Biology subjects

Lackner, A. I.

Publications and source records attributed to Lackner, A. I..

3 recordsLinked to original sources

bioRxiv2026

CytoRipple: Mapping Tissue Polarization through Subcellular Cytoskeleton Dynamics

Spatial multi-omic technologies entail simultaneous measurement of tens-to-thousands of molecular features (e.g. RNA, protein). While cell type and state profiling is the major focus of spatial multi-omic analyses, cytoskeletal proteins are often solely utilized for cell segmentation and quality control. Here, we introduce a new computational framework, CytoRipple, that leverages these concomitant spatially-resolved single-cell measurements of cytoskeleton proteins to identify tissue-level vector fields. Polarization vectors are known to associate with cell movement and phenotype, inferring their physical orientation. We validate these associations across biological contexts and reveal how polarization vector fields can be harnessed to discover multi-cellular structures (e.g. "streams" of cells with similar polarizations). These multi-cellular cytoskeleton dynamics associate with distinct phenomena, such as vector "divergence" with CD8+ T cell activation and "streams" with spatially segmented stages of the anti-tumor immune response. Together, these data support a role for CytoRipple in revealing a dynamic layer across spatial multi-omic platforms.

bioinformatics↗

bioRxiv2023

NOTCH3 signalling controls human trophoblast stem cell expansion and differentiation

Failures in growth and differentiation of the early human placenta are associated with severe pregnancy disorders such as preeclampsia and fetal growth restriction. However, regulatory mechanisms controlling development of its epithelial cells, the trophoblasts, remain poorly elucidated. Using trophoblast stem cells (TSCs), trophoblast organoids (TB-ORGs) and primary cytotrophoblasts (CTBs) of early pregnancy, we herein show that autocrine NOTCH3 signalling controls human placental expansion and differentiation. NOTCH3 receptor was specifically expressed in proliferative CTB progenitors and its active form, the nuclear NOTCH3 intracellular domain (NOTCH3-ICD), interacted with the transcriptional co-activator Mastermind-like 1 (MAML1). Doxycyclin-inducible expression of dominant-negative MAML1 in TSC lines provoked cell fusion and upregulation of genes specific for multinucleated syncytiotrophoblasts, the differentiated hormone-producing cell type of the placenta. However, progenitor expansion and markers of trophoblast stemness and proliferation were suppressed. Accordingly, inhibition of NOTCH3 signalling diminished growth of TB-ORGs whereas overexpression of NOTCH3-ICD in primary CTBs and TSCs showed opposite effects. In conclusion, the data suggest that canonical NOTCH3 signalling plays a key role in human placental development promoting self-renewal of CTB progenitors.

developmental biology↗

bioRxiv2022

The human placenta dictates the phenotype of decidual macrophages.

During human pregnancy, placenta-derived extravillous trophoblasts (EVT) invade the decidua and communicate with maternal immune cells. The decidua can be distinguished into basalis (decB) and parietalis (decP), the latter being unaffected by placentation. By defining a novel gating strategy, we report accumulation of myeloid cells in decB. We identified a decidua basalis-associated macrophage (decBAM) population with a differential transcriptome and secretome when compared to decidua parietalis-associated macrophages (decPAMs). decBAMs are CD11chi and efficient inducers of Tregs, proliferate in situ and secrete high levels of CXCL1, CXCL5, M-CSF, and IL-10. In contrast, decPAMs exert a dendritic cell-like, motile phenotype characterized by induced expression of HLA class II molecules, enhanced phagocytosis, and the ability to activate T cells. Strikingly, EVT-conditioned media are able to convert decPAMs into a decBAM phenotype. Cumulatively, these findings assign distinct macrophage phenotypes to decidual areas depending on placentation and further highlight a critical role for EVTs in the induction of pregnancy-tolerant macrophage polarization. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=131 SRC="FIGDIR/small/486171v3_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@130f55dorg.highwire.dtl.DTLVardef@13cad47org.highwire.dtl.DTLVardef@942b9forg.highwire.dtl.DTLVardef@1bbe575_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsIn this study, we identified so far unrecognized, placenta-induced immune responses at the maternal-fetal interface. Altogether, we imply that placenta-derived trophoblasts induce a pregnancy-tolerant phenotype by suppressing antigen-presenting cell-like functions in maternal tissue macrophages.

immunology↗