ABSTRACT

End-stage organ failure is the irreversible and fatal impairment of a vital organ, such as the heart, lung, kidney, or liver. End-stage organ failure affects millions of people. The current treatment is organ transplantation, which is severely limited by a shortage of donor organs. Scientists have been trying to tissue-engineer organs outside of the body that can be used as replacements for failing organs, but these efforts have been challenged by the difficulty of creating networks of small blood vessels that can perfuse large pieces of tissue. Studies have shown that when cells are given the freedom to organize and assemble themselves in low-gravity conditions called microgravity, they establish important cell-cell relationships and can form tissue structures such as capillary tubes. In this research, using the liver as a model organ, the research team will investigate how microgravity conditions onboard the International Space Station may be used to facilitate development of a large, vascularized tissue graft. The researchers hypothesize that a combination of factors, including the microgravity environment unique to the International Space Station, will produce a functional and vascularized liver tissue. The research results will include a time-lapse video of how the different cell types organize themselves in response to a growth factor gradient in microgravity. This will allow investigators to better understand how microgravity regulates tissue formation. In addition to the scientific objectives, the research team will raise public awareness of the potential benefits of biomedical research in space through efforts in K-12 education, mentoring groups underrepresented in S.T.E.M., public outreach, and industry partnership.

This project centers around two research goals. First, the microgravity environment of the ISS will be used to cerate a macroscopic, vascularized liver tissue. The researchers hypothesize that the combination of an environment of 3D spatial freedom, a perfusion force within a central conduit that does not have to compete with the gravitational force, and sustained, directional angiogenic gradient will support the development of a functional, vascularized liver graft. The liver organoids will be developed by co-culturing induced pluripotent stem cell (iPSC)-derived hepatocytes with human umbilical vein endothelial cells (HUVECs) and human mesenchymal stem cells (MSCs). The organoids will then be loaded into tissue culture vessels with a hollow fiber conduit to support the flow of blood and bile. The physiological response of the tissue graft will be assessed to validate the model through both laboratory assays and xenotransplantation. The second goal is to characterize the effect of microgravity and directional angiogenic gradients on 3D intercellular interactions and microvascular organization. By using live-cell, time-lapse confocal microscopy, the effect of these environmental factors on the co-cultured cells of the organoids will be examined. This portion of the project will advance fundamental understanding of how cells respond to a microgravity environment with respect to tissue self-assembly, which will support future work to advance the engineering of 3-dimensional tissue constructs.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

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