Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Barcelona 08028, Spain.
CIBER en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid 28029, Spain.
ACS Appl Mater Interfaces. 2021 Sep 22;13(37):44108-44123. doi: 10.1021/acsami.1c13630. Epub 2021 Sep 8.
Most morphogenetic and pathological processes are driven by cells responding to the surrounding matrix, such as its composition, architecture, and mechanical properties. Despite increasing evidence for the role of extracellular matrix (ECM) in tissue and disease development, many substitutes still fail to effectively mimic the native microenvironment. We established a novel method to produce macroscale (>1 cm) mesenchymal cell-derived matrices (CDMs) aimed to mimic the fibrotic tumor microenvironment surrounding epithelial cancer cells. CDMs are produced by human adipose mesenchymal stem cells cultured in sacrificial 3D scaffold templates of fibronectin-coated poly-lactic acid microcarriers (MCs) in the presence of macromolecular crowders. We showed that decellularized CDMs closely mimic the fibrillar protein composition, architecture, and mechanical properties of human fibrotic ECM from cancer masses. CDMs had highly reproducible composition made of collagen types I and III and fibronectin ECM with tunable mechanical properties. Moreover, decellularized and MC-free CDMs were successfully repopulated with cancer cells throughout their 3D structure, and following chemotherapeutic treatment, cancer cells showed greater doxorubicin resistance compared to 3D culture in collagen hydrogels. Collectively, these results support the use of CDMs as a reproducible and tunable tool for developing 3D cancer models.
大多数形态发生和病理过程都是由细胞对周围基质的反应驱动的，例如基质的组成、结构和力学性质。尽管越来越多的证据表明细胞外基质（ECM）在组织和疾病发展中的作用，但许多替代品仍然无法有效地模拟天然微环境。我们建立了一种生产大规模（>1cm）间充质细胞衍生基质（CDM）的新方法，旨在模拟围绕上皮癌细胞的纤维性肿瘤微环境。CDM 是通过在存在大分子拥挤剂的情况下，用人脂肪间充质干细胞在纤维连接蛋白涂覆的聚乳酸微载体（MC）的牺牲 3D 支架模板中培养而产生的。我们表明，去细胞化的 CDM 非常类似于源自癌症组织的人纤维性 ECM 的纤维状蛋白组成、结构和力学特性。CDM 具有高度可重复的组成，由 I 型和 III 型胶原和纤维连接蛋白 ECM 组成，具有可调节的机械性能。此外，去细胞化和无 MC 的 CDM 可以成功地在其 3D 结构中重新填充癌细胞，并且在用阿霉素进行化疗处理后，与在胶原水凝胶中进行 3D 培养相比，癌细胞表现出更强的阿霉素耐药性。总之，这些结果支持使用 CDM 作为开发 3D 癌症模型的可重复和可调谐工具。
