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No radical treatment is available for the regeneration of dysfunction and defects in airway epithelia. Artificial tracheae made of polypropylene and collagen sponge were used in clinical studies to reconstitute tracheae after resection. For early epithelialization of the luminal surface of the artificial trachea, a model was established, that is, an artificial trachea covered with human-induced pluripotent stem cell-derived airway epithelial cells (hiPSC-AECs) was transplanted into a tracheal defect in an immunodeficient rat. Unlike the cell types of hiPSC-derived cells that are currently used in clinical studies, AECs maintain tissues by proliferation and differentiation of basal cells into various cell types that constitute AECs constantly. Therefore, post-transplantation, the proportion of each cell type, such as ciliated and goblet cells, may change; however, no studies have examined this possibility. In this study, using our hiPSC-AEC-transplanted rat model, we investigated changes in the proportion of each cell type in hiPSC-AECs pre-transplantation and post-transplantation. As a result, the proportion of each cell type changed post-transplantation. The proportion of ciliated, basal, and club cells increased, and the proportion of goblet cells decreased post-transplantation. In addition, the proportion of each cell type in engrafted hiPSC-AECs is more similar to the proportion of each cell type in normal proximal airway tissue than the proportion of each cell type pre-transplantation. The results of this study are useful for the development of therapeutic techniques using hiPSC-AEC transplantation.

Previous studies transplanted human-induced pluripotent stem cells (hiPSCs)-derived mesenchymal stem cells (iMSCs) into thyroid cartilage defect of X-liked severe combined immunodeficiency (X-SCID) rats and confirmed transplanted cell survival and cartilage regeneration. Thus, this study aimed to investigate the contribution of iMSC transplantation to thyroid cartilage regeneration of nude rats. iMSCs were induced from hiPSCs via a neural crest cell lineage. Then, clumps formed from an iMSC/extracellular matrix complex were transplanted into thyroid cartilage defects in nude rats. The larynx was removed and histological and immunohistochemical analyses were performed 4 or 8 weeks after the transplantation. Human nuclear antigen (HNA)-positive cells were observed in 11 of 12 (91.7%) rats, which indicated that transplanted iMSCs survived in thyroid cartilage defects in nude rats. HNA-positive cells co-expressed SOX9, and type II collagen was identified around HNA-positive cells in 8 of 12 rats (66.7%), which indicated cartilage-like regeneration. Cartilage-like regeneration in nude rats in this study was comparable to the previous report on X-SCID rats (HNA-positive cells were observed in all 14 rats and cartilage-like regeneration was observed in 10 of 14 rats). This result suggests that nude rats could be an alternative to X-SCID rats in thyroid cartilage regeneration experiments using iMSCs, and this nude rat cartilage transplantation model may develop cartilage regeneration research concerning fewer problems such as infection due to immunosuppression.

Introduction: Early postoperative regeneration of the middle ear mucosa is essential for the prevention of postoperative refractory otitis media and recurrent cholesteatoma. As a means for intractable otitis media management, we focused on human induced pluripotent stem cell (hiPSC)-derived airway epithelial cells (AECs), which have been used in upper airway mucosal regeneration and transplantation therapy. In this study, we transplanted hiPSC-derived AECs into the middle ear of immunodeficient rats. Methods: Following the preparation of AEC sheets from hiPSCs, the bilateral middle ear mucosa of X-linked severe combined immunodeficient rats was scraped, and the AEC sheets were transplanted in the ears unilaterally. Results: Human nuclear antigen (HNA)-positive ciliated cells were observed on the transplanted side of the middle ear cavity surface in three of six rats in the 1-week postoperative group and in three of eight rats in the 2-week postoperative group. No HNA-positive cells were found on the control side. The percentage of HNA-positive ciliated cells in the transplanted areas increased in the 2-week postoperative group compared with the 1-week group, suggesting survival of hiPSC-derived AECs. Additionally, HNA-positive ciliated cells were mainly located at sites where the original ciliated cells were localized. Immunohistochemical analysis showed that the transplanted AECs contained cytokeratin 5- and mucin 5AC-positive cells, indicating that both basal cells and goblet cells had regenerated within the middle ear cavity. Conclusions: The results of this study are an important first step in the establishment of a novel transplantation therapy for chronic otitis media.

The 5-year overall survival rate remains approximately 50% for head and neck (H&N) cancer patients, even though new cancer drugs have been approved for clinical use since 2016. Cancer drug studies are now moving toward the use of three-dimensional culture models for better emulating the unique tumor microenvironment (TME) and better predicting in vivo response to cancer treatments. Distinctive TME features, such as tumor geometry, heterogenous cellularity, and hypoxic cues, notably affect tissue aggressiveness and drug resistance. However, these features have not been fully incorporated into in vitro H&N cancer models. This review paper aims to provide a scholarly assessment of the designs, contributions, and limitations of in vitro models in H&N cancer drug research. We first review the TME features of H&N cancer that are most relevant to in vitro drug evaluation. We then evaluate a selection of advanced culture models, namely, spheroids, organotypic models, and microfluidic chips, in their applications for H&N cancer drug research. Lastly, we propose future opportunities of in vitro H&N cancer research in the prospects of high-throughput drug screening and patient-specific drug evaluation.

The laryngotracheal cartilage is a cardinal framework for the maintenance of the airway for breathing, which occasionally requires reconstruction. Because hyaline cartilage has a poor intrinsic regenerative ability, various regenerative approaches have been attempted to regenerate laryngotracheal cartilage. The use of autologous mesenchymal stem cells (MSCs) for cartilage regeneration has been widely investigated. However, long-term culture may limit proliferative capacity. Human-induced pluripotent stem cell-derived MSCs (iMSCs) can circumvent this problem due to their unlimited proliferative capacity. This study aimed to investigate the efficacy of iMSCs in the regeneration of thyroid cartilage in immunodeficient rats. Herein, we induced iMSCs through neural crest cell intermediates. For the relevance to prospective future clinical application, induction was conducted under xeno-free/serum-free conditions. Then, clumps fabricated from an iMSC/extracellular matrix complex (C-iMSC) were transplanted into thyroid cartilage defects in immunodeficient rats. Histological examinations revealed cartilage-like regenerated tissue and human nuclear antigen (HNA)-positive surviving transplanted cells in the regenerated lesion. HNA-positive cells co-expressed SOX9, and type II collagen was identified around HNA-positive cells. These results indicated that the transplanted C-iMSCs promoted thyroid cartilage regeneration and some of the iMSCs differentiated into chondrogenic lineage cells. Induced MSCs may be a promising candidate cell therapy for human laryngotracheal reconstruction.

The 5-year overall survival rate remains approximately 50% for head and neck (H&N) cancer patients, even though new cancer drugs have been approved for clinical use since 2016. Cancer drug studies are now moving toward the use of three-dimensional culture models for better emulating the unique tumor microenvironment (TME) and better predicting in vivo response to cancer treatments. Distinctive TME features, such as tumor geometry, heterogenous cellularity, and hypoxic cues, notably affect tissue aggressiveness and drug resistance. However, these features have not been fully incorporated into in vitro H&N cancer models. This review paper aims to provide a scholarly assessment of the designs, contributions, and limitations of in vitro models in H&N cancer drug research. We first review the TME features of H&N cancer that are most relevant to in vitro drug evaluation. We then evaluate a selection of advanced culture models, namely, spheroids, organotypic models, and microfluidic chips, in their applications for H&N cancer drug research. Lastly, we propose future opportunities of in vitroH&Ncancer research in the prospects of high-throughput drug screening and patient-specific drug evaluation. [ABSTRACT FROM AUTHOR]