Jain Ishita, Chan Alex H P, Yang Guang, He Hao, Lam Johnny, Sung Kyung, Huang Ngan F
Department of Cardiothoracic Surgery, Stanford University, Stanford, CA, 94305, USA.
Stanford Cardiovascular Institute, Stanford University, Stanford, CA, 94305, USA.
NPJ Regen Med. 2025 Apr 22;10(1):21. doi: 10.1038/s41536-025-00408-z.
Despite the therapeutic potential of mesenchymal stromal cells (MSC), there is limited understanding of optimal extracellular matrix (ECM) environments to manufacture these cells. We developed tissue chips to study the effects of multi-factorial ECM environments under manufacturable stiffness ranges and multi-component ECM compositions. Manufacturing qualities of cell expansion potential, immunomodulation, and differentiation capacity were examined. The results show stiffness effects, with 900 kPa substrates supporting higher proliferation and osteogenic differentiation, along with anti-inflammatory IL-10 expression, whereas 150 kPa substrates promoted adipogenic differentiation at 150 kPa, suggesting that optimal ECM environments may differ based on manufacturing goals. ECM biochemistries containing fibronectin and laminin further modulated MSC manufacturing qualities across various stiffnesses. Proteomic and transcriptomic analyses revealed unique ECM combinations that induced higher levels of angiogenic and immunomodulatory cytokines, compared to single factor ECMs. These findings demonstrate that optimized ECM environments enhance MSC manufacturing quality.
尽管间充质基质细胞（MSC）具有治疗潜力，但对于制造这些细胞的最佳细胞外基质（ECM）环境的了解仍然有限。我们开发了组织芯片，以研究在可制造的硬度范围和多组分ECM组成下多因素ECM环境的影响。检测了细胞扩增潜力、免疫调节和分化能力的制造质量。结果显示出硬度效应，900 kPa的基质支持更高的增殖和成骨分化，同时伴有抗炎性白细胞介素-10的表达，而150 kPa的基质在150 kPa时促进脂肪生成分化，这表明最佳的ECM环境可能因制造目标而异。含有纤连蛋白和层粘连蛋白的ECM生物化学物质进一步调节了不同硬度下的MSC制造质量。蛋白质组学和转录组学分析揭示了与单因素ECM相比，能诱导更高水平血管生成和免疫调节细胞因子的独特ECM组合。这些发现表明，优化的ECM环境可提高MSC的制造质量。
