The metzincin family of metalloproteases coordinates tissue developmental processes through regulation of growth factor availability, receptor signaling, and cell-cell/cell-matrix adhesion. While roles for select metzincins in controlling trophoblast functions in human placental development have been described, a comprehensive understanding of metzincin dynamics during trophoblast differentiation is lacking. To address this knowledge gap, single cell transcriptomic datasets derived from first trimester chorionic villi and decidua were used to decipher metzincin expression profiles and kinetics in diverse cell types within the utero-placental interface. Further, specific protease-substrate interactions within progenitor trophoblasts were examined to better define the progenitor niche. Within the uterine-placental compartment, 43 metzincin proteases were expressed across 15 cell-type clusters. Metzincin subgroups expressed in placental trophoblasts, placental mesenchymal cells, uterine stromal, and immune cells included multiple matrix metalloproteases (MMPs), a disintegrin and metalloproteases (ADAMs), a disintegrin and metalloproteases with thrombospondin repeats (ADAMTSs), pappalysins, and astacins. Within the trophoblast compartment, eight distinct trophoblasts states were identified: four cytotrophoblast (CTB), one syncytiotrophoblast precursor (SCTp), two column CTB (cCTB), and one extravillous trophoblast (EVT). Within these states 7 MMP, 8 ADAM, 4 ADAMTS, 2 pappalysin, and 3 astacin proteases were expressed. Cell trajectory modeling shows that expression of most (19/24) metzincins increase during EVT differentiation, though expression of select metalloproteases increase along the villous pathway. Eleven metzincins (ADAM10, -17, MMP14, -15, -19, -23B, ADAMTS1, -6, -19, TLL-1, -2) showed enrichment within CTB progenitors, and analysis of metzincin-substrate interactions identified ∼150 substrates and binding partners, including FBN2 as an ADAMTS6-specific substrate. Together, this work characterizes the metzincin landscape in human first trimester trophoblasts and establishes insight into the roles specific proteases perform within distinct trophoblast niches and across trophoblast differentiation. This resource serves as a guide for future investigations into the roles of metzincin proteases in human placental development.

金属蛋白酶的 metzincin 家族通过调节生长因子可用性、受体信号和细胞-细胞/细胞-基质粘附来协调组织发育过程。虽然已经描述了选择的 metzincin 在控制人胎盘发育中的滋养层功能中的作用，但缺乏对滋养层分化过程中 metzincin 动力学的全面了解。为了解决这一知识差距，来自早孕期绒毛膜绒毛和蜕膜的单细胞转录组数据集被用于破译子宫-胎盘界面内不同细胞类型的 metzincin 表达谱和动力学。此外，检查了祖细胞滋养细胞内的特定蛋白酶-底物相互作用，以更好地定义祖细胞生态位。在子宫-胎盘腔内，43 种 metzincin 蛋白酶在 15 个细胞类型簇中表达。在胎盘滋养细胞、胎盘间充质细胞、子宫间质细胞和免疫细胞中表达的 Metzincin 亚群包括多种基质金属蛋白酶 (MMP)、解整合素和金属蛋白酶 (ADAM)、具有血小板反应蛋白重复序列​​的解整合素和金属蛋白酶 (ADAMTS)、冠毛素和虾红素。在滋养细胞隔室内，确定了八种不同的滋养细胞状态：四种细胞滋养细胞 (CTB)、一种合体滋养细胞前体 (SCTp)、两列 CTB (cCTB) 和一种绒毛外滋养细胞 (EVT)。在这些状态中，表达了 7 种 MMP、8 种 ADAM、4 种 ADAMTS、2 种冠毛素和 3 种虾红素蛋白酶。细胞轨迹建模表明，大多数 (19/24) metzincins 的表达在 EVT 分化过程中增加，尽管选择的金属蛋白酶的表达沿着绒毛通路增加。十一麦津星（ADAM10，-17，MMP14，-15，-19，-23B，ADAMTS1，-6，-19，TLL-1，-2）显示 CTB 祖细胞内富集，并且对 metzincin-底物相互作用的分析确定了 ~150 个底物和结合合作伙伴，包括FBN2作为ADAMTS6特定底物。总之，这项工作描述了人类早孕期滋养细胞中的 metzincin 景观，并建立了对特定蛋白酶在不同滋养细胞生态位和跨滋养细胞分化中所发挥作用的洞察力。该资源可作为未来研究麦津辛蛋白酶在人类胎盘发育中的作用的指南。