Synthetic Heparan Sulfate Hydrogels Regulate Neurotrophic Factor Signaling and Neuronal Network Activity.

Autor: Latchoumane CV; Regenerative Bioscience Center, University of Georgia, Athens, Georgia 30602, United States.; Edgar L. Rhodes Center for ADS, College of Agriculture and Environmental Sciences, University of Georgia, Athens, Georgia 30602, United States., Chopra P; Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia 30602, United States., Sun L; Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, and Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht 3583, The Netherlands., Ahmed A; Regenerative Bioscience Center, University of Georgia, Athens, Georgia 30602, United States., Palmieri F; Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, and Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht 3583, The Netherlands., Wu HF; Department of Biochemistry and Molecular Biology, Franklin College of Arts and Sciences, University of Georgia, Athens, Georgia 30602, United States.; Department of Cellular Biology, Franklin College of Arts and Sciences, University of Georgia, Athens, Georgia 30602, United States., Guerreso R; Regenerative Bioscience Center, University of Georgia, Athens, Georgia 30602, United States.; Edgar L. Rhodes Center for ADS, College of Agriculture and Environmental Sciences, University of Georgia, Athens, Georgia 30602, United States., Thorne K; Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia 30602, United States., Zeltner N; Department of Biochemistry and Molecular Biology, Franklin College of Arts and Sciences, University of Georgia, Athens, Georgia 30602, United States.; Department of Cellular Biology, Franklin College of Arts and Sciences, University of Georgia, Athens, Georgia 30602, United States.; Center for Molecular Medicine, University of Georgia, Athens, Georgia 30602, United States.; Division of Neuroscience, Biomedical and Translational Sciences Institute, University of Georgia, Athens, Georgia 30602, United States., Boons GJ; Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia 30602, United States.; Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, and Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht 3583, The Netherlands.; Department of Chemistry, University of Georgia, Athens, Georgia 30602, United States., Karumbaiah L; Regenerative Bioscience Center, University of Georgia, Athens, Georgia 30602, United States.; Edgar L. Rhodes Center for ADS, College of Agriculture and Environmental Sciences, University of Georgia, Athens, Georgia 30602, United States.; Division of Neuroscience, Biomedical and Translational Sciences Institute, University of Georgia, Athens, Georgia 30602, United States.
Jazyk: angličtina
Zdroj: ACS applied materials & interfaces [ACS Appl Mater Interfaces] 2022 Jun 29; Vol. 14 (25), pp. 28476-28488. Date of Electronic Publication: 2022 Jun 16.
DOI: 10.1021/acsami.2c01575
Abstrakt: Three-dimensional (3D) synthetic heparan sulfate (HS) constructs possess promising attributes for neural tissue engineering applications. However, their sulfation-dependent ability to facilitate molecular recognition and cell signaling has not yet been investigated. We hypothesized that fully sulfated synthetic HS constructs (bearing compound 1 ) that are functionalized with neural adhesion peptides will enhance fibroblast growth factor-2 (FGF2) binding and complexation with FGF receptor-1 (FGFR1) to promote the proliferation and neuronal differentiation of human neural stem cells (hNSCs) when compared to constructs with unsulfated controls (bearing compound 2 ). We tested this hypothesis in vitro using 2D and 3D substrates consisting of different combinations of HS tetrasaccharides (compounds 3 and 4 ) and an engineered integrin-binding chimeric peptide (CP), which were assembled using strain-promoted alkyne-azide cycloaddition (SPAAC) chemistry. Results indicated that the adhesion of hNSCs increased significantly when cultured on 2D glass substrates functionalized with chimeric peptide. hNSCs encapsulated in 1 -CP hydrogels and cultured in media containing the mitogen FGF2 exhibited significantly higher neuronal differentiation when compared to hNSCs in 2 -CP hydrogels. These observations were corroborated by Western blot analysis, which indicated the enhanced binding and retention of both FGF2 and FGFR1 by 1 as well as downstream phosphorylation of extracellular signal-regulated kinases (ERK1/2) and enhanced proliferation of hNSCs. Lastly, calcium activity imaging revealed that both 1 and 2 hydrogels supported the neuronal growth and activity of pre-differentiated human prefrontal cortex neurons. Collectively, these results demonstrate that synthetic HS hydrogels can be tailored to regulate growth factor signaling and neuronal fate and activity.
Databáze: MEDLINE