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The main function of the respiratory tract is gas exchange. Because dysfunction of gas exchange is lethal, a lot of people die of respiratory diseases every year. Many researchers are attempting to elucidate the pathophysiology of respiratory diseases and develop effective drugs using several in vitro respiratory models. Recently, respiratory organoids are widely used as human respiratory models. Respiratory organoids are self-organized three-dimensional tissue-like structures that are derived from pluripotent stem cells or tissue stem cells. Because respiratory organoids derived from a patient's stem cells carry its genetic mutation, they are widely used to recapitulate respiratory genetic diseases. It has been reported that some respiratory genetic diseases, such as cystic fibrosis, primary ciliary dyskinesia, pulmonary alveolar proteinosis, or Hermansky-Pudlak syndrome, could be recapitulated using respiratory organoids. Moreover, because respiratory organoids possess innate immune response activity, they are also used as a model for respiratory infectious diseases. It has been reported that some respiratory diseases which are caused by the infection of pathogens, such as respiratory syncytial virus, seasonal influenza viruses, human parainfluenza virus, measles virus, enterovirus, or cryptosporidium spp., could be reproduced using respiratory organoids. This review introduces the current status and future prospects of respiratory organoids in respiratory disease research.

The liver is a major organ responsible for maintaining the body's homeostasis and xenobiotic metabolism. Liver transplantation is essential for the alleviation of many severe liver diseases. However, there are many patients who cannot receive liver transplants because of donor shortage. Therefore development of effective therapeutic drugs that can replace the need for liver transplantation is desired. To this end, model cells that faithfully reproduce hepatic functions are essential. It is expected that human induced pluripotent stem cell (iPS)-derived hepatocyte-like cells, which faithfully reproduce hepatic functions, would be a valuable tool for drug discovery. Hepatic differentiation from human iPS cells has been performed using growth factors, but the hepatic differentiation efficiency was quite low and liver functions of human iPS cell-derived hepatocyte-like cells were lower than those of primary human hepatocytes. Therefore we tried to improve the hepatic differentiation technology using gene transfer, genome editing, three-dimensional culture, and extracellular matrix technologies. As a result, the purity of human iPS cell-derived hepatocyte-like cells was improved into 90% or more, and the liver functions of human iPS cell-derived hepatocyte-like cells were improved to a level comparable to primary human hepatocytes. In this article, we introduce the research results we have acquired over the last decade.

Hepatocyte-like cells differentiated from human pluripotent stem cells (such as human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells) are expected to be utilized in drug screening. However, the hepatocyte differentiation efficiency and hepatic functions of hepatocyte-like cells were not sufficient to perform ES/iPS cell-based drug discovery. Therefore, we decided to improve the method of hepatocyte differentiation from human ES/iPS cells. To enhance this hepatocyte differentiation efficiency, hepatocyte-related transcription factors, such as forkhead box protein A2 (FOXA2) and hepatocyte nuclear factor 1 alpha (HNF1α), were overexpressed during the hepatocyte differentiation process. In addition, to enhance the functions of hepatocyte-like cells, these cells were cultured in three dimensional (3D) conditions using a Nanopillar plate. By FOXA2 and HNF1α overexpression, human ES/iPS cells could efficiently (more than 80%) differentiate into albumin-positive hepatocyte-like cells. Various hepatic functions, including albumin secretion and drug metabolism capacities, of the hepatocyte-like cells were significantly enhanced by performing 3D cell culture. These results suggest that the method of hepatocyte differentiation could be improved by using gene transfer and 3D cell culture technologies. We believe that these new hepatocyte-like cells would be useful tools in drug development.

A commonly used admixture of commercially available ointments and/or creams was selected from the prescribed sheets in our hospital, and questionnaire to dermatologists. To assess the relationship between permeability of corticosteroid through murine skin and clinical effects in human, we attempted to investigate the vasoconstrictor activity of these admixtures of topical corticosteroid by double-blind controlled study. Test samples were occluded at random on the back of 20 healthy volunteers for 4 hours. The vasoconstrictor activity of corticosteroid creams (Lidomex) alone was significantly large as compared with that of ointments alone. The vasoconstrictor activity of corticosteroid in the admixture of Lidomex ointment and urea ointments or heparinoid ointment was 1.5-2 fold significantly larger than that from ointments alone. The extent of the stability of the emulsion after mixing was related to the vasoconstrictor activity. These experiments demonstrated a close relationship between the vasoconstrictor activity of human skin and permeability of hairless mice skin. These results suggested that the vasoconstrictor activity of topical corticosteroids mixed with commercially available ointments and/or creams depends upon their physicochemical characteristics.