Lung Regeneration: Endogenous and Exogenous Stem Cell Mediated Therapeutic Approaches
International Journal of Molecular Sciences
Int. J. Mol. Sci. 2016, 17, 128; doi:10.3390/ijms17010128
Khondoker M. Akram 1, Neil Patel 2, Monica A. Spiteri 2 and Nicholas R. Forsyth 3,*
The tissue turnover of unperturbed adult lung is remarkably slow. However, after injury or insult, a specialised group of facultative lung progenitors become activated to replenish damaged tissue through a reparative process called regeneration. Disruption in this process results in healing by fibrosis causing aberrant lung remodelling and organ dysfunction. Post-insult failure of regeneration leads to various incurable lung diseases including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis. Therefore, identification of true endogenous lung progenitors/stem cells, and their regenerative pathway are crucial for next-generation therapeutic development. Recent studies provide exciting and novel insights into postnatal lung development and post-injury lung regeneration by native lung progenitors. Furthermore, exogenous application of bone marrow stem cells, embryonic stem cells and inducible pluripotent stem cells (iPSC) show evidences of their regenerative capacity in the repair of injured and diseased lungs. With the advent of modern tissue engineering techniques, whole lung regeneration in the lab using de-cellularised tissue scaffold and stem cells is now becoming reality. In this review, we will highlight the advancement of our understanding in lung regeneration and development of stem cell mediated therapeutic strategies in combating incurable lung diseases.
Lung disease is a major cause of morbidity and mortality worldwide. Despite being highly quiescent, the lung’s ability to regenerate extensively after injury suggests that this regenerative capability could be promoted and utilised in disease condition where loss of lung tissue occurs, and the lung fails to regenerate. Endogenous stem cells are indispensable during normal tissue turnover and repair or regeneration after injury to restore the function of an organ. This seems to be true for the lung as well. However, understanding of the endogenous stem/progenitor cell population involved and the underlying mechanisms that control the proper regeneration of lung tissue remains broadly elusive. Although several animal injury models provide evidence of compartmental stem/progenitor activation and proliferation, the underlying signalling pathway that initiates this regenerative activity is largely unknown. Evidence suggests that, in many disease conditions, prenatal lung developmental signalling is reactivated. Our understanding in mammalian lung development, in particular the process of alveologenesis, is poorly understood. However, the recent advent of organotypic ex vivo models, such as “tracheosphere” and “alveolosphere” culture offer novel platforms for studying stem/progenitor dynamics and associated signalling pathways that could be involved in lung regeneration. Furthermore, derivation of lung progenitors from ESCs and iPSCs for the repair of lung after injury and disease condition opens another exciting avenue towards development of regenerative therapeutics for lung disease. In this case, however, the pluripotent nature of ESCs or iPSCs could present a potential risk of teratogenic effects, which needs to be rigorously addressed before moving into human clinical trial. Much study, so far, has been done to evaluate MSC-mediated cell therapy in various lung conditions, albeit mostly in animal models. In this case, it is important to note that the bulk of studies suggest the infused MSCs exhibits reparative/healing effects mostly through paracrine or immunomodulatory effects on recipient lung tissue, but not by engraftment. Thus, it is imperative to view MSC therapy as cell-based immunomodulatory therapy rather than as attempts to regenerate or reconstitute lung tissues . Nonetheless, much effort has been taken to date to understand the molecular mechanisms of lung development, disease dynamics and its regenerative process. Much, of course, still remains to be determined. By combining the strength of basic studies along with rational clinical approaches we can fully unravel the power and promise of next-generation regenerative therapeutics in the field of lung disease in the coming years.