ISS: Liver Tissue Engineering in Space

终末期器官衰竭是重要器官如心脏、肺、肾或肝的不可逆和致命的损害。 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，但由于供体器官短缺而受到严重限制。 科学家们一直在尝试在体外组织工程器官，以替代衰竭的器官，但这些努力受到了挑战，因为很难创造出可以灌注大块组织的小血管网络。 研究表明，当细胞在称为微重力的低重力条件下自由组织和组装时，它们建立了重要的细胞间关系，并可以形成毛细血管等组织结构。 在这项研究中，使用肝脏作为模型器官，研究小组将研究如何利用国际空间站上的微重力条件来促进大型血管化组织移植物的开发。 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功能性和血管化的肝脏组织。研究结果将包括一个延时视频，展示不同类型的细胞如何在微重力下组织自己以应对生长因子梯度。 这将使研究人员更好地了解微重力如何调节组织形成。 除了科学目标外，研究小组还将通过K-12教育，指导S.T.E.M.中代表性不足的团体，公众推广和行业合作。该项目围绕两个研究目标。首先，将利用国际空间站的微重力环境制作肉眼可见的血管化肝组织。 研究人员假设，3D空间自由的环境，中央管道内的灌注力不必与重力竞争，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肝移植物的开发。 将通过将诱导多能干细胞（iPSC）衍生的肝细胞与人脐静脉内皮细胞（HUVEC）和人间充质干细胞（MSC）共培养来开发肝类器官。 然后将类器官装载到具有中空纤维导管的组织培养容器中，以支持血液和胆汁的流动。 将评估组织移植物的生理反应，以通过实验室测定和异种移植验证模型。 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，延时共聚焦显微镜，将检查这些环境因素对类器官的共培养细胞的影响。 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，这将支持未来的工作，以推进三维组织结构的工程。该奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

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.