title: Chemotactic recruitment of adult neural progenitor cells into multifunctional hydrogels providing sustained SDF-1α release and compatible structural support.
abstract: Without chemotactic cues and structural support, cavitary brain lesions typically fail to recruit endogenous neural progenitor cells (NPCs). Toward resolving this, we engineered multifunctional biomaterials comprising injectable gelatin-hydroxyphenylpropionic acid (Gtn-HPA) hydrogels and dextran sulfate/chitosan polyelectrolyte complex nanoparticles (PCNs) that delivered stromal cell-derived factor-1α (SDF-1α). Over 7 d of interface with in vitro tissue simulant containing adult rat hippocampal NPCs (aNPCs) and their neuronal progeny, Gtn-HPA/SDF-1α-PCN hydrogels promoted chemotactic recruitment to enhance infiltration of aNPCs by 3- to 45-fold relative to hydrogels that lacked SDF-1α or vehicles to sustain SDF-1α release. When cross-linked with 0.85-0.95 mM HO, Gtn-HPA/SDF-1α-PCN hydrogels provided optimally permissive structural support for migration of aNPCs. Specific matrix metalloproteinase (MMP) inhibitors revealed that 42, 30, and 55% of cell migration into Gtn-HPA/SDF-1α-PCN hydrogels involved MMP-2, 3, and 9, respectively, demonstrating the hydrogels to be compatible toward homing endogenous NPCs, given their expression of similar MMPs. Interestingly, PCNs utilized FGF-2 found in situ to induce chemokinesis, potentiate SDF-1α chemotactic recruitment, and increase proliferation of recruited cells, which collectively orchestrated a higher number of migrated aNPCs. Overall, Gtn-HPA/SDF-1α-PCN hydrogels prove to be promising biomaterials for injection into cavitary brain lesions to recruit endogenous NPCs and enhance neural tissue repair/regeneration.
authors.affiliation: Tissue Engineering Laboratories, VA Boston Healthcare System, Mail Stop 151 Research, 150 S. Huntington Ave., Boston, MA 02130, USA.
authors.forename: Teck Chuan
authors.initials: TC
authors.lastname: Lim
authors.forename: Swetha
authors.initials: S
authors.lastname: Rokkappanavar
authors.forename: Wei Seong
authors.initials: WS
authors.lastname: Toh
authors.forename: Li-Shan
authors.initials: LS
authors.lastname: Wang
authors.forename: Motoichi
authors.initials: M
authors.lastname: Kurisawa
authors.forename: Myron
authors.initials: M
authors.lastname: Spector
mesh_terms: D053687:Adult Stem Cells / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001930:Brain Injuries / Q000473:pathology / Q000628:therapy; D054377:Chemokine CXCL12 / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects*; D017364:Collagenases / Q000494:pharmacology; D003692:Delayed-Action Preparations / Q000494:pharmacology; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D020100:Hydrogels / Q000494:pharmacology*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D053758:Nanoparticles; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: C575935:CXCL12 protein, rat; D054377:Chemokine CXCL12; D003692:Delayed-Action Preparations; D020100:Hydrogels; D061965:Matrix Metalloproteinase Inhibitors; D016222:Fibroblast Growth Factor 2; D017364:Collagenases