Georgescu Andrei, Oved Joseph Hai, Galarraga Jonathan H, Cantrell Thomas, Mehta Samira, Dulmovits Brian M, Olson Timothy S, Fattahi Pouria, Wang Anni, Candarlioglu Pelin L, Muvaffak Asli, Kim Michele M, Aydin Sezin Aday, Seo Jeongyun, Diffenderfer Eric S, Lynch Anthony, Worthen G Scott, Huh Dan Dongeun
Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA; Vivodyne Inc., Philadelphia, PA 19104, USA.
Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Cell Stem Cell. 2024 Dec 5;31(12):1847-1864.e6. doi: 10.1016/j.stem.2024.11.003.
Here, we present a bioengineering approach to emulate the human bone marrow in vitro. Our developmentally inspired method uses self-organization of human hematopoietic stem and progenitor cells and vascular endothelial cells cultured in a three-dimensional microphysiological system to create vascularized, perfusable tissue constructs that resemble the hematopoietic vascular niche of the human marrow. The microengineered niche is capable of multilineage hematopoiesis and can generate functionally mature human myeloid cells that can intravasate into perfused blood vessels, providing a means to model the mobilization of innate immune cells from the marrow. We demonstrate the application of this system by presenting a specialized model of ionizing radiation-induced bone marrow injury and a multiorgan model of acute innate immune responses to bacterial lung infection. Furthermore, we introduce an advanced platform that enables large-scale integration and automated experimentation of the engineered hematopoietic tissues for preclinical screening of myelotoxicity due to anti-cancer drugs.
在此，我们展示了一种在体外模拟人类骨髓的生物工程方法。我们受发育启发的方法利用在三维微生理系统中培养的人类造血干细胞和祖细胞以及血管内皮细胞的自组织，来创建类似于人类骨髓造血血管微环境的血管化、可灌注组织构建体。这种微工程化的微环境能够进行多谱系造血，并能产生功能成熟的人类髓系细胞，这些细胞可侵入灌注的血管，为模拟先天免疫细胞从骨髓中的动员提供了一种手段。我们通过展示电离辐射诱导的骨髓损伤的专门模型和细菌肺部感染的急性先天免疫反应的多器官模型，来证明该系统的应用。此外，我们引入了一个先进平台，该平台能够对工程化造血组织进行大规模整合和自动化实验，用于抗癌药物骨髓毒性的临床前筛选。
