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.

Radiation-induced lung toxicity – cellular and molecular mechanisms of pathogenesis, management, and literature review

“…MSCs can successfully migrate towards the injured site in the lung upon irradiation and differentiate into distinct lung cell types, including AT I/II cells and endothelial cells. Preclinical studies reported that lung fibrosis can be modulated by administration of MSCs [195,196]. In these settings, adoptive transfer of MSCs did limit radiation-induced endothelial cell loss in the early phase after irradiation and promoted tissue repair through the secretion of superoxide dismutase 1 (SOD1) [197] and the anti-fibrotic factors hepatocyte growth factor (HGF) and prostaglandin E2 (PGE2) [198].…”

Regulation of JAM2 Expression in the Lungs of Streptozotocin-Induced Diabetic Mice and Human Pluripotent Stem Cell-Derived Alveolar Organoids

“…Fibrosis is the last stage of chronic inflammatory responses and is characterized by the excessive deposition of the extracellular matrix, leading to tissue dysfunction in the affected organs [25]. Accumulating evidence suggests that MSCs have great potential in the treatment of fibrosis due to their abilities to act on proinflammatory and profibrotic factors such as oxidative stress, the TGF-β signaling pathway, and hypoxia [26][27][28]. Consistent with previous studies, we found that diabetic mice appeared to have a thickening alveolar wall, increased expression of SMA, and a massive infiltration of leukocytes in the lung tissue, exhibiting an obvious fibrosis.…”

Lights and Shadows in the Use of Mesenchymal Stem Cells in Lung Inflammation, a Poorly Investigated Topic in Cystic Fibrosis

“…Concerning pulmonary tissues, increasing evidences support MSCs regenerative properties. Indeed, they were able to engraft and to differentiate into lung epithelial cells under experimental conditions such as irradiation, bleomycin, or LPS-induced injury [86][87][88]. A systematic review of seventeen studies on rodents models of bleomycin-induced pulmonary fibrosis, describes the beneficial effects of MSCs, mostly derived from bone marrow, in improving alveolar injury and in decreasing lung fibrosis and collagen content [86].…”

“…Data arising out of MSCs-based clinical trials demonstrate the variability of the use of this therapy in terms of MSCs source, route, timing, and dosage of administration. As very recently reviewed by Zanoni M. et al [87], the lack of consensus on these parameters (route, timing and dosage) together with the paucity of standardized methods for MSCs harvesting, request further studies in order to include MSCs therapy in the clinical practice in the near future. Moreover, donor variance, senescence, cryopreservation, and sources are among the main variables that can affect cellular therapies based on MSCs [116,117].…”