Department of Biological and Biomedical Engineering, McGill University, Montréal, Québec, Canada.
Department of Chemical Engineering, McGill University, Montréal, Québec, Canada.
Biomater Sci. 2021 Oct 26;9(21):7247-7256. doi: 10.1039/d1bm00799h.
The placental syncytiotrophoblast is a multinucleated layer that regulates transport between the mother and fetus. Fusion of trophoblasts is essential to form this layer, but this process can be disrupted in pregnancy-related disorders such as preeclampsia. Disease progression is also associated with changes in the extracellular matrix (ECM), but whether disease-specific ECM compositions play any causal role in establishing syncytiotrophoblast disease phenotypes remains unknown. Here, we develop a decellularization-based platform to isolate and characterize the role of human placental ECM composition on cell function, while controlling for the confounding effects of matrix structure and mechanics that can arise in conventional tissue decellularization/recellularization experiments. Using this approach, we demonstrate that ECM compositional changes that occur in preeclampsia have a statistically significant effect on adhesion, spreading, and fusion of placental trophoblasts. Proteomic analysis of ECM content then allowed us to identify and recreate selected differences in matrix composition; indicating that replacement of normally present Type IV Collagen by Type I Collagen in preeclampsia significantly affects fusion efficiency. These results indicate that disease-specific matrix compositions can play an important role in trophoblast fusion, suggesting novel matrix-targeting therapeutic strategies for pregnancy-related disorders. More broadly, this work demonstrates the utility of a decellularization-based approach in understanding the functional contributions of matrix composition in driving cellular disease phenotypes.
胎盘合体滋养层是一层多核细胞层，调节着母体和胎儿之间的物质转运。滋养层细胞的融合对于形成这个层至关重要，但这个过程在与妊娠相关的疾病中，如子痫前期，会被打乱。疾病的进展也与细胞外基质（ECM）的变化有关，但疾病特异性 ECM 成分是否在建立合体滋养层疾病表型中发挥任何因果作用仍不清楚。在这里，我们开发了一种基于去细胞化的平台，以分离和表征人胎盘 ECM 成分对细胞功能的作用，同时控制传统组织去细胞化/再细胞化实验中可能出现的基质结构和力学的混杂影响。使用这种方法，我们证明了子痫前期中发生的 ECM 组成变化对胎盘滋养层细胞的黏附、铺展和融合有统计学意义的影响。然后，对 ECM 含量的蛋白质组学分析使我们能够识别和重现基质组成的某些差异；表明在子痫前期中，通常存在的 IV 型胶原被 I 型胶原取代，这显著影响融合效率。这些结果表明，疾病特异性基质组成可以在滋养层融合中发挥重要作用，为与妊娠相关的疾病提供了新的基质靶向治疗策略。更广泛地说，这项工作证明了基于去细胞化的方法在理解基质组成在驱动细胞疾病表型中的功能贡献方面的效用。
