2. Academic Validation
  3. Three-dimensional bioprinted glioblastoma microenvironments model cellular dependencies and immune interactions

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

  • Cell Res. 2020 Oct;30(10):833-853. doi: 10.1038/s41422-020-0338-1.
Min Tang  # 1,  Qi Xie  # 2 3 4 5 6,  Ryan C Gimple  # 7 8 9,  Zheng Zhong 1,  Trevor Tam 1,  Jing Tian 1,  Reilly L Kidwell 7 8,  Qiulian Wu 7 8,  Briana C Prager 7 8 9 10,  Zhixin Qiu 7 8,  Aaron Yu 7 8,  Zhe Zhu 7 8,  Pinar Mesci 8 11 12,  Hui Jing 13,  Jacob Schimelman 1,  Pengrui Wang 14,  Derrick Lee 7 8,  Michael H Lorenzini 7 8,  Deobrat Dixit 7 8,  Linjie Zhao 7 8,  Shruti Bhargava 7 8,  Tyler E Miller 15,  Xueyi Wan 16,  Jing Tang 17 18 19,  Bingjie Sun 1,  Benjamin F Cravatt 13,  Alysson R Muotri 8 11 12 20 21,  Shaochen Chen 22 23 24,  Jeremy N Rich 25 26 27
Affiliations

Affiliations

  • 1 Department of NanoEngineering, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
  • 2 Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA, 92037, USA. [email protected].
  • 3 Sanford Consortium for Regenerative Medicine, 2880 Torrey Pines Scenic Drive, La Jolla, CA, 92037, USA. [email protected].
  • 4 School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China. [email protected].
  • 5 Key Laboratory of Growth Regulation and Translation Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China. [email protected].
  • 6 Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang 310024, China. [email protected].
  • 7 Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA, 92037, USA.
  • 8 Sanford Consortium for Regenerative Medicine, 2880 Torrey Pines Scenic Drive, La Jolla, CA, 92037, USA.
  • 9 Department of Pathology, Case Western University, Cleveland, OH, USA.
  • 10 Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA.
  • 11 Department of Cellular & Molecular Medicine, School of Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
  • 12 Department of Pediatrics/Rady Children's Hospital San Diego, School of Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
  • 13 The Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
  • 14 Materials Science and Engineering Program, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
  • 15 Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
  • 16 Division of Biological Sciences, University of California San Diego, La Jolla, CA, 92093, USA.
  • 17 School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China.
  • 18 Key Laboratory of Growth Regulation and Translation Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China.
  • 19 Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang 310024, China.
  • 20 Kavli Institute for Brain and Mind, University of California San Diego, La Jolla, CA, 92093, USA.
  • 21 Center for Academic Research and Training in Anthropogeny (CARTA), La Jolla, CA, 92093, USA.
  • 22 Department of NanoEngineering, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA. [email protected].
  • 23 Materials Science and Engineering Program, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA. [email protected].
  • 24 Department of Bioengineering, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA. [email protected].
  • 25 Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA, 92037, USA. [email protected].
  • 26 Sanford Consortium for Regenerative Medicine, 2880 Torrey Pines Scenic Drive, La Jolla, CA, 92037, USA. [email protected].
  • 27 Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, CA, 92037, USA. [email protected].
  • # Contributed equally.
PMID: 32499560 DOI: 10.1038/s41422-020-0338-1
Abstract

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.

Figures
Products