Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2022.02.15.480614

Transcriptomic mapping of the metzincin landscape in human trophoblasts

Wächter, J.·Shannon, M. J.·Castellana, B.·Baltayeva, J.·Beristain, A. G.
View original source ↗Export metadata ↓

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. Summary StatementSingle cell RNA sequencing characterizes the expression of multiple metzincin proteases within first trimester placental trophoblasts. Examination of protease-substrate interactions within cytotrophoblasts identifies potential interactions between ADAMTS6 and FBN2. HighlightsO_LISingle cell RNA sequencing identifies 24 distinct metzincin proteases expressed in human first trimester trophoblasts C_LIO_LILineage trajectory modelling shows that metzincin genes are dynamic and likely control processes in progenitor, mid-point, and end-point states of trophoblast differentiation. C_LIO_LIADAMTS6, and its putative substrate FBN2, localize specifically to progenitor trophoblasts C_LI

Source connections

Explore related subjects

developmental biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Wächter, J., Shannon, M. J., Castellana, B., Baltayeva, J., Beristain, A. G.. 2022-02-16. Transcriptomic mapping of the metzincin landscape in human trophoblasts. https://doi.org/10.1101/2022.02.15.480614

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Hyaluronic acid dynamics are regulated by neural crest cells and NEDD4 in the developing cardiac outflow tract valves

The extracellular matrix (ECM) is essential for cardiac valve development, with hyaluronic acid (HA) playing a critical role in cardiac cushion formation. While HA is required for atrioventricular valve development, its role in semilunar valve formation remains poorly understood. The ubiquitin ligase NEDD4 is essential for cardiac outflow tract development, particularly within cardiac neural crest cells, however its role in semilunar valve development has been unexplored. Here, we demonstrate that neural crest-specific deletion of NEDD4 in mice disrupts outflow tract valve development, resulting in abnormal leaflet number and morphology. Analysis of valve ECM revealed a specific reduction in HA within the neural crest-derived valve mesenchyme, while other ECM components such as fibronectin and versican remained unaffected. In contrast, deletion of NEDD4 in endocardium-derived valve mesenchyme did not alter HA abundance. Using NEDD4-deficient neural crest cells, we further demonstrate a cell-autonomous requirement for NEDD4 in regulating HA abundance, with in vitro evidence supporting impaired HA synthesis rather than increased turnover of HA in the ECM. Our findings identify a previously unrecognised role for NEDD4 in regulating HA synthesis in cardiac neural crest cells, revealing a cell-type-specific mechanism governing semilunar valve development and highlighting distinct cellular requirements for ECM regulation across cardiac valve populations.

developmental biology↗
bioRxiv2026

Cxcr2 is required for ductal outgrowth and shapes the stromal microenvironment in postnatal mammary gland development

Mammary gland development requires coordinated signaling between epithelial and stromal compartments. While CXC chemokine receptor 2 (CXCR2) is known to regulate inflammatory and tissue remodeling processes in disease, including breast cancer, its role in mammary gland morphogenesis is not well understood. Here, we examined postnatal mammary gland development in germline Cxcr2 knockout mice. Loss of Cxcr2 resulted in delayed ductal outgrowth, reduced epithelial area, and altered stromal architecture, including decreased adipocyte size and increased collagen deposition, despite preserved branching organization. These defects occurred in the context of severe systemic immune dysregulation, marked by expansion of granulocytic populations and loss of adaptive immune cells. Together, our findings indicate that CXCR2 indirectly regulates mammary gland development through coordination between the epithelium and stroma, rather than acting through epithelial cell-intrinsic mechanisms. Because the same myeloid expansion, immune suppression, and collagen-rich stromal remodeling that CXCR2 controls during normal development are hallmarks of the pro-tumorigenic breast microenvironment, these findings establish CXCR2 as a regulator of the immune and stromal landscape of the mammary gland and provide a developmental framework for understanding its contributions to the breast tumor microenvironment.

developmental biology↗
bioRxiv2026

Endogenous Mechanical Reporters Encode the Global Mechanical Landscape of Morphogenesis

Developmental systems usually comprise multiple genetically programmed morphogenetic events within a mechanically continuous environment, yet how individual processes interact and contribute to the overall mechanical landscape remains unknown. Here, we introduce the concept of mechanical reporter: endogenous tissues function as in situ probes of the embedded mechanical landscape. We exemplified cephalic furrow (CF) migration as a mechanical reporter in gastrulating Drosophila. Using optogenetics and genetics, we revealed that CF displacement reflects the combined effect of both force and tissue mechanical properties. By incorporating condition-specific mechanical landscape into a continuum minimal-response model, we developed a framework to quantitatively predict the reporter dynamics. Using different genetic mutants, we successfully decoded changes in the mechanical landscape from CF dynamics in gastrulating Drosophila. Overall, we established a predictive framework that uses CF dynamics to infer changes in the global mechanical landscape. Beyond this, the concept of mechanical reporter provides a general strategy for systematically understanding and decoding complex mechanical environments in living systems.

developmental biology↗