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Cyto-friendly polymerization at cell surfaces modulates cell fate by clustering cell-surface receptors.

ABSTRACT: Lots of strategies, e.g. using multivalent synthetic polymers, have been developed to control the spatial distribution of cell-surface receptors, thus modulating the cell function and fate in a custom-tailored manner. However, clustering cell-surface receptors via multivalent synthetic polymers is highly dependent on the structure as well as the ligand-density of the polymers, which may impose difficulties on the synthesis of polymers with a high density of ligands. Here, we pioneered the utilization of a cyto-friendly polymerization at the cell surface to cluster cell-surface receptors. As a proof of concept, an anti-CD20 aptamer conjugated macromer was initially synthesized, which was then efficiently and stably introduced onto the Raji cell surface via ligand-receptor interaction. With the assistance of an initiator, i.e. ammonium peroxysulfate (APS), the macromer bound onto the Raji cell surface polymerized, inducing the clustering of CD20 receptors, and thereby triggering cell apoptosis. This cell-surface polymerization induced cell-surface receptor crosslinking could alternatively be applied in modulating the fates and functions of other cells, especially those mediated by the spatial distribution of cell-surface receptors, such as T cell activation. Our work opens new possibilities in the area of chemical biology to some extent.

SUBMITTER: Qi J

PROVIDER: S-EPMC8152676 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Proliferative vitreoretinopathy (PVR) is a blinding disease frequently occurring after retinal detachment surgery. Adhesion, migration and matrix remodeling of dedifferentiated retinal pigment epithelial (RPE) cells characterize the onset of the disease. Treatment options are still restrained and identification of factors responsible for the abnormal behavior of the RPE cells will facilitate the development of novel therapeutics. Galectin-3, a carbohydrate-binding protein, was previously found to inhibit attachment and spreading of retinal pigment epithelial cells, and thus bares the potential to counteract PVR-associated cellular events. However, the identities of the corresponding cell surface glycoprotein receptor proteins on RPE cells are not known. Here we characterize RPE-specific Gal-3 containing glycoprotein complexes using a proteomic approach. Integrin-?1, integrin-?3 and CD147/EMMPRIN, a transmembrane glycoprotein implicated in regulating matrix metalloproteinase induction, were identified as potential Gal-3 interactors on RPE cell surfaces. In reciprocal immunoprecipitation experiments we confirmed that Gal-3 associated with CD147 and integrin-?1, but not with integrin-?3. Additionally, association of Gal-3 with CD147 and integrin-?1 was observed in co-localization analyses, while integrin-?3 only partially co-localized with Gal-3. Blocking of CD147 and integrin-?1 on RPE cell surfaces inhibited binding of Gal-3, whereas blocking of integrin-?3 failed to do so, suggesting that integrin-?3 is rather an indirect interactor. Importantly, Gal-3 binding promoted pronounced clustering and co-localization of CD147 and integrin-?1, with only partial association of integrin-?3. Finally, we show that RPE derived CD147 and integrin-?1, but not integrin-?3, carry predominantly ?-1,6-N-actyl-D-glucosamine-branched glycans, which are high-affinity ligands for Gal-3. We conclude from these data that extracellular Gal-3 triggers clustering of CD147 and integrin-?1 via interaction with ?1,6-branched N-glycans on RPE cells and hypothesize that Gal-3 acts as a positive regulator for CD147/integrin-?1 clustering and therefore modifies RPE cell behavior contributing to the pathogenesis of PVR. Further investigations at this pathway may aid in the development of specific therapies for PVR.

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Cyto-friendly polymerization at cell surfaces modulates cell fate by clustering cell-surface receptors.

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