GLYCOSAMINOGLYCAN-BASED BIOMATRIX EMBEDDED WITH POLYELECTROLYTE COMPLEX NANOPARTICLES FOR CONTROLLED SIGNALING REGULATION IN STEM CELL NICHE
Wei-Hong Jian1, Tzu-Wei Wang1,2
1National Tsing Hua University, Taiwan;
2Harvard Medical School, USA
Neural stem cells (NSCs) provide potential therapeutic strategy for neural tissue repair after traumatic injury, stroke and degenerative neural disease. However, poor regenerative capability of NSCs in the lesion site due to the inflammatory response, loss of structural support and trophic factors limits their therapeutic efficacy. Normal extracellular matrix (ECM) is constructed by several molecules such as hyaluronic acid (HA) and proteoglycans which provide an ideal microenvironment for binding and stabilization of growth factors, chemokines and other ECM proteins from degradation by proteinases and serve as a niche for promoting NSC proliferation in vivo. In this study, we specifically develop an ECM-mimetic hydrogel composed of high molecular weight HA and glycosaminoglycan-based polyelectrolyte complex nanoparticles (PCNs) to deliver stromal cell-derived factor-1α (SDF-1α) and fibroblast growth factor-2 (FGF-2) in response to matrix metalloproteinase (MMP) activity within the injured site. SDF-1α bounded on heparan sulfate is known to optimize SDF-1α presentation and to recruit endogenous NSCs to the wound area. On the other hand, continuous expression of FGF-2 that is complexed with chondroitin sulfate plays a critical role in regulating injury-induced NSC proliferation and differentiation. The protection and sustainable controlled delivery of both growth factors are achieved by the conjugation of MMP-cleavable and MMP-inactive peptides linked on the PCNs in HA hydrogel. The combination of growth factor-loaded PCNs and biodegradable hydrogel is expected to
enhance chemotactic recruitment and survival of endogenous NSCs and provide a stem cell niche to promote NSC proliferation and differentiation for neural tissue repair and regeneration.