Biomaterial Microenvironments to Support the Generation of New Neurons in the Adult Brain

Abstract

Neural stem cells (NSC) in two regions of the adult mammalian brain-the subventricular zone (SVZ) and hippocampus-continuously generate new neurons, enabled by a complex repertoire of factors that precisely regulate the activation, proliferation, differentiation, and integration of the newborn cells. A growing number of studies also report low-level neurogenesis in regions of the adult brain outside these established neurogenic niches-potentially via NSC recruitment or activation of local, quiescent NSCs-under perturbations such as ischemia, cell death, or viral gene delivery of proneural growth factors. We have explored whether implantation of engineered biomaterials can stimulate neurogenesis in normally quiescent regions of the brain. Specifically, recombinant versions of factors found within the NSC microenvironment, Sonic hedgehog, and ephrin-B2 were conjugated to long polymers, thereby creating highly bioactive, multivalent ligands that begin to emulate components of the neurogenic niche. In this engineered biomaterial microenvironment, new neuron formation was observed in normally non-neurogenic regions of the brain, the striatum, and the cortex, and combining these multivalent biomaterials with stromal cell-derived factor-1a increased neuronal commitment of newly divided cells seven-to eightfold in these regions. Additionally, the decreased hippocampal neurogenesis of geriatric rodents was partially rescued toward levels of young animals. We thus demonstrate for the first time de novo neurogenesis in both the cortex and striatum of adult rodents stimulated solely by delivery of synthetic biomaterial forms of proteins naturally found within adult neurogenic niches, offering the potential to replace neurons lost in neurodegenerative disease or injury as an alternative to cell implantation. STEM CELLS

Hyaluronic Acid and Its Derivatives in Coating and Delivery Systems: Applications in Tissue Engineering, Regenerative Medicine and Immunomodulation

“…A recent study proposed a long‐term biomaterial delivery system made of HA conjugated with bioactive ephrin‐B2. This biomaterial was developed in order to promote newborn neurons in regions of the brain that are in a state or period of inactivity.…”

“…Furthermore, the in vivo experiments with rats presented that an appropriate release of those proteins led to cell self‐renewal and differentiation. The fraction of newly divided cells were expressed by DCX staining (early neuronal marker) after striatal injection …”

Versatile click alginate hydrogels crosslinked via tetrazine–norbornene chemistry

“…Hydrogels are highly hydrated, crosslinked polymer networks that resemble the environment of natural soft tissue, making them attractive materials for a variety of biomedical applications such as tissue engineering, drug delivery, and vaccines [1][2][3][4][5][6][7]. Alginate biopolymers are versatile, naturally derived linear polysaccharides comprised of repeating (1,4)-linked β-D-mannuronic and α-Lguluronic acid, and can be crosslinked to form hydrogels via a variety of ionic and covalent crosslinking methods [8,9].…”

Nanomedicine Approaches to Modulate Neural Stem Cells in Brain Repair

“…The role of NPs was to increase the bioactive agent neuroprotective efficacy, reduce the required dose, and facilitate the transport through the BBB without compromising its integrity. Moreover, polymeric conjugates (100 nm) based on hyaluronic acid conjugated with multiple molecules of ephrin-B2 and sonic hedgehog per polymer chain have also been successfully used to stimulate neurogenesis in normally quiescent regions of the brain [14]. The multivalent ligand induced a sixfold increase in the fraction of newly divided neuronal precursors in the adult rat striatum.…”