ISS: Liver Tissue Engineering in Space

终末期器官衰竭是指心脏、肺、肾或肝脏等重要器官不可逆的致命损害。终末期器官衰竭影响着数百万人。目前的治疗方法是器官移植，这受到供体器官短缺的严重限制。科学家们一直在尝试对体外器官进行组织工程，以替代衰竭的器官，但这些努力一直受到挑战，因为很难建立能够为大片组织灌流的小血管网络。研究表明，当细胞被赋予在称为微重力的低重力条件下组织和组装自己的自由时，它们建立了重要的细胞-细胞关系，并可以形成毛细管等组织结构。在这项研究中，研究小组将以肝脏为模型器官，研究国际空间站上的微重力条件如何被用来促进大型血管组织移植物的开发。研究人员假设，包括国际空间站独特的微重力环境在内的多种因素的组合，将产生具有功能和血管的肝组织。研究结果将包括一段时间推移的视频，展示不同类型的细胞如何组织起来，以响应微重力下的生长因子梯度。这将使研究人员更好地了解微重力是如何调节组织形成的。除了科学目标，研究团队还将通过K-12教育、在科技教育中代表性不足的指导小组、公众宣传和行业合作等努力，提高公众对太空生物医学研究潜在好处的认识。该项目围绕两个研究目标。首先，国际空间站的微重力环境将被用来切除宏观的、有血管的肝组织。研究人员假设，3D空间自由的环境、不必与重力竞争的中央管道内的灌注力以及持续的定向血管生成梯度的组合将支持功能性、血管化的肝移植的发展。诱导多能干细胞(IPSC)来源的肝细胞与人脐静脉内皮细胞(HUVECs)和人间充质干细胞(MSCs)共培养可形成类肝器官。然后，这些有机物质将被装载到组织培养血管中，并使用中空纤维管道来支持血液和胆汁的流动。将通过实验室测试和异种移植来评估组织移植物的生理反应，以验证该模型。第二个目标是表征微重力和定向血管生成梯度对3D细胞间相互作用和微血管组织的影响。通过使用活细胞、时间推移共聚焦显微镜，将检测这些环境因素对共培养的有机物细胞的影响。该项目的这一部分将促进对细胞如何响应微重力环境的组织自组装的基本理解，这将支持未来推进三维组织结构工程的工作。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.