Sulfation of Glycosaminoglycan Hydrogels Instructs Cell Fate and Chondral versus Endochondral Lineage Decision of Skeletal Stem Cells In Vivo

Exit from multipotency and lineage commitment of mesenchymal stroma cells (MSC) depends on microenvironmental cues the stem-cell niche but steering cell fate into desired in vivo remains a challenge. Increasing evidence suggests that glycosaminoglycans (GAGs) can be used to activate or sequester growth factors with specific action depending sulfation levels. It is postulated differentially sulfated biomaterials aid developmental instruction MSC guide tissue morphogenesis vivo. By application new injectable TGFβ-loaded heparin-PEG-hydrogel authors here gain ability control skeletal down chondral versus endochondral pathway status. High allows for long-term TGFβ-retention silencing Hedgehog-, BMP-, WNT-pathways installing prochondrogenic antihypertrophic which permitted permanent, collagen-type-II-rich neocartilage resistance calcification bone formation. Selective 6-O/N-desulfation heparin supports Hedgehog/BMP/WNT-signaling switching differentiation strong hypertrophic/osteogenic marker expression calcification. This work identifies GAG as crucial signal determine via prohypertrophic pathways, providing first proof-of-principle how modification-patterns lineage-choice during