title: Chondroitin Sulfate Glycosaminoglycan Hydrogels Create Endogenous Niches for Neural Stem Cells.
abstract: Neural stem cells (NSCs) possess great potential for neural tissue repair after traumatic injuries to the central nervous system (CNS). However, poor survival and self-renewal of NSCs after injury severely limits its therapeutic potential. Sulfated chondroitin sulfate glycosaminoglycans (CS-GAGs) linked to CS proteoglycans (CSPGs) in the brain extracellular matrix (ECM) have the ability to bind and potentiate trophic factor efficacy, and promote NSC self-renewal in vivo. In this study, we investigated the potential of CS-GAG hydrogels composed of monosulfated CS-4 (CS-A), CS-6 (CS-C), and disulfated CS-4,6 (CS-E) CS-GAGs as NSC carriers, and their ability to create endogenous niches by enriching specific trophic factors to support NSC self-renewal. We demonstrate that CS-GAG hydrogel scaffolds showed minimal swelling and degradation over a period of 15 days in vitro, absorbing only 6.5 ± 0.019% of their initial weight, and showing no significant loss of mass during this period. Trophic factors FGF-2, BDNF, and IL10 bound with high affinity to CS-GAGs, and were significantly (p < 0.05) enriched in CS-GAG hydrogels when compared to unsulfated hyaluronic acid (HA) hydrogels. Dissociated rat subventricular zone (SVZ) NSCs when encapsulated in CS-GAG hydrogels demonstrated ∼88.5 ± 6.1% cell viability in vitro. Finally, rat neurospheres in CS-GAG hydrogels conditioned with the mitogen FGF-2 demonstrated significantly (p < 0.05) higher self-renewal when compared to neurospheres cultured in unconditioned hydrogels. Taken together, these findings demonstrate the ability of CS-GAG based hydrogels to regulate NSC self-renewal, and facilitate growth factor enrichment locally.
authors.affiliation: Regenerative Bioscience Center, ADS Complex, The University of Georgia , 425 River Road, Athens, Georgia 30602, United States.
authors.forename: Lohitash
authors.initials: L
authors.lastname: Karumbaiah
authors.forename: Syed Faaiz
authors.initials: SF
authors.lastname: Enam
authors.affiliation: Joint Department of Biomedical Engineering NC State University/UNC-Chapel Hill , 4204 B Engineering Building III, Raleigh, North Carolina 27695, United States.
authors.forename: Ashley C
authors.initials: AC
authors.lastname: Brown
authors.forename: Tarun
authors.initials: T
authors.lastname: Saxena
authors.affiliation: Regenerative Bioscience Center, ADS Complex, The University of Georgia , 425 River Road, Athens, Georgia 30602, United States.
authors.forename: Martha I
authors.initials: MI
authors.lastname: Betancur
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Barker
authors.forename: Ravi V
authors.initials: RV
authors.lastname: Bellamkonda
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000008:administration & dosage; D049109:Cell Proliferation; D002478:Cells, Cultured; D002809:Chondroitin Sulfates / Q000737:chemistry*; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage; D020100:Hydrogels / Q000737:chemistry*; D058953:Neural Stem Cells / Q000166:cytology*; D051381:Rats; D054457:Tissue Scaffolds / Q000737:chemistry*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D020100:Hydrogels; C038142:chondroitin sulfate glycosaminoglycan; D016222:Fibroblast Growth Factor 2; D002809:Chondroitin Sulfates