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Abstract
Stiff nuclei in cell-dense microenvironments may serve as distinct biomechanical cues for cell migration, but such a possibility has not been tested experimentally. As a first step addressing this question, we altered nuclear stiffness of endothelial cells (ECs) by reducing the expression of A-type lamins using siRNA, and investigated the migration of T cells on and under EC layers. While most T cells crawling on control EC layers avoided crossing over EC nuclei, a significantly higher fraction of T cells on EC layers with reduced expression of A-type lamins crossed over EC nuclei. This result suggests that stiff EC nuclei underlying T cells may serve as “duro-repulsive” cues to direct T cell migration toward less stiff EC cytoplasm. During subendothelial migration under EC layers with reduced expression of A-type lamins, T cells made prolonged contact and substantially deformed EC nuclei, resulting in reduced speed and directional persistence. This result suggests that EC nuclear stiffness promotes fast and directionally persistent subendothelial migration of T cells by allowing minimum interaction between T cells and EC nuclei.
Highlights
To address how EC nuclear stiffness affects the migration of T cells on and under EC layers, we reduced expression levels of A-type lamins in ECs using a small interfering RNA targeting the gene encoding A-type lamin (LMNA) to decrease nuclear stiffness
We demonstrated that T cell migration on and under EC layers were significantly influenced by the EC nuclear stiffness, suggesting that stiff nuclei of cells comprising cell-dense microenvironments can be critical mechanical cues guiding migration of other cells
We further demonstrated that frequencies of avoiding crossing over EC nuclei were significantly decreased when EC A-type lamin expression levels were reduced by small interfering RNA (siRNA)-mediated LMNA knockdown (LMNA-KD)
Summary
After TEM, leukocytes underneath the endothelium migrate substantial distances to breach the basement membrane and reach interstitial spaces[22,29] (Fig. 1). During this subendothelial migration, leukocytes migrating in the narrow gaps between the layers of ECs and pericytes/basement membranes are likely to interact with EC nuclei. The motility patterns of T cells interacting with LMNA knockdown (LMNA-KD) ECs were compared with those of T cells interacting with control siRNA-treated ECs (control ECs) or untreated ECs. T cells on LMNA-KD ECs crossed over EC nuclei more frequently than T cells on control or untreated ECs, indicating stiff nuclei of ECs can serve as “duro-repulsive” cues for guiding T cells crawling on EC layers. These results suggest that stiff EC nuclei can promote fast and directionally persistent migration by allowing relatively minimal interactions between EC nuclei and T cells underneath
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