Fully Synthetic Heparan Sulfate-Based Neural Tissue Construct That Maintains the Undifferentiated State of Neural Stem Cells

Abstract

Heparin and heparan sulfate (HS) are attractive components for constructing biomaterials due to their ability to recruit and regulate the activity of growth factors. The structural and functional heterogeneity of naturally derived heparin and HS is, however, an impediment for the preparation of biomaterials for regenerative medicine. To address this problem, we have prepared hydrogels modified by well-defined synthetic HS-derived disaccharides. Human induced pluripotent cellderived neural stem cells (HIP-NSCs) encapsulated in a polyethylene glycol-based hydrogel modified by a pendent HS disaccharide that is a known ligand for fibroblast growth factor-2 (FGF-2) exhibited a significant increase in proliferation and self-renewal. This observation is important because evidence is emerging that undifferentiated stems cells can yield significant therapeutic benefits via their paracrine signaling mechanisms. Our data indicate that the HS disaccharide protects FGF-2, which has a very short biological half-live, from degradation. It is anticipated that, by careful selection of a synthetic HS oligosaccharide, it will be possible to control retention and release of specific growth factor, which in turn will provide control over cell fate.

The 3- O -sulfation of heparan sulfate modulates protein binding and lyase degradation

“…This observation indicates that the latter sulfotransferase can install the 3-OS motifs of compounds 3C and 9C. It is the expectation that the identified ligands are attractive for incorporation into biomaterial scaffolds to provide bioactive cues to modulate Nrp-1 activity for neuronal patterning and functional vasculature (38).…”

Engineered Sulfated Polysaccharides for Biomedical Applications

“…Furthermore, self‐renewal markers SOX1 and astrocytic markers GFAP were significantly upregulated, indicating an increased potential of the sulfated HS oligosaccharides to induce cell differentiation. [ 506 ]…”

“…Furthermore, self-renewal markers SOX1 and astrocytic markers GFAP were significantly upregulated, indicating an increased potential of the sulfated HS oligosaccharides to induce cell differentiation. [506] Stem Cell Differentiation: Whereas HS has important functions in stem cell maintenance, both HS and CS are also involved in ESC transition from a state of self-renewal to cell fate commitment into multiple lineages. Irrespective of the specific stem cell fate, an overall increase in HS content and DS has been observed during differentiation.…”

A novel exchange method to access sulfated molecules

“…Organosulfates and sulfamates contain polar functional groups that are important for the study of molecular interactions in the life sciences, such as: neurodegeneration 1 ; plant biology 2 ; neural stem cells 3 ; heparan binding 4 ; and viral infection 5 . Recent total syntheses including 11-saxitoxinethanoic acid 6 , various saccharide assemblies 7 – 10 , and seminolipid 11 have all relied on the incorporation of a highly polar organosulfate motif.…”

“…An explanation for this relates to the Lewis basicity of the amine-SO 3 complex (Py-SO 3 (pK a = 5.23); Me 3 N-SO 3 (pK a = 10.63)). The sp 3 hybridised Lewis base of Me 3 N donates electrons more strongly into the LUMO of SO 3 forming a hard-hard Lewis adduct with increased stability and decreased reactivity compared to sp 2 hybridised Lewis base seen in Py-SO 3 24 . Next, using the knowledge obtained from the sulfate ester optimisation and our prior work on sulfamates 20 , initial conditions of switching to Me 3 NSO 3 resulted in quantitative conversion of the benzyl sulfamate (Scheme 1).…”