The burgeoning field of cell therapies is rapidly expanding, offering the promise to tackle complex and unsolved healthcare problems. One prominent example is represented by CAR T-cells, which have been introduced into the clinic for treating a variety of cancers. Promising cell therapeutics have also been developed to promote tissue regeneration, showing high potencies for the treatment of damaged liver. Nevertheless, in the remit of regenerative medicine, cell-therapy efficacies remain suboptimal as a consequence of the low engraftment of injected cells to the existing surrounding tissue. Herein, we present a facile approach to enhance the adhesion and engraftment of therapeutic hepatic progenitor cells (HPCs) through specific and homogeneous cell surface modification with exogenous polysaccharides, without requiring genetic modification. Coated HPCs exhibit significantly increased markers of adhesion and cell spreading and demonstrate preferential interactions with certain extra-cellular matrix proteins. Moreover, they display enhanced binding to endothelial cells and 3D liver microtissues. This translatable methodology shows promise for improving therapeutic cell engraftment, offering a potential alternative to liver transplantation in end-stage liver disease.
© 2025. The Author(s).

CD44 is a transmembrane glycoprotein linked to various biological processes reliant on epigenetic plasticity, which include development, inflammation, immune responses, wound healing and cancer progression. Although it is often referred to as a cell surface marker, the functional regulatory roles of CD44 remain elusive. Here we report the discovery that CD44 mediates the endocytosis of iron-bound hyaluronates in tumorigenic cell lines, primary cancer cells and tumours. This glycan-mediated iron endocytosis mechanism is enhanced during epithelial-mesenchymal transitions, in which iron operates as a metal catalyst to demethylate repressive histone marks that govern the expression of mesenchymal genes. CD44 itself is transcriptionally regulated by nuclear iron through a positive feedback loop, which is in contrast to the negative regulation of the transferrin receptor by excess iron. Finally, we show that epigenetic plasticity can be altered by interfering with iron homeostasis using small molecules. This study reveals an alternative iron-uptake mechanism that prevails in the mesenchymal state of cells, which illuminates a central role of iron as a rate-limiting regulator of epigenetic plasticity.