Stem Cells and Pulmonary Fibrosis: Cause or Cure?

Abstract

Pulmonary fibrosis is a feature of a number of important lung diseases, and alveolar epithelial injury plays a key role in their pathogenesis. Traditionally, type II alveolar epithelial cells have been viewed as the progenitor cells of the alveolar epithelium; however, recent studies have identified a number of other progenitor and stem cell populations that may participate in alveolar epithelial repair. These studies suggest that the injury microenvironment plays a role in regulation of progenitor cell populations. In human idiopathic pulmonary fibrosis, epithelial abnormalities including altered cell cycling characteristics, hyperplasia, and metaplasia are observed, suggesting that dysregulation of epithelial progenitor cells contributes to the characteristic aberrant repair process. Reactivation of developmental signaling pathways such as the Wnt-β-catenin pathway is implicated in the dysregulation of these cells, and targeting these pathways may provide opportunities for therapeutic intervention. There has been a great deal of interest in the delivery of exogenous stem cells as a therapeutic strategy, and various stem and progenitor cell populations have improved outcomes in animal lung fibrosis models. The contributions of these cells to alveolar epithelial regeneration have been variable, and secretion of soluble mediators has been implicated in the beneficial effects. It remains to be seen whether the promising results seen in the preclinical studies will translate to human disease, and the first studies using mesenchymal stem cells in clinical trials for fibrotic lung disease are underway. Strategies using other stem cell populations hold promise, but currently these are a lot further from the bedside.

Mesenchymal Stem Cell Therapy Protects Lungs from Radiation-Induced Endothelial Cell Loss by Restoring Superoxide Dismutase 1 Expression

“…However, there is a lack of preclinical and clinical studies of stem cell therapy for radiation-induced adverse effects in the lung, particularly in radiation-induced fibrosis (54,75). There are also only few ongoing clinical trials with mesenchymal stem cells (MSCs), also referred to as multipotent mesenchymal stromal cells (MPSCs) in chronic lung disease, including their therapeutic application in patients with idiopathic pulmonary fibrosis (77).…”

Therapeutic effect of lung mixed culture-derived epithelial cells on lung fibrosis

“…5,12 In fact, MSCs have been approved for use in clinical trials in patients with IPF. 8 In studies showing beneficial effects of MSCs in the BLM model, however, lung fibrotic injury was significantly reduced by delivery of MSCs during not the fibrotic phase but the early inflammatory phase. 5 Similarly, it has been demonstrated that bone marrow mesenchymal stromal cells systemically injected into mice during the fibrotic phase of radiation-induced lung injury mostly acquire a fibroblast phenotype.…”

Cell Therapy Trials for Lung Diseases: Progress and Cautions

“…Subsequent research has identified three related but distinct biological roles for TREM-2: as a phagocytic and immune modulatory receptor on macrophages, as a neuroprotective factor expressed on microglia (reviewed in Reference 5), and as a regulator of osteoclast differentiation (6). Myeloid cell TREM-2 has been found to be induced during inflammation (7), to secrete antiinflammatory cytokines and tame TLR signaling (8)(9)(10), and to act as a direct phagocytic receptor for bacteria (11). Thus, TREM-2 may also have a role to play in sepsis.…”

“…With respect to MSC effects on lung fibrosis, a systematic review of the English language literature identifies 12 published manuscripts that have investigated the effects of syngeneic, allogeneic, or xenogeneic MSC administration in mouse, rat, or pig models of bleomycininduced lung fibrosis, the most commonly used preclinical model (8,9). Notably, MSC administration by either systemic or intratracheal route during the early stage of the injury ameliorates acute inflammation and is protective against subsequent development of fibrotic changes.…”

“…Notably, MSC administration by either systemic or intratracheal route during the early stage of the injury ameliorates acute inflammation and is protective against subsequent development of fibrotic changes. These effects occur in the absence of what appears to be any substantive engraftment of the MSCs in the lung, and limited available data so far implicate release of soluble antiinflammatory mediators as contributing to the MSC effects (8,9). Importantly, administration of MSCs at time intervals longer than 7 days after bleomycin administration had no effect on established fibrotic changes in either mouse or pig lungs (10,11).…”