Astrocytic scar restricting glioblastoma via glutamate-MAO-B activity in glioblastoma-microglia assembloid
Authors
Yen N Diep ; Hee Jung Park ; Joon-Ho Kwon ; Minh Tran ; Hae Young Ko ; Hanhee Jo ; Jisu Kim ; Jee-In Chung ; Tai Young Kim ; Dongwoo Kim ; Jong Hee Chang ; You Jung Kang ; C Justin Lee ; Mijin Yun ; Hansang Cho
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.