Self-assembling peptides for stem cell and tissue engineering.
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ABSTRACT:
SUBMITTER: Tatman PD
PROVIDER: S-EPMC4803621 | biostudies-literature | 2016 Apr
REPOSITORIES: biostudies-literature
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Project description:Spinal cord regeneration using stem cell transplantation is a promising strategy for regenerative therapy. Stem cells transplanted onto scaffolds that can mimic natural extracellular matrix (ECM) have the potential to significantly improve outcomes. In this study, we strived to develop a cell carrier by culturing neural stem cells (NSCs) onto electrospun 2D and 3D constructs made up of specific crosslinked functionalized self-assembling peptides (SAPs) featuring enhanced biomimetic and biomechanical properties. Morphology, architecture, and secondary structures of electrospun scaffolds in the solid-state and electrospinning solution were studied step by step. Morphological studies showed the benefit of mixed peptides and surfactants as additives to form thinner, uniform, and defect-free fibers. It has been observed that β-sheet conformation as evidence of self-assembling has been predominant throughout the process except for the electrospinning solution. In vitro NSCs seeded on electrospun SAP scaffolds in 2D and 3D conditions displayed desirable proliferation, viability, and differentiation in comparison to the gold standard. In vivo biocompatibility assay confirmed the permissibility of implanted fibrous channels by foreign body reaction. The results of this study demonstrated that fibrous 2D/3D electrospun SAP scaffolds, when shaped as micro-channels, can be suitable to support NSC transplantation for regeneration following spinal cord injury.
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Project description:Peptide-based engineered hydrogel scaffolds present several advantages over traditional protein or polymeric hydrogels by imparting more robust control over hydrogel properties. In this manuscript, we report the synthesis and characterization of a leucine zipper (LZ) based self-assembling hydrogel for use in tissue engineering applications. Although, LZ hydrogels posses several advantages, the stability of these hydrogels has always been elusive. In this study, we have standardized the procedure for creating a stable LZ hydrogel. Pore-size was tunable by altering the peptide concentration from 7% to 12% by weight. In order to create a microenvironment for cell adhesion, the LZ polypeptide was functionalized by the incorporation of the cell attachment RGD domain. In vivo implantation of the LZ scaffolds in a mouse model showed absence of foreign body reaction to the scaffold. In vivo experiments with human marrow stem cells (HMSCs) in immunocompromised mice showed the biological property of the hydrogel to promote cell attachment, proliferation and its ability to support neovascularization. Our results show for the first time, that it is possible to generate a functional and stable LZ scaffold that can be used in vivo for tissue engineering applications.
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Project description:Self-assembling peptides are a type of biomaterial rapidly emerging in the fields of biomedicine and material sciences due to their promise in biocompatibility and effectiveness at controlled release. These self-assembling peptides can form diverse nanostructures in response to molecular interactions, making them versatile materials. Once assembled, the peptides can mimic biological functions and provide a combinatorial delivery of therapeutics such as cytokines and drugs. These self-assembling peptides are showing success in biomedical settings yet face unique challenges that must be addressed to be widely applied in the clinic. Herein, we describe self-assembling peptides' characteristics and current applications in immunomodulatory therapeutics.
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Project description:Fluorescent hydrogels (FH) have a variety of potential applications in the field of soft electronics. However, fabrication of mechanically stable and printable fluorescent hydrogels remains challenging. Here, we report a kind of fluorescent hydrogel based on the co-assembly of peptide motif and transition metal ions. The metal ions are captured in the hydrogel network at specific positions through covalently linked ligands on the peptide hydrogelators. This efficiently prevents the aggregation and self-quenching of organometallic chromophores. In addition, the formation of metal-ligand complexes introduces additional interactions to stabilize the hydrogel network, making the FH even more stable after the incorporation of metal ions. The FH is optically transparent but highly fluorescent. By using three different metal ions, the white light fluorescent supramolecular hydrogel has been achieved. As a proof-of-principle, we demonstrate the printability of the hydrogels to various patterns. We anticipate that with the improved fluorescent performance and stability, this kind of FH can find broad applications in extrusion-based 3D printing for the construction of soft electronics.
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Project description:High levels of serum low-density lipoprotein (LDL) cholesterol contribute to atherosclerosis, a key risk factor of cardiovascular diseases. PCSK9 is a circulatory enzyme that downregulates expression of hepatic LDL receptors, concomitantly increasing serum LDL-C. This work investigates a small, self-assembling peptide, EPep2-8, as a peptide inhibitor of PCSK9. EPep2-8 is a multidomain peptide comprising a self-assembling domain, E2, conjugated to a bioactive domain, Pep2-8, previously shown to inhibit PCSK9. The E2 domain facilitates self-assembly of EPep2-8 into long, nanofibrous polymers with an underlying supramolecular β-sheet secondary structure. Intermolecular interactions between nanofibers drive EPep2-8 to form a thixotropic and cytocompatible hydrogel in aqueous and charge-neutral solutions. These properties enable EPep2-8 to be delivered as an in situ depot for regulation of lipoprotein homeostasis. In surface plasmon resonance studies, EPep2-8 bound specifically to PCSK9 with an apparent, noncovalent, and irreversible dissociation, significantly improving the binding affinity of Pep2-8 alone (KD = 667 ± 48 nM). Increased binding affinity of EPep2-8 is primarily due to the superstoichiometric interaction of the peptide with PCSK9. Promisingly, EPep2-8 retains bioactivity in vitro, engendering dose-dependent uptake of LDL-C in hepatocytes. This mechanism of self-assembly on a target site may be a simple method to improve the affinity of peptide inhibitors.
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Project description:We present herein characteristics of a conjugate in which dL5, a fluorogen activating protein (FAP), and AEAEAKAK, an amphiphilic peptide, are combined to form a solid-phase fluorescence detection platform. The FAP dL5 is a covalently linked dimer of two identical light chain variable fragments which activates the fluorescence of the fluorogen malachite green (MG). The amphiphilic peptide of sequence AEAEAKAK is a building block of stimuli-responsive materials that undergoes sol-gel phase transition at high ionic strengths. We hypothesize that the novel bifunctional protein containing both the FAP and the amphiphile, termed dL5_EAK coassembles with the self-assembling peptide [AEAEAKAK]2 (EAK16-II) to form an insoluble membrane composite whereby the fluorescence enhancement function of the FAP domain remains intact. Denaturing polyacrylamide electrophoresis indicated that greater than 78% of dL5_EAK incorporates into the EAK16-II membrane. Conversely, less than 32% of dL5 without the EAK sequence associates with the insoluble fraction of EAK16-II in buffers. Membranes containing dL5_EAK and EAK16-II exhibited at least 4-fold higher fluorescence intensity compared to mixtures containing dL5 and EAK16-II. Scanning electron microscopy revealed the presence of particulates, presumably FAPs, scattered on the membrane fibrils. The evidence suggests a system of materials that can be developed into in situ forming local sensors by immobilizing dL5 into coacervate, on which MG can be detected. It is envisioned that dL5 membranes can be established in diseased locales to monitor infiltration and migration of inflammatory cells marked with antibodies conjugated to MG.
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Project description:Neural stem cells-based therapies have shown great potential for central nervous system regeneration, with three-dimensional (3D) culture systems representing a key technique for tissue engineering applications, as well as disease modeling and drug screenings. Self-assembling peptides (SAPs), providing biomimetic synthetic micro-environments regulating cellular functionality and tissue repair, constitute a suitable tool for the production of complex tissue-like structures in vitro. However, one of the most important drawbacks in 3D cultures, obtained via animal-derived substrates and serum-rich media, is the reproducibility and tunability of a standardized methodology capable to coax neural differentiation of different human cell lines. In this work we cultured four distinct human neural stem cell (hNSC) lines in 3D synthetic multifunctionalized hydrogel (named HYDROSAP) for up to 6 weeks. Three-dimensional cultures of differentiating hNSCs exhibited a progressive differentiation and maturation over time. All hNSCs-derived neurons in 3D culture system exhibited randomly organized entangled networks with increasing expression of GABAergic and glutamatergic phenotypes and presence of cholinergic ones. Oligodendrocytes formed insulating myelin sheaths positive for myelin basic protein (MBP). In summary, results demonstrated a successfully standardized and reproducible 3D cell culture system for hNSC differentiation and maturation in serum-free conditions useful for future therapies.
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Project description:Hydrogel materials that display inherent activity against bacteria can be used to directly treat accessible wounds to prevent or kill existing infection. Hydrogels composed of self-assembling ?-hairpin peptides, having a high content of arginine, were found to be extremely effective at killing both gram-positive and gram-negative bacteria, including multi-drug resistant Pseudomonas aeruginosa. No added antibacterial agents are necessary to realize activity. Using self-assembling peptides for material construction allows facile structure-activity relationships to be determined since changes in peptide sequence at the monomer level are directly transposed to the bulk material's antibacterial properties. SAR studies show that arginine content largely influences the hydrogel's antibacterial activity, and influences their bulk rheological properties. These studies culminated in an optimized gel, composed of the peptide PEP6R (VKVRVRVRV(D)PPTRVRVRVKV). PEP6R gels prepared at 1.5 wt % or higher concentration, demonstrate high potency against bacteria, but are cytocompatible toward human erythrocytes as well as mammalian mesenchymal stem cells. Rheological studies indicate that the gel is moderately stiff and displays shear-thin recovery behavior, allowing its delivery via simple syringe.
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Project description:Recombinant llama heavy-chain antibody fragments (VHHs) are promising tools in the field of targeted nanomedicine. 7D12, a VHH against the epidermal growth factor receptor (EGFR) that is overexpressed in various cancers, has been evaluated as an effective cancer-targeting VHH in multiple studies. The small size of VHHs (15-20 kDa) results in a low circulation half-life, which can be disadvantageous for certain applications. A solution to this problem is to attach VHHs to the surface of nanoparticles to increase the hydrodynamic radius of the conjugate. This approach simultaneously allows the incorporation of different VHHs and other targeting moieties and therapeutic components into one structure, creating multispecificity and versatility for therapy and diagnosis. Here, we present the construction of highly defined 7D12-containing nanoparticles by utilizing thermoresponsive diblock elastin-like peptides that reversibly self-assemble into micellar structures. The resulting particles have a hydrodynamic radius of 24.3 ± 0.9 nm and retain full EGFR-binding capacity. We present proof of concept of the usability of such particles by controlled incorporation of a photosensitizer and show that the resulting nanoparticles induce EGFR-specific light-induced cell killing. This approach is easily extended to the controlled incorporation of various functional modules, improving therapy and diagnosis with targeted nanomedicine.
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Project description:The ionic-complementary self-assembling peptides discovered by Zhang Shuguang have solution-to-gel (sol-gel) transition capacity and one such peptide RADA16 has been commercialized into hemostatic agents. However, their sol-gel transition ability was not obvious because the peptide aqueous solution with a concentration greater than 1% w/v appeared to be thick and viscous. The current report describes PP-type self-assembling peptides. In addition to the ionic-complementary sequence, they have prolines at both ends of the sequence. This feature has led to better solubility, lower viscosity of the peptide solution, and simplified synthesis and purification processes while maintaining the great gelling performance of the ionic-complementary peptides. The PP-type peptides self-assembled into a well-organized nanofiber scaffold as shown by TEM. Among the PP-type peptides, the PRVDP9 sequence peptide was tested as a hemostatic agent and a mucosal elevating agent. The results were comparable to the classic RADA16. The PP-type self-assembling peptides have superior sol-gel transition ability. Therefore, it is predicted that they will be more suitable to be transported through catheters or endoscopes and have higher commercialization potential as compared with the classic self-assembling peptide sequences.
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