Sun Avery Rui, Ramli Md Faris H, Shen Xingyu, Kannivadi Ramakanth Karthikbabu, Chen Dixiao, Hu Yang, Vidyasekar Prasanna, Foo Roger S, Long Yuchen, Zhu Jin, Ackers-Johnson Matthew, Young Jennifer L
Mechanobiology Institute (MBI), National University of Singapore, Singapore, Singapore.
Department of Biomedical Engineering, College of Design and Engineering, National University of Singapore, Singapore, Singapore.
Nat Mater. 2025 Jun 12. doi: 10.1038/s41563-025-02234-6.
Extracellular matrix remodelling of cardiac tissue is a key contributor to age-related cardiovascular disease and dysfunction. Such remodelling is multifaceted including changes to the biochemical composition, architecture and mechanics, clouding our understanding of how and which extracellular matrix properties contribute to a dysfunctional state. Here we describe a decellularized extracellular matrix-synthetic hydrogel hybrid scaffold that independently confers two distinct matrix properties-ligand presentation and stiffness-to cultured cells in vitro, allowing for the identification of their specific roles in cardiac ageing. The hybrid scaffold maintains native matrix composition and organization of young or aged murine cardiac tissue, whereas its mechanical properties can be independently tuned to mimic young or aged tissue stiffness. Seeding these scaffolds with murine primary cardiac fibroblasts, we identify distinct age- and matrix-dependent mechanisms of cardiac fibroblast activation, matrix remodelling and senescence. Importantly, we show that the ligand presentation of a young extracellular matrix can outweigh the profibrotic stiffness cues typically present in an aged extracellular matrix in maintaining or driving cardiac fibroblast quiescence. Ultimately, these tunable scaffolds can enable the discovery of specific extracellular targets to prevent ageing dysfunction and promote rejuvenation.
心脏组织的细胞外基质重塑是与年龄相关的心血管疾病和功能障碍的关键因素。这种重塑是多方面的，包括生化组成、结构和力学的变化，这使我们难以理解细胞外基质的哪些特性以及如何导致功能失调状态。在这里，我们描述了一种去细胞化的细胞外基质-合成水凝胶混合支架，它能在体外独立赋予培养细胞两种不同的基质特性——配体呈现和硬度，从而能够确定它们在心脏衰老中的特定作用。该混合支架保留了年轻或老年小鼠心脏组织的天然基质组成和结构，而其力学性能可独立调节以模拟年轻或老年组织的硬度。将小鼠原代心脏成纤维细胞接种到这些支架上，我们确定了心脏成纤维细胞激活、基质重塑和衰老的不同年龄和基质依赖性机制。重要的是，我们表明，在维持或驱动心脏成纤维细胞静止方面，年轻细胞外基质的配体呈现可以超过老年细胞外基质中通常存在的促纤维化硬度信号。最终，这些可调节的支架能够发现特定的细胞外靶点，以预防衰老功能障碍并促进年轻化。
