Abstract
We report a new class of amyloid-inspired peptide hydrogels that was designed and based on α-synuclein protein for which hydrogel formation is triggered by various stimuli, such as heating/cooling or changes in pH. The peptides resemble a cross-β-sheet-rich amyloid, and they assemble into a nanofibrous meshwork that mimics the natural extracellular matrix. Our design principle allows easy manipulation of the gelator sequence to exploit the desirable properties of amyloids for use in cell replacement therapies for neurodegenerative diseases. The amyloid hydrogels facilitate the attachment and neuronal differentiation of mesenchymal stem cells (MSCs) and assist in the delivery and engraftment of MSCs in the substantia nigra and caudate putamen of a Parkinsonian mouse model. A responsive, water-trapping biopolymer can fight neurodegenerative illnesses by promoting the growth and survival of implanted stem cells. Regenerating damaged portions of the nervous system with stem cells is a promising therapy for Alzheimer's and Parkinson's diseases, but ensuring cell viability in damaged brain tissue is challenging. Inspired by amyloid proteins that self-assemble into robust fibrils, Samir Maji from the Indian Institute of Technology in Mumbai, John Forsythe from Monash University in Melbourne and co-workers have developed peptide-based materials that turn into hydrogels on changing the pH or temperature. The hydrogels' nanofibrous, mesh-like structure and tunable stiffness proved favourable for cell replacement therapy. Experiments with Parkinsonian mouse models revealed that stem cells cultured on the hydrogels preferentially differentiated towards neurons and could be easily implanted thanks to the gels' ability to re-liquefy. Inspired by a popular self-assembled motif in proteins called amyloids, we have developed a series of hydrogels composed of amyloid nanofibrils. The gelation process could be induced via different stimuli, such as heating/cooling or change of pH. Human mesenchymal stem cells preferentially differentiate toward neurons when cultured on these hydrogels. Moreover, its shear thinning property facilitates transplantation of stem cells into the brain with minimally invasive surgery. We demonstrate here the utilization of injectable amyloid hydrogels, which promotes cell survival as well as neuronal differentiation in vivo.
Highlights
Amyloids are highly ordered, self-assembled proteins/peptides that were originally implicated in several neurological disorders, such as Alzheimer’s and Parkinson’s disease, owing to their aberrant folding.[1]amyloids are recognized as a common protein structure with native biological functions in several host organisms[2] including mammals,[3] which support the survival of the host rather than being pathogenic
Recent investigations suggest that α-Syn amyloid fibrils, the end product of the aggregation pathway, are less toxic than soluble oligomers both in vitro[38] and in vivo.[39]
We hypothesized that non-toxic amyloid-based hydrogels could be designed from the α-Syn core segment
Summary
Self-assembled proteins/peptides that were originally implicated in several neurological disorders, such as Alzheimer’s and Parkinson’s disease, owing to their aberrant folding.[1]amyloids are recognized as a common protein structure with native biological functions in several host organisms[2] including mammals,[3] which support the survival of the host rather than being pathogenic. Cell transplantation holds great therapeutic potential for the regeneration of the central nervous system, but poor cell survival upon transplantation remains a significant problem.[12,13,14] the hostile environment of a diseased/damaged brain and lack of a proper microenvironment further limits cell viability.[15] A suitable biomaterial can provide physical support, retain the cells in the implant and facilitate recovery To this end, our group and several others have demonstrated that engineered amyloid fibrils support cell adhesion and growth.[16,17,18] Recently, amyloid-based biomimetic hybrid materials have been used for bone tissue engineering applications.[19] We previously designed self-healing amyloid hydrogels from the Aβ42 C-terminus that promote the adhesion and differentiation of mesenchymal stem cells (MSCs) in vitro.[17] Notably, the higher-order alignment and unique mechanical strength of these amyloid hydrogels enable them to direct stem cell differentiation to neuronal lineages
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