Hydrogels Derivatized With Cationic Moieties or Functional Peptides as Efficient Supports for Neural Stem Cells

Abstract

The increasing incidence of neurodegenerative diseases such as Alzheimer's or Parkinson's disease represents a significant burden for patients and national health systems. The conditions are primarily caused by the death of neurons and other neural cell types. One important aim of current stem cell research is to find a way to replace the lost cells. In this perspective, neural stem cells (NSCs) have been considered as a promising tool in the field of regenerative medicine. The behavior of NSCs is modulated by environmental influences, for example hormones, growth factors, cytokines, and extracellular matrix molecules or biomechanics. These factors can be studied by using well-defined hydrogels, which are polymeric networks of synthetic or natural origin with the ability to swell in water. These gels can be modified with a variety of molecules and optimized with regard to their mechanical properties to mimic the natural extracellular environment. In particular modifications applying distinct units such as functional domains and peptides can modulate the development of NSCs with regard to proliferation, differentiation and migration. One well-known peptide sequence that affects the behavior of NSCs is the integrin recognition sequence RGD that has originally been derived from fibronectin. In the present review we provide an overview concerning the applications of modified hydrogels with an emphasis on synthetic hydrogels based on poly(acrylamides), as modified with either cationic moieties or the peptide sequence RGD. This knowledge might be used in tissue engineering and regenerative medicine for the therapy of spinal cord injuries, neurodegenerative diseases and traumata.

Keywords: RGD; cationic moieties; extracellular matrix; functional peptides; hydrogels; integrin; neural stem cells.

FIGURE 1

Integrin-mediated intracellular signaling activated by adhesion of cells to a RGD-modified hydrogel. The crosstalk of integrin to the peptide sequence RGD activates many signaling pathways, which are mostly initiated by the activation of the focal adhesion kinase (FAK). Together with the protein tyrosine kinase Src, FAK may regulate small GTPases of the RhoA subfamily like CDC42, Rac and Rho-A, which may modulate the actin cytoskeleton. Furthermore the cytoskeleton may be regulated by the activation of the focal adhesion core region, which is build by FAK and paxillin in the first stratum, followed by talin and vinculin, which interact with actin through molecules like α-actinin. The interaction with actin has influences on the adhesion and migration of cells, as well as on the gene expression via the organization of the nucleus, which is linked to the cytoskeleton. Additionally integrins may have direct influence on the gene expression through the shuttle of FAK into the nucleus. There FAK targets the ubiquitination of the cell cycle mediator p53 and may act as a transcription co-regulator. The differentiation, proliferation and survival of the cells may be influenced through integrins alone or in combination with growth factor receptors like the epidermal growth factor receptor and the platelet-derived growth factor via the activation of mitogen-activated protein kinase/Erk, Jnk or phosphoinositide 3-kinase/Akt (Schwartz and Ginsberg, 2002; Yamada and Even-Ram, 2002; Giancotti and Tarone, 2003; Guarda et al., 2009; Ivaska and Heino, 2011; Dalby et al., 2014).

FIGURE 2

Exemplary synthesis of a synthetic hydrogel system and examples for hydrogels bearing cationic moieties and the RGD sequence.