The
development from stem cells to adult tissues requires the delicate
presentation of numerous crucial inductive cues and the activation
of associated signaling pathways. The Notch signaling pathways triggered
by ligands such as Jagged-1 have been demonstrated to be essential
in various development processes especially in osteogenesis and ossification.
However, few studies have capitalized on the osteoinductivity of the
Jagged-1 mimetic ligands to enhance the osteogenesis and skeleton
regeneration. In this study, we conjugate the porous hyaluronic acid
hydrogels with a Jagged-1 mimetic peptide ligand (Jagged-1) and investigate
the efficacy of such biomimetic functionalization to promote the mechanotransduction
and osteogenesis of human mesenchymal stem cells by activating the
Notch signaling pathway. Our findings indicate that the immobilized
Jagged-1 mimetic ligand activates Notch signaling via the upregulation of NICD and downstream MSX2, leading to the enhanced
mechanotransduction and osteogenesis of stem cells. We further demonstrate
that the functionalization of the Jagged-1 ligand in the porous scaffold
promotes angiogenesis, regulates macrophage recruitment and polarization,
and enhances in situ regeneration of rat calvarial
defects. Our findings provide valuable guidance to the design of development-inspired
bioactive biomaterials for diverse biomedical applications.