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Evolutionarily conserved sequence motif analysis guided development of chemically defined hydrogels for therapeutic angiogenesis

ABSTRACT: Biologically ligands (e.g., RGDS from fibronectin: Fn-RGD) play a critical role in the development of chemically defined biomaterials. However, there has been limited progress in recent decades towards discovering novel extracellular-matrix-protein-derived ligands for translational applications. Here, by combining motif analysis of evolutionarily conserved RGD-containing regions in laminin (Ln) with functional microarray screening, we identified a Ln-derived angiogenic peptide (LDAP) that showed enhanced proangiogenic activities over commonly used Fn-RGD. Mechanistic studies using RNA-sequencing of LDAP functionalized hydrogels showed an improved angiogenic transcriptome over Fn-RGD functionalized hydrogels and high similarity to Matrigel, attributed to the ability of LDAP to engage both Ln- and Fn-binding integrins. Injectable hydrogels functionalized with LDAP, along with MMP-QK (a VEGF-mimetic peptide), exhibited increased functional recovery over decellularized extracellular matrix (dECM) and alginates functionalized with Fn-RGD and MMP-QK in a mouse ischemic hindlimb model, illustrating the power of the strategy to rapidly develop potent chemically-defined biomaterials for therapeutic applications.

ORGANISM(S): Homo sapiens

PROVIDER: GSE126717 | GEO | 2020/09/21

REPOSITORIES: GEO

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Role of immediate early genes in the development of salivary gland organoids in polyisocyanopeptide hydrogels

Project description:Human salivary gland organoids have opened tremendous possibilities for regenerative medicine in patients undergoing radiotherapy for the treatment of head and neck cancer. However, their clinical translation is greatly limited by the current use of Matrigel for organoid derivation and expansion. Here, we envisage that the use of a fully, synthetic hydrogel based on the oligo(-ethylene glycol) functionalized polymer polyisocyanopeptides (PICs) can provide an environment suitable for the generation and expansion of salivary gland organoids (SGOs) after optimization of PIC polymer properties. We demonstrate that PIC hydrogels decorated with the cell-binding peptide RGD allow SGO formation from salivary gland (SG)-derived stem cells. This self-renewal potential is preserved for only 4 passages. It was found that SGOs differentiated prematurely in PIC hydrogels affecting their self-renewal capacity. Similarly, SGOs show decreased expression of immediate early genes (IEGs) after culture in PIC hydrogels. Activation of multiple signalling pathways involved in IEG expression by β-adrenergic agonist isoproterenol, led to increased stem cell self-renewal capacity as measured by organoid forming efficiency (OFE). These results indicate that PIC hydrogels are promising 3D matrices for SGOs, with the option to be used clinically, after further optimization of the hydrogel and culture conditions.

2022-12-10 | GSE220084 | GEO

Dynamics of integrin α5β1, fibronectin, and their complex

Project description:Integrin α5β1 mediates cell adhesion to the extracellular matrix (ECM) by binding fibronectin (Fn). Selectivity for Fn by α5β1 is achieved through recognition of an RGD motif in the 10th type-III Fn domain (Fn10) and the synergy site in the 9th type-III Fn domain (Fn9). However, details of the interaction dynamics are unknown. Here, we compared synergy-site and Fn-truncation mutations for their α5β1-binding affinities and stabilities. We also interrogated binding of the α5β1 ectodomain headpiece fragment to Fn using hydrogen deuterium exchange mass spectrometry (HDX MS) to probe binding sites and sites of integrin conformational change. Our results suggest the synergistic effect of Fn9 requires both specific residues and a folded domain. We found some residues considered important for synergy are required for stability. Additionally, we show decreases in fibronectin HDX are localized to a synergy peptide containing contacting residues in two β-strands, an intervening loop in Fn9, and the RGD-containing loop in Fn10, indicative of binding sites. We also identified binding sites in the α5-subunit β-propeller domain for the Fn9 synergy site and in the β1-subunit βI domain for Fn10 based on decreases in α5β1 HDX. Interestingly, the dominant effect of Fn binding was an increase in α5β1 deuterium exchange distributed over multiple sites that undergo changes in conformation or solvent accessibility and appear to be sites where energy is stored in the higher-energy, open-integrin conformation. Together, our results highlight regions important for α5β1 binding to Fn and dynamics associated with this interaction.

2022-08-09 | PXD031508 | Pride

Characterization of a novel 3D-FN-silk breast cancer model

Project description:To offer a robust and highly characterized three-dimensional (3D) model for anti-cancer drug discovery and basic research, we developed a 3D system in which the immortalized breast cancer cell lines MCF-7 and MDA-MB-231 were grown in recombinantly produced spider silk functionalized with the cell adhesion motif from fibronectin (FN-silk). The aim of this study is to evaluate whole-transcriptome changes driven by growth in such 3D model.

2023-09-13 | GSE209570 | GEO

The role of residue chirality of polypeptide hydrogels in regulating local immune microenvironment for anti-tumor immune responses

Project description:The impact of chirality on immune response has attracted great interest in cancer vaccine research recently. However, the study of chiral synthetic polypeptide hydrogels as cancer vaccines as well as of the impact of biomaterials itself for antitumor immunotherapy has rarely been reported. Herein, we demonstrated the key role of residue chirality of polypeptides hydrogels in antitumor immunity and local immune microenvironment regulation. Compared to poly(γ-ethyl-L-glutamate)-based hydrogels (L-Gel), poly(γ-ethyl-D-glutamate)-based hydrogels (D-Gel) induced greater immune cell infiltration. Unexpectedly, D-Gel caused higher levels of suppressive markers on antigen-presenting cells and even induced stronger T cells exhaustion than L-Gel. Finally, D-Gel established a local chronic inflamed and immunosuppressive microenvironment and showed insufficient anti-tumor effects. Conversely, the milder host immune responses induced by L-Gel led to more effective tumor inhibition. This study provides new insights on the role of residue chirality in the regulation of local immune microenvironment and affecting antitumor immune response.

2024-03-14 | GSE261299 | GEO

Project description:Transcriptome profiling of mesenchymal stem cells cultured in 3D functionalized hydrogels

| PRJNA453896 | ENA

First trimester human placenta prevents breast cancer cell attachment to the matrix: the role of extracellular matrix

Project description:The placenta is a nonsupportive microenvironment for cancer cells. We showed that breast cancer cells (BCCL) were eliminated from placental implantation sites. During implantation, the placenta manipulates its surrounding matrix, which may induce BCCL elimination. Here, we explored the effect of placenta-induced ECM manipulations on BCCL. During experiments, BCCL (MCF-7/T47D) were cultured on placenta/BCCL-conditioned ECM (Matrigel used for first trimester placenta/BCCL culture and cleared by NH4OH). After culturing the cells, we analyzed cancer cell phenotype (death, count, aggregation, MMP) and signaling (microarray analysis and pathway validation). We found that the BCCL did not attach to previous placental implantation sites and instead, similarly to anoikis-resistant cells, migrated away, displayed increased MMP levels/activity, and formed aggregates in distant areas. T47D were less affected than the MCF-7 cells, since MCF-7 also showed modest increases in cell death, EMT, and increased proliferation. Microarray analysis of the MCF-7 highlighted changes in the integrin, estrogen, EGFR, and TGFb pathways. Indeed, placental ECM reduced ERa, induced Smad3/JNK phosphorylation and increased integrin-a5 expression (RGD-dependent integrin) in the BCCL. Addition of RGD or TGFbR/JNK inhibitors reversed the phenotypic changes. This study helps explain the absence of metastases to the placenta and why advanced cancer is found in pregnancy, and provides possible therapeutic targets for anoikis-resistant cells.

2017-09-07 | GSE103581 | GEO

Engineered Peptide-Functionalized Hydrogels Modulate RNA Transcriptome of Human Nucleus Pulposus Cells In Vitro

Project description:Engineered Peptide-Functionalized Hydrogels Modulate RNA Transcriptome of Human Nucleus Pulposus Cells In Vitro

| PRJNA644918 | ENA

Enhancing Cell-Based Regenerative Therapies with Peptide-Modified Thermo-responsive Citrate-Based Biomaterials for Treatment of Critical Limb Ischemia

Project description:Critical limb ischemia (CLI) poses a significant health challenge, marked by severe morbidity and limited treatment options leading to high mortality rates. Despite the promise of cell-based therapy, challenges such as poor cell survival and engraftment during and after cell delivery hinder its efficacy. This study explores the potential of peptide-modified thermo-responsive citrate-based biomaterials as carriers for endothelial cell delivery to promote vascular regeneration in CLI. Specifically, various pro-survival peptides were covalently tethered to poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) to investigate their effect on the delivery of vascular endothelial cells to skeletal muscle tissue. After screening with in vitro and in vivo experiments, laminin-derived peptide A5G81 and VEGF-derived peptide QK were identified to promote endothelial cell spreading, proliferation, and prolonged cell survival when tethered onto PPCN The viscoelastic properties of PPCN provided protection against shear stress induced cell death during injection, while the peptides regulated endothelial cell behavior via distinct molecular pathways. Importantly, intramuscular delivery of endothelial cells with PPCN-A5G81 and PPCN-QK in a murine hindlimb ischemia model resulted in significant improvements in limb perfusion, tissue preservation and functional outcomes. Furthermore, endothelial cell delivery with PPCN-A5G81 and PPCN-QK also promoted positive skeletal muscle remodeling following ischemic injury. These findings underscore the potential of bioactive materials as novel cell delivery carriers for CLI therapy, with implications for advancing regenerative therapeutics and revolutionizing CLI treatment strategies.

2024-04-12 | GSE263721 | GEO

Comparison of murine whole gene expression on ligand immobilized surfaces

Project description:For the studies of cell migration in various micro-environments, self-assembled monolayer surfaces presenting adhesive ligand, RGD peptide, were used for the assay. Presentation of RGD ligands was based on the immobilization reaction with alkanethiols on a gold surface. There were differences in cell morphology and migration according to the ligand affinity (linear vs. cyclic RGD) and manner of ligand presentation (dynamic vs. non-dynamic). In dynamic surface experiment, cells initially grown on the fibronectin-coated patterns were exposed to either linear or cyclic RGD while in non-dynamic surface experiment cells interacted with the immobilized RGD from the beginning. Goal was to compare how the affinity and spatio-temporal exposure of ligand affect the overall transcriptional profiling. Five conditioned surfaces were prepared by chemical treatment for cell culture: Fibronectin, Dynamic linear RGD, Dynamic cyclic RGD, Non-dynamic linear RGD, and Non-dynamic cyclic RGD surfaces. Reference: cells cultured in standard tissue culture flasks. Biological replicates: triplicates for each experiment (each surface was 1.25 cm x 1.25 cm and three surfaces were used for each condition). When reached 70-80% of confluency, cells from the triplicates were pooled and harvested for RNA extraction. Hybridization replicates: 4 replicates for each condition.

2014-10-15 | E-GEOD-62304 | biostudies-arrayexpress

Quaking is a global regulator of muscle-specific alternative splicing in vertebrates [siRNA data]

Project description:This work provides the first evidence that Qk is a global regulator of splicing in vertebrates, defines a new splicing regulatory network in muscle, and suggests that overlapping splicing networks contribute to the complexity of changes in alternative splicing during differentiation. Alternative splicing contributes to muscle development and differentiation, but the complete set of muscle splicing factors and their combinatorial interactions are not known. Previously work identifies ACUAA (STAR motif) as an enriched sequence near muscle-specific alternative exons such as Capzb exon 9. We did mass spectrometry of proteins selected by wild type and mutant Capzb intron 9 RNA affinity chromatography, and identified Quaking (Qk), a protein known to regulate mRNA function through ACUAA motifs in 3' UTRs. We show that in myoblasts, Qk promotes inclusion of Capzb exon 9 in opposition to repression by PTB. Qk knockdown in myoblasts has little effect on transcript levels, but alters inclusion of 824 cassette exons whose adjacent intron sequences are enriched in ACUAA motifs. During differentiation to myotubes, Qk levels increase 2-3 fold, suggesting a mechanism for Qk-responsive exon regulation. We captured the PTB splicing regulatory network and intersected it with the Qk network, identifying overlap between the functions of Qk and PTB. Approximately 60% of exons whose inclusion is altered during myogenesis appear to be under control of one or both of these splicing factors in myoblasts. This series is the C2C12 Qk and PTB siRNA data. It is 12 arrays: 3 PTB siRNA arrays , 3 Qk siRNA arrays, and 6 mock siRNA arrays.

2013-06-05 | E-GEOD-40961 | biostudies-arrayexpress

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