Astrocytic scar restricting glioblastoma via glutamate-MAO-B activity in glioblastoma-microglia assembloid

  • Biomater Res. 2023 Jul 19;27(1):71. doi: 10.1186/s40824-023-00408-4.
Yen N Diep  #  1  2  3 ,  Hee Jung Park  #  4 ,  Joon-Ho Kwon  #  5  6 ,  Minh Tran  1  2  3 ,  Hae Young Ko  4 ,  Hanhee Jo  4 ,  Jisu Kim  4 ,  Jee-In Chung  4 ,  Tai Young Kim  5 ,  Dongwoo Kim  4 ,  Jong Hee Chang  7 ,  You Jung Kang  1  2 ,  C Justin Lee  8  9  10 ,  Mijin Yun  11 ,  Hansang Cho  12  13  14
Affiliations
  • 1. Institute of Quantum Biophysics, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
  • 2. Department of Biophysics, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
  • 3. Department of Intelligent Precision Healthcare Convergence, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
  • 4. Department of Nuclear Medicine, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
  • 5. Center for Cognition and Sociality, Institute for Basic Science, Daejeon, 34126, Republic of Korea.
  • 6. Department of Biomedical Engineering, Ulsan National Institute of Science & Technology, Ulsan, 44919, Republic of Korea.
  • 7. Department of Neurosurgery, Severance Hospital, Seoul, 120-752, Republic of Korea.
  • 8. Center for Cognition and Sociality, Institute for Basic Science, Daejeon, 34126, Republic of Korea. [email protected].
  • 9. Department of Biomedical Engineering, Ulsan National Institute of Science & Technology, Ulsan, 44919, Republic of Korea. [email protected].
  • 10. Korea University-Korea Institute of Science and Technology, Graduate School of Convergence Technology, Korea University, Seoul, 136-701, Republic of Korea. [email protected].
  • 11. Department of Nuclear Medicine, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea. [email protected].
  • 12. Institute of Quantum Biophysics, Sungkyunkwan University, Suwon, 16419, Republic of Korea. [email protected].
  • 13. Department of Biophysics, Sungkyunkwan University, Suwon, 16419, Republic of Korea. [email protected].
  • 14. Department of Intelligent Precision Healthcare Convergence, Sungkyunkwan University, Suwon, 16419, Republic of Korea. [email protected].
  • # Contributed equally.
PMID: 37468961 DOI: 10.1186/s40824-023-00408-4
Abstract

Background: Glial scar formation is a reactive glial response confining injured regions in a central nervous system. However, it remains challenging to identify key factors formulating glial scar in response to glioblastoma (GBM) due to complex glia-GBM crosstalk.

Methods: Here, we constructed an astrocytic scar enclosing GBM in a human assembloid and a mouse xenograft model. GBM spheroids were preformed and then co-cultured with microglia and astrocytes in 3D Matrigel. For the xenograft model, U87-MG cells were subcutaneously injected to the Balb/C nude female mice.

Results: Additional glutamate was released from GBM-microglia assembloid by 3.2-folds compared to GBM alone. The glutamate upregulated astrocytic monoamine oxidase-B (MAO-B) activity and chondroitin sulfate proteoglycans (CSPGs) deposition, forming the astrocytic scar and restricting GBM growth. Attenuating scar formation by the glutamate-MAO-B inhibition increased drug penetration into GBM assembloid, while reducing GBM confinement.

Conclusions: Taken together, our study suggests that astrocytic scar could be a critical modulator in GBM therapeutics.

Keywords
Assembloid; Glial scar formation; Glioblastoma; Glutamate; MAO-B; Microglia.
Products