There is an urgent need for better treatment of lung diseases that are a major cause of morbidity and mortality worldwide. This urgency is illustrated by the current COVID-19 health crisis.... Show moreThere is an urgent need for better treatment of lung diseases that are a major cause of morbidity and mortality worldwide. This urgency is illustrated by the current COVID-19 health crisis. Moderate-to-extensive lung injury characterizes several lung diseases, and not only therapies that reduce such lung injury are needed but also those that regenerate lung tissue and repair existing lung injury. At present, such therapies are not available, but as a result of a rapid increase in our understanding of lung development and repair, lung regenerative therapies are on the horizon. Here, we discuss existing targets for treatment, as well as novel strategies for development of pharmacological and cell therapy-based regenerative treatment for a variety of lung diseases and clinical studies. We discuss how both patient-relevant in vitro disease models using innovative culture techniques and other advanced new technologies aid in the development of pulmonary regenerative medicine. Show less
Ng-Blichfeldt, J.P.; Jong, T. de; Kortekaas, R.K.; Wu, X.H.; Lindner, M.; Guryev, V.; ... ; Gosens, R. 2019
Transforming growth factor-beta (TGF-beta)-induced fibroblast-to-myofibroblast differentiation contributes to remodeling in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis,... Show moreTransforming growth factor-beta (TGF-beta)-induced fibroblast-to-myofibroblast differentiation contributes to remodeling in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis, but whether this impacts the ability of fibroblasts to support lung epithelial repair remains little explored. We pretreated human lung fibroblasts [primary (phFB) or MRC5 cells] with recombinant human TGF-beta to induce myofibroblast differentiation, then cocultured them with adult mouse lung epithelial cell adhesion molecule-positive cells (EpCAM(+)) to investigate their capacity to support epithelial organoid formation in vitro. While control phFB and MRC5 lung fibroblasts supported organoid formation of mouse EpCAM(+) cells, TGF-beta pretreatment of both phFB and MRC5 impaired organoid-supporting ability. We performed RNA sequencing of TGF beta-treated phFB. which revealed altered expression of key Wnt signaling pathway components and Wnt/beta-catenin target genes, and modulated expression of secreted factors involved in mesenchymal-epithelial signaling. TGF-beta profoundly skewed the transcriptional program induced by the Wnt/beta-catenin activator CHIR99021. Supplementing organoid culture media recombinant hepatocyte growth factor or fibroblast growth factor 7 promoted organoid formation when using TGF-beta pretreated fibroblasts. In conclusion, TGF-beta-induced myofibroblast differentiation results in Wnt/beta-catenin pathway skewing and impairs fibroblast ability to support epithelial repair likely through multiple mechanisms, including modulation of secreted growth factors. Show less
The hominin record from southern Asia for the early Late Pleistocene epoch is scarce. Well-dated and well-preserved fossils older than ∼45,000 years that can be unequivocally attributed to Homo... Show moreThe hominin record from southern Asia for the early Late Pleistocene epoch is scarce. Well-dated and well-preserved fossils older than ∼45,000 years that can be unequivocally attributed to Homo sapiens are lacking. Here we present evidence from the newly excavated Fuyan Cave in Daoxian (southern China). This site has provided 47 human teeth dated to more than 80,000 years old, and with an inferred maximum age of 120,000 years. The morphological and metric assessment of this sample supports its unequivocal assignment to H. sapiens. The Daoxian sample is more derived than any other anatomically modern humans, resembling middle-to-late Late Pleistocene specimens and even contemporary humans. Our study shows that fully modern morphologies were present in southern China 30,000-70,000 years earlier than in the Levant and Europe. Our data fill a chronological and geographical gap that is relevant for understanding when H. sapiens first appeared in southern Asia. The Daoxian teeth also support the hypothesis that during the same period, southern China was inhabited by more derived populations than central and northern China. This evidence is important for the study of dispersal routes of modern humans. Finally, our results are relevant to exploring the reasons for the relatively late entry of H. sapiens into Europe. Some studies have investigated how the competition with H. sapiens may have caused Neanderthals' extinction (see ref. 8 and references therein). Notably, although fully modern humans were already present in southern China at least as early as ∼80,000 years ago, there is no evidence that they entered Europe before ∼45,000 years ago. This could indicate that H. neanderthalensis was indeed an additional ecological barrier for modern humans, who could only enter Europe when the demise of Neanderthals had already started. Show less
