Volume 30, No 10, Oct 2020

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 30 Issue 10, October 2020: 833-853

ORIGINAL ARTICLES

Three-dimensional bioprinted glioblastoma microenvironments model cellular dependencies and immune interactions

Min Tang¹ , Qi Xie^2,3,4,5,6,* , Ryan C. Gimple^2,3,7 , Zheng Zhong¹ , Trevor Tam¹ , Jing Tian¹ , Reilly L. Kidwell^2,3 , Qiulian Wu^2,3 , Briana C. Prager^2,3,7,8 , Zhixin Qiu^2,3 , Aaron Yu^2,3 , Zhe Zhu^2,3 , Pinar Mesci^3,9,10 , Hui Jing¹¹ , Jacob Schimelman¹ , Pengrui Wang¹² , Derrick Lee^2,3 , Michael H. Lorenzini^2,3 , Deobrat Dixit^2,3 , Linjie Zhao^2,3 , Shruti Bhargava^2,3 , Tyler E. Miller¹³ , Xueyi Wan¹⁴ , Jing Tang^4,5,6 , Bingjie Sun¹ , Benjamin F. Cravatt¹¹ , Alysson R. Muotri^3,9,10,15,16 , Shaochen Chen^1,12,17,* , Jeremy N. Rich^2,3,18,*

¹Department of NanoEngineering, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
²Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA
³Sanford Consortium for Regenerative Medicine, 2880 Torrey Pines Scenic Drive, La Jolla, CA 92037, USA
⁴School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China
⁵Key Laboratory of Growth Regulation and Translation Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China
⁶Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang 310024, China
⁷Department of Pathology, Case Western University, Cleveland, OH, USA
⁸Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA
⁹Department of Cellular & Molecular Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA
¹⁰Department of Pediatrics/Rady Children’s Hospital San Diego, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA
¹¹The Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
¹²Materials Science and Engineering Program, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
¹³Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
¹⁴Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA
¹⁵Kavli Institute for Brain and Mind, University of California San Diego, La Jolla, CA 92093, USA
¹⁶Center for Academic Research and Training in Anthropogeny (CARTA), La Jolla, CA 92093, USA
¹⁷Department of Bioengineering, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
¹⁸Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, CA 92037, USA
^†These authors contributed equally: Min Tang, Qi Xie, Ryan C. Gimple
Correspondence: Qi Xie(xieqi@westlake.edu.cn)Shaochen Chen(chen168@eng.ucsd.edu)Jeremy N. Rich(drjeremyrich@gmail.com)

Brain tumors are dynamic complex ecosystems with multiple cell types. To model the brain tumor microenvironment in a reproducible and scalable system, we developed a rapid three-dimensional (3D) bioprinting method to construct clinically relevant biomimetic tissue models. In recurrent glioblastoma, macrophages/microglia prominently contribute to the tumor mass. To parse the function of macrophages in 3D, we compared the growth of glioblastoma stem cells (GSCs) alone or with astrocytes and neural precursor cells in a hyaluronic acid-rich hydrogel, with or without macrophage. Bioprinted constructs integrating macrophage recapitulate patient-derived transcriptional profiles predictive of patient survival, maintenance of stemness, invasion, and drug resistance. Whole-genome CRISPR screening with bioprinted complex systems identified unique molecular dependencies in GSCs, relative to sphere culture. Multicellular bioprinted models serve as a scalable and physiologic platform to interrogate drug sensitivity, cellular crosstalk, invasion, context-specific functional dependencies, as well as immunologic interactions in a species-matched neural environment.

https://doi.org/10.1038/s41422-020-0338-1

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