Sulfation‐Tunable Peptide‐Glycosaminoglycan Hydrogels for Hematopoietic Stem and Progenitor Cell Expansion

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ABSTRACT Integrating tunable mechanics with matrix‐mediated cytokine retention and presentation is a central challenge in creating synthetic extracellular matrix (ECM) mimics. Here, we establish a predictive framework for supramolecular hydrogels formed by co‐assembly of rationally designed glycosaminoglycan (GAG)‐binding peptides with GAGs of defined sulfation. By systematically varying peptide aromaticity and GAG sulfation, we control peptide secondary structure and bulk mechanics of the resulting hydrogel networks while maintaining rapid, ECM‐like stress relaxation. We discover that highly sulfated GAGs act as potent cofactors, inducing a coil‐to‐β‐sheet transition that triggers gelation in peptides lacking intrinsic assembly motifs. Applying this framework to human hematopoietic stem cell (HSC) culture, we use a Design‐of‐Experiments workflow to identify an optimal, charge‐balanced formulation within a coupled biochemical‐mechanical design space. This optimized hydrogel combines tunable cytokine retention with viscoelastic support to enable hematopoietic stem and progenitor cell expansion with preservation of primitive HSC‐associated phenotypes and retained clonogenic potential. Relative to standard suspension culture, the optimized hydrogel shifts the balance from bulk numerical expansion toward preferential preservation of primitive stem cell function, establishing a modular, sequence‐programmable strategy to engineer peptide–GAG niches for regenerative medicine.

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