines released by recruited immune cells, such as macrophages and lymphocytes, promote the recruitment and differentiation of resident fibroblasts and circulating fibrocytes into ECM-secreting myofibroblasts. Fibroblasts and myofibroblasts may also originate from epithelial cells that have gone through the EMT process. (C) Activated myofibroblasts remodel ECM, actively promoting tissue repair by epithelial and endothelial cells and restoring lung function. (D) Disregulation of wound healing process and persisted inflammatory environment promote lung tissue fibrosis [29,30,31,32,33,34,35,36,37,38].

Figure 2

Differences in normal and fibrotic bronchoalveolar tissue. Schematic representation of (A) normal bronchoalveolar tissue and (B) fibrotic bronchoalveolar tissue [12,14,28,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83].

Figure 3

Mesenchymal stem cells (MSCs). (A) Multipotency of MSCs. (B) MSC markers and the secretome [7,9,10,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101].

Figure 4

Mesenchymal stem cell-based therapy. Search for article appearing in PUBMED database over the past 10 years using the mesh terms “Mesenchymal Stem Cells” AND “Cell- and Tissue-Based Therapy” in the Advance research builder option.

Figure 5

Mesenchymal stem cell regulation of the lung fibrotic microenvironment. MSCs protect radiation-injured lungs against ROS secreting superoxide dismutase enzymes and reduce inflammatory signaling, inhibiting immune cell activation by the release of immunosuppressive cytokines. They also limit fibrotic response by reducing myofibroblast differentiation from epithelial cells and fibroblasts and ECM deposition [6,15,28,46,114,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200].

Figure 6

Mesenchymal stem cell-based clinical trials in lung diseases. Search for clinical studies reported in https://clinicaltrials.gov database using “Mesenchymal Stem Cells” and “Lung Disease” as keywords for the search.