Dynamically Crosslinked Poly(ethylene‐glycol) Hydrogels Reveal a Critical Role of Viscoelasticity in Modulating Glioblastoma Fates and Drug Responses in 3D. Issue 1 (16th November 2022)

• Record Type: Journal Article
• Authors: Sinha, Sauradeep; Ayushman, Manish; Tong, Xinming; Yang, Fan
• Is Part Of: Advanced healthcare materials. Volume 12:Issue 1(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-11-16
• Subjects: 3D disease models -- drug responses -- glioblastoma multiforme -- hydrogels -- stress relaxation -- viscoelasticity; Biomedical materials -- Periodicals; 610.28
• DOI: 10.1002/adhm.202202147
• Languages: English
• ISSNs: 2192-2640

Abstract

Abstract: Glioblastoma multiforme (GBM) is the most prevalent and aggressive brain tumor in adults. Hydrogels have been employed as 3D in vitro culture models to elucidate how matrix cues such as stiffness and degradation drive GBM progression and drug responses. Recently, viscoelasticity has been identified as an important niche cue in regulating stem cell differentiation and morphogenesis in 3D. Brain is a viscoelastic tissue, yet how viscoelasticity modulates GBM fate and drug response remains largely unknown. Using dynamic hydrazone crosslinking chemistry, a poly(ethylene‐glycol)‐based hydrogel system with brain‐mimicking stiffness and tunable stress relaxation is reported to interrogate the role of viscoelasticity on GBM fates in 3D. The hydrogel design allows tuning stress relaxation without changing stiffness, biochemical ligand density, or diffusion. The results reveal that increasing stress relaxation promotes invasive GBM behavior, such as cell spreading, migration, and GBM stem‐like cell marker expression. Furthermore, increasing stress relaxation enhances GBM proliferation and drug sensitivity. Stress‐relaxation induced changes on GBM fates and drug response are found to be mediated through the cytoskeleton and transient receptor potential vanilloid‐type 4. These results highlight the importance of incorporating viscoelasticity into 3D in vitro GBM models and provide novel insights into how viscoelasticity modulates GBM cell fates. Abstract : Brain‐mimicking, fast‐relaxing hydrogels (left) promote glioblastoma multiforme (GBM) chemosensitivity and enhance GBM invasive phenotype including cell spreading, migration, and proliferation. Stress relaxation induced chemosensitivity is associated with enhanced actomyosin cytoskeletal formations, GBM stem‐like cell marker expression, transient receptor potential vanilloid‐type 4 activity, and reduced nascent protein deposition. Conversely, slow‐relaxing hydrogels (right) induce opposite trends in corresponding cell fates and chemosensitivity.