Carvalho Emily M, Ding Erika A, Saha Atul, Garcia Diana Cruz, Weldy Anna, Zushin Peter-James H, Stahl Andreas, Aghi Manish K, Kumar Sanjay
Department of Chemical and Biomolecular Engineering, University of California, Berkeley, CA, 94720, USA.
Department of Neurosurgery, University of California, San Francisco, CA, 94158, USA.
Adv Mater. 2024 Dec;36(50):e2404885. doi: 10.1002/adma.202404885. Epub 2024 Nov 7.
Hyaluronic acid (HA), the primary component of brain extracellular matrix, is increasingly used to model neuropathological processes, including glioblastoma (GBM) tumor invasion. While elastic hydrogels based on crosslinked low-molecular-weight (LMW) HA are widely exploited for this purpose and have proven valuable for discovery and screening, brain tissue is both viscoelastic and rich in high-MW (HMW) HA, and it remains unclear how these differences influence invasion. To address this question, hydrogels comprised of either HMW (1.5 MDa) or LMW (60 kDa) HA are introduced, characterized, and applied in GBM invasion studies. Unlike LMW HA hydrogels, HMW HA hydrogels relax stresses quickly, to a similar extent as brain tissue, and to a greater extent than many conventional HA-based scaffolds. GBM cells implanted within HMW HA hydrogels invade much more rapidly than in their LMW HA counterparts and exhibit distinct leader-follower dynamics. Leader cells adopt dendritic morphologies similar to invasive GBM cells observed in vivo. Transcriptomic, pharmacologic, and imaging studies suggest that leader cells exploit hyaluronidase, an enzyme strongly enriched in human GBMs, to prime a path for followers. This study offers new insight into how HA viscoelastic properties drive invasion and argues for the use of highly stress-relaxing materials to model GBM.
透明质酸（HA）是脑细胞外基质的主要成分，越来越多地被用于模拟神经病理过程，包括胶质母细胞瘤（GBM）的肿瘤侵袭。虽然基于交联低分子量（LMW）HA的弹性水凝胶已被广泛用于此目的，并已证明对发现和筛选有价值，但脑组织既具有粘弹性又富含高分子量（HMW）HA，目前尚不清楚这些差异如何影响侵袭。为了解决这个问题，引入了由HMW（1.5 MDa）或LMW（60 kDa）HA组成的水凝胶，对其进行了表征，并应用于GBM侵袭研究。与LMW HA水凝胶不同，HMW HA水凝胶能快速释放应力，其程度与脑组织相似，且比许多传统的基于HA的支架更大。植入HMW HA水凝胶中的GBM细胞比植入LMW HA水凝胶中的细胞侵袭速度快得多，并表现出明显的“领导者-跟随者”动态。领导者细胞采用类似于体内观察到的侵袭性GBM细胞的树突形态。转录组学、药理学和成像研究表明，领导者细胞利用透明质酸酶（一种在人类GBM中高度富集的酶）为跟随者开辟道路。这项研究为HA的粘弹性特性如何驱动侵袭提供了新的见解，并主张使用高应力松弛材料来模拟GBM。
