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Transitions of biological tissues between solid‐like and liquid‐like phases have been of great recent interest. Here, the first successful cell‐by‐cell evaluation of tissue viscoelastic transition is presented. An in situ micro‐mechanical perturbation is applied to a microtissue, and the resulting volumetric deformation is evaluated using 3D light‐sheet microscopy and digital image correlation (DIC), quantifying both solid‐like, well‐aligned displacement and liquid‐like swirling motion between individual cells. The viscoelastic transition of fibroblasts is crucial in fundamental physiological events, such as placentation, cancer dissemination, and wound healing. This study investigates 3D organoid systems modeling maternal‐fetal and tumor‐stroma interfaces, demonstrating established molecular and structural parallels. The analysis visualizes individual cells in stromal‐epithelial interactions and how they collectively alter tissue viscoelastic properties. It also enables in‐silico microdissection, linking single‐cell viscoelasticity with multi‐channel fluorescence. RNAseq analysis of endometrial stromal fibroblasts shows that decidualization activates mechano‐transcriptional regulators, including myocardin‐related transcription factors (MRTFs), associated with increased cellular contractility and actomyosin mobilization. Knocking down MRTFA in cancer‐associated fibroblasts in the tumor‐fibroblast co‐culture 3D model induces significant changes in fibroblast properties, mirroring those observed in the maternal‐fetal interface model, highlighting parallels between placentation and cancer invasion. This analysis confirms existing beliefs and discovers new insights broadly applicable to studying organoids, embryos, tumors, and other tissues. 

Abstract CD44 is an extracellular matrix receptor implicated in cancer progression. CD44 increases the invasibility of skin (SF) and endometrial stromal fibroblasts (ESF) by cancer and trophoblast cells. We reasoned that the evolution of CD44 expression can affect both, the fetal–maternal interaction through CD44 in ESF as well as vulnerability to malignant cancer through expression in SF. We studied the evolution of CD44 expression in mammalian SF and ESF and demonstrate that in the human lineage evolved higher CD44 expression. Isoform expression in cattle and human is very similar suggesting that differences in invasibility are not due to the nature of expressed isoforms. We then asked whether the concerted gene expression increase in both cell types is due to shared regulatory mechanisms or due to cell type-specific factors. Reporter gene experiments with cells and cis-regulatory elements from human and cattle show that the difference of CD44 expression is due to cis effects as well as cell type-specific trans effects. These results suggest that the concerted expression increase is likely due to selection acting on both cell types because the evolutionary change in cell type-specific factors requires selection on cell type-specific functions. This scenario implies that the malignancy enhancing effects of elevated CD44 expression in humans likely evolved as a side-effect of positive selection on a yet unidentified other function of CD44. A possible candidate is the anti-fibrotic effect of CD44 but there are no reliable data showing that humans and primates are less fibrotic than other mammals.