Transcriptomic mapping of the metzincin landscape in human trophoblasts

Abstract

The metzincin family of metalloproteases coordinates cell and tissue developmental processes through regulation of growth factor availability, receptor signaling, and cell-cell/cell-matrix adhesion. During placental development, while distinct roles for metzincin proteases in controlling specific trophoblast functions have been described, a comprehensive assessment of metzincins during discrete stages of trophoblast differentiation has yet to be performed. Here we provide a comprehensive single cell transcriptomic resource of metzincin protease expression in diverse states of human trophoblasts from first trimester placental and decidual tissues. In the 8 distinct trophoblasts states categorized [four progenitor cytotrophoblast (CTB), one syncytiotrophoblast precursor (SCTp), two column CTB (cCTB), and one extravillous trophoblast (EVT) state], we identified 24 metzincin genes. These included 12 adamalysins, 2 pappalysins, 3 astacins and 7 matrixins. Cell trajectory modeling shows that expression of most (19/24) metzincins increases across CTB to EVT differentiation, though select proteases also increase as CTB fuse into syncytiotrophoblast. Within the CTB niche, single-cell velocity ordering identified 11 metzincins (ADAM10, -17, MMP14, -15, -19, -23B, ADAMTS1, -6, -19, TLL-1, -2) expressed in progenitors proximal to the predicted origin. Analysis of metzincin-substrate interactions within the CTB niche revealed ~150 substrates and binding partners, including FBN2 as an ADAMTS6-specific substrate preferentially expressed in trophoblast progenitors. Together, this work characterizes the metzincin transcriptomic landscape in human first trimester trophoblasts and establishes insight into the roles specific proteases perform within distinct trophoblast niches and across differentiation. This resource serves as a guide for future investigations into the roles of metzincin proteases in human placental development.

Single-cell assessment of trophoblast stem cell-based organoids as human placenta-modeling platforms

“…2B). We assessed the Hippo 17 , BMP 18 , WNT 19 , VEGF 20, 21 , NOTCH 19 , metalloprotease/extracellular matrix 22, 23 , and EGF 24 gene families because of their importance in regulating trophoblast renewal, differentiation, and function. Centrality analysis assessed which trophoblast-subtype predominantly produced ligands and which subtype expressed receptors for those ligands (correlated receivers).…”