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Orthotopic transplantation of the bioengineered lung using a mouse-scale perfusion-based bioreactor and human primary endothelial cells.

ABSTRACT: Whole lung engineering and the transplantation of its products is an ambitious goal and ultimately a viable solution for alleviating the donor-shortage crisis for lung transplants. There are several limitations currently impeding progress in the field with a major obstacle being efficient revascularization of decellularized scaffolds, which requires an extremely large number of cells when using larger pre-clinical animal models. Here, we developed a simple but effective experimental pulmonary bioengineering platform by utilizing the lung as a scaffold. Revascularization of pulmonary vasculature using human umbilical cord vein endothelial cells was feasible using a novel in-house developed perfusion-based bioreactor. The endothelial lumens formed in the peripheral alveolar area were confirmed using a transmission electron microscope. The quality of engineered lung vasculature was evaluated using box-counting analysis of histological images. The engineered mouse lungs were successfully transplanted into the orthotopic thoracic cavity. The engineered vasculature in the lung scaffold showed blood perfusion after transplantation without significant hemorrhage. The mouse-based lung bioengineering system can be utilized as an efficient ex-vivo screening platform for lung tissue engineering.

SUBMITTER: Tomiyama F

PROVIDER: S-EPMC10994903 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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Orthotopic transplantation of the bioengineered lung using a mouse-scale perfusion-based bioreactor and human primary endothelial cells.

Tomiyama Fumiko F Suzuki Takaya T Watanabe Tatsuaki T Miyanaga Jun J Suzuki Anna A Ito Takayasu T Murai Sho S Suzuki Yuyo Y Niikawa Hiromichi H Oishi Hisashi H Notsuda Hirotsugu H Watanabe Yui Y Hirama Takashi T Onodera Ken K Togo Takeo T Noda Masafumi M Waddell Thomas K TK Karoubi Golnaz G Okada Yoshinori Y

Scientific reports 20240404 1

Whole lung engineering and the transplantation of its products is an ambitious goal and ultimately a viable solution for alleviating the donor-shortage crisis for lung transplants. There are several limitations currently impeding progress in the field with a major obstacle being efficient revascularization of decellularized scaffolds, which requires an extremely large number of cells when using larger pre-clinical animal models. Here, we developed a simple but effective experimental pulmonary bi ...[more]

PMID: 38575597

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Project description:BackgroundColorectal cancer (CRC) represents a major malignancy that poses a significant threat to human health worldwide. The establishment of a reliable and pathologically relevant orthotopic model of CRC is crucial for gaining a deeper understanding of its molecular mechanisms and for developing more effective therapies. Nonetheless, the development of such models is fraught with challenges primarily owing to the technical complexities associated with the transplantation of CRC cells into the intestinal epithelium.MethodsThe luminal surface of the cecum was externalized to visualize the entire process involved in the transplantation of CRC cells into the cecal epithelium of BALB/c athymic nude mice. The cecal epithelium was mechanically removed, preserving the integrity of the submucosal layer. Caco-2 CRC cells were subsequently inoculated onto the epithelium-depleted surface of the cecum to reproduce the development of CRC within the epithelial layer. The successful removal of the epithelium and transplantation of Caco-2 cells were verified through the use of appropriate fluorescent labeling techniques and examination with a fluorescence stereoscopic microscope.ResultsFollowing orthotopic transplantation, Caco-2 cells formed tumors in the cecum, where tumors progressed from a flat monolayer epithelium to thickened aberrant crypt foci, and then to protruding polyps, aided by mesenchymal cells infiltrating the tumors to form a stalk region, and eventually to large tumors invading the submucosa. Throughout this process, Caco-2 cells retained stem cell and fetal intestinal signatures, regardless of their location within the tumors or their proliferative status. Histopathological analysis further suggested that interactions between the transplanted Caco-2 cells and the surrounding normal epithelial and mesenchymal cells play critical roles in tumor development and in the elimination of normal epithelial cells from the tumor in this model.ConclusionsThis study established a novel orthotopic model of CRC within the mouse cecum. Tumor development and progression in this model include sequential morphological changes from a flat monolayer to large invasive tumors. The establishment of this orthotopic CRC model, which mimics tumor development in a more natural microenvironment, provides new opportunities to investigate the molecular mechanisms underlying CRC and to evaluate novel anticancer therapies in pathologically relevant contexts.

Dataset Information

Orthotopic transplantation of the bioengineered lung using a mouse-scale perfusion-based bioreactor and human primary endothelial cells.

Publications

Orthotopic transplantation of the bioengineered lung using a mouse-scale perfusion-based bioreactor and human primary endothelial cells.

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