Stem Cell Treatment for Chronic Lung Diseases

Abstract

Chronic lung diseases such as idiopathic pulmonary fibrosis and cystic fibrosis or chronic obstructive pulmonary disease and asthma are leading causes of morbidity and mortality worldwide with a considerable human, societal and financial burden. In view of the current disappointing status of available pharmaceutical agents, there is an urgent need for alternative more effective therapeutic approaches that will not only help to relieve patient symptoms but will also affect the natural course of the respective disease. Regenerative medicine represents a promising option with several fruitful therapeutic applications in patients suffering from chronic lung diseases. Nevertheless, despite relative enthusiasm arising from experimental data, application of stem cell therapy in the clinical setting has been severely hampered by several safety concerns arising from the major lack of knowledge on the fate of exogenously administered stem cells within chronically injured lung as well as the mechanisms regulating the activation of resident progenitor cells. On the other hand, salient data arising from few ‘brave' pilot investigations of the safety of stem cell treatment in chronic lung diseases seem promising. The main scope of this review article is to summarize the current state of knowledge regarding the application status of stem cell treatment in chronic lung diseases, address important safety and efficacy issues and present future challenges and perspectives. In this review, we argue in favor of large multicenter clinical trials setting realistic goals to assess treatment efficacy. We propose the use of biomarkers that reflect clinically inconspicuous alterations of the disease molecular phenotype before rigid conclusions can be safely drawn.

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

“…Importantly, we identified SOD1 by an MS approach as a paracrine factor that is secreted by aortic and BM-MSCs, but in particularly high amounts by AoMSCs. This corroborates the general view that engraftment in the lung is currently not considered the main mechanism by which MSCs repair a diseased lung tissue (36,78). Consistently we detected only a few, preferably single donor cells in WTI lung sections while circulating enhanced green fluorescent protein [EGFP(+)] MSCs could be detected in peripheral blood even 25 weeks after transplantation, supporting the idea that tissue protection is due to paracrine signaling (44).…”

Paracrine factors from mesenchymal stem cells attenuate epithelial injury and lung fibrosis

“…MSCs were first identified in the bone marrow in 1976 (24) and have since been shown to express a broad spectrum of secreted molecules, including interferon (IFN)-γ, interleukin (IL)-1β, IL-6, IL-10, transforming growth factor (TGF)-β1, vascular endothelial growth factor (VEGF), stromal derived factor (SDF)-1, HGF, KGF, prostaglandin PGE2, amongst others (17,18). Through the action of these soluble mediators, BM-MSCs have been shown to modulate the activation, proliferation, and downstream effects of inflammatory and immune cells in both the innate and adaptive immune systems; including neutrophils, macrophages and lymphocytes (25,26).…”

“…Previous studies have shown that the paracrine factors of MSCs have anti-apoptotic effects in vitro on cardiac cells (27,28), pancreatic β cells (29) and hepatocytes (19). BM-MSCs are known to produce several epithelial specific growth factors, including HGF and KGF (17,18), which have been proven to initiate a variety of biological responses including migration, proliferation, and morpho genesis in AECs (30)(31)(32)(33). Therefore it can be speculated that the protective roles of MSC-CM on AECs may be associated with the epithelial specific growth factors secreted by BM-MSCs and the synergistic effects of these factors.…”

“…BM-MSCs can differentiate into mature non-hematopoietic cells of multiple tissues that can facilitate the repair of injured organs, such as the liver, lung, heart and kidney (14). However, numerous studies have shown that lung epithelial or endothelial cells are rarely derived from BM-MSCs (15,16), therefore engraftment in the lung as structural epithelium or endothelium is not currently considered the mechanism by which BM-MSCs can repair lung tissue (17). Previous evidence has shown however, that BM-MSCs can migrate to injured tissues, communicate with injured parenchyma cells, and function in the wound healing process through the production of paracrine-soluble cytokines and growth factors, which modulate the regeneration of the epithelium and endothelium (18).…”

Ethics and Policy Issues for Stem Cell Research and Pulmonary Medicine

“…[5][6][7][8][9][10] For example, stem cells and regenerative medicine may off er solutions for disorders as diverse as acute lung injury, ARDS, idiopathic pulmonary fi brosis, COPD, genetic disorders (eg, cystic fi brosis and sickle cell disease), and reactive airway disease. [11][12][13][14] Translating stem cell-based therapies for the respiratory tract faces a number of hurdles, including ensuring safety and optimizing routes of delivery and dosage, but excitement abounds. 15 Th e clinical use of stem cell-based therapies is not just theoretical.…”