Synthetic Viscoelastic Activating Cells for T Cell Engineering and Cancer Therapy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1013816 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25939476_1.fastq.gz | Fastqsanger.gz | |||
| SRR25939476_2.fastq.gz | Fastqsanger.gz | |||
| SRR25939477_1.fastq.gz | Fastqsanger.gz | |||
| SRR25939477_2.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 4 of 4 |
Similar Datasets
Project description:Immunotherapy shows promise in cancer treatment, but its effectiveness and durability remain limited, and improved technology for engineering immune cells is necessary. Here we develop a scalable platform that creates synthetic viscoelastic activating cells (SynVACs) with programmable mechanical and chemical properties. We demonstrate that the viscoelastic nature of SynVACs significantly impacts T cell functionality. Compared to rigid or elastic microspheres, SynVACs greatly enhance human T cell expansion, achieving approximately 90% chimeric antigen receptor (CAR) transduction efficiency. Additionally, SynVACs promote CD8+ T cell generation while suppressing regulatory T cell formation, resulting in enhanced tumor killing capability. Notably, expanding CAR-T cells with SynVACs leads to a ten-fold increase in T memory stem cells (TMSCs). These engineered CAR-T cells exhibit superior efficacy in eliminating tumor cells in a human lymphoma and ovarian xenograft mouse model, persisting in vivo for longer time period. These findings underscore the crucial role of mechanical signals in T cell engineering and highlight SynVACs' potential in CAR-T therapy and imunoengineering applications.
2023-09-12 | GSE242531 | GEO
Project description:Synthetic Notch (synNotch) receptors are modular synthetic components that are genetically engineered into mammalian cells to detect signals presented by neighboring cells and respond by activating prescribed transcriptional programs. To date, synNotch has been used to program therapeutic cells and pattern morphogenesis in multicellular systems. However, cell-presented ligands have limited versatility for applications that require spatial precision, such as tissue engineering. To address this, we developed a suite of materials to activate synNotch receptors and serve as generalizable platforms for generating user-defined material-to-cell signaling pathways. First, we demonstrate that synNotch ligands, such as GFP, can be conjugated to cell- generated ECM proteins via genetic engineering of fibronectin produced by fibroblasts. We then used enzymatic or click chemistry to covalently link synNotch ligands to gelatin polymers to activate synNotch receptors in cells grown on or within a hydrogel. To achieve microscale control over synNotch activation in cell monolayers, we microcontact printed synNotch ligands onto a surface. We also patterned tissues comprising cells with up to three distinct phenotypes by engineering cells with two distinct synthetic pathways and culturing them on surfaces microfluidically patterned with two synNotch ligands. We showcase this technology by co-transdifferentiating fibroblasts into skeletal muscle or endothelial cell precursors in user-defined spatial patterns towards the engineering of muscle tissue with prescribed vascular networks. Collectively, this suite of approaches extends the synNotch toolkit and provides novel avenues for spatially controlling cellular phenotypes in mammalian multicellular systems, with many broad applications in developmental biology, synthetic morphogenesis, human tissue modeling, and regenerative medicine.
2024-06-12 | GSE269373 | GEO
Project description:Synthetic Notch (synNotch) receptors are modular synthetic components that are genetically engineered into mammalian cells to detect signals presented by neighboring cells and respond by activating prescribed transcriptional programs. To date, synNotch has been used to program therapeutic cells and pattern morphogenesis in multicellular systems. However, cell-presented ligands have limited versatility for applications that require spatial precision, such as tissue engineering. To address this, we developed a suite of materials to activate synNotch receptors and serve as generalizable platforms for generating user-defined material-to-cell signaling pathways. First, we demonstrate that synNotch ligands, such as GFP, can be conjugated to cell- generated ECM proteins via genetic engineering of fibronectin produced by fibroblasts. We then used enzymatic or click chemistry to covalently link synNotch ligands to gelatin polymers to activate synNotch receptors in cells grown on or within a hydrogel. To achieve microscale control over synNotch activation in cell monolayers, we microcontact printed synNotch ligands onto a surface. We also patterned tissues comprising cells with up to three distinct phenotypes by engineering cells with two distinct synthetic pathways and culturing them on surfaces microfluidically patterned with two synNotch ligands. We showcase this technology by co-transdifferentiating fibroblasts into skeletal muscle or endothelial cell precursors in user-defined spatial patterns towards the engineering of muscle tissue with prescribed vascular networks. Collectively, this suite of approaches extends the synNotch toolkit and provides novel avenues for spatially controlling cellular phenotypes in mammalian multicellular systems, with many broad applications in developmental biology, synthetic morphogenesis, human tissue modeling, and regenerative medicine.
2024-06-12 | GSE269381 | GEO
Project description:Synthetic biology has focused on engineering genetic modules that operate orthogonally from the host cells. A synthetic circuit, however, can be designed to reprogram the host proteome, which in turn enhances the function of the synthetic circuit. Here, we apply this holistic synthetic biology concept by exploiting the crosstalk between metabolic networks in cells, leading to a protein environment more favorable for protein synthesis. Specifically, we show that a local module expressing translation machinery can reprogram the bacterial proteome, changing the expression levels of more than 780 proteins. The integration of the proteins synthesized by the local modules and the reprogramed proteome generate a cell-free system that can synthesize a diverse set of proteins in different reaction formats, with up to 5-fold higher expression level than classical cell-free systems. Our work demonstrates a holistic approach that integrates synthetic and systems biology concepts. This approach has the potential to achieve outcomes not possible by only local, orthogonal circuits.
2020-05-14 | PXD018858 | Pride
Project description:Engineering large-scale perfused tissues via synthetic 3D soft microfluidics
| PRJNA751477 | ENA
Project description:Integration of synthetic CpG Free DNA induces de novo DNAme in the flanking CpG island. Cellular differentiation requires global changes to DNA methylation (DNAme), where it functions to regulate transcription factor and chromatin remodeling activity, and genome interpretation. Here, we describe a simple DNAme engineering approach in pluripotent stem cells (PSCs), extending across large stretches of CpG dense “islands (CGIs).” Integration of synthetic CpG free single-stranded DNA (ssDNA) induces a target CpG Island Methylation Response (CIMR) in multiple PSC lines, Nt2d1 embryonal carcinoma cells, and mouse PSCs, but not in highly methylated CpG Island Methylator Phenotype (CIMP) positive cancer lines. CIMR DNAme at MLH1 spans the CGI, is robustly maintained throughout cellular differentiation, suppresses target gene activity, and sensitizes derived cardiomyocytes and thymic epithelial cells to the chemotherapy cisplatin. Additional CIMR DNAme is reported on at TP53 and ONECUT1 CGIs. Collectively, this new resource enables total CpG Island DNAme engineering in pluripotency and the genesis of novel epigenetic models of development and disease
2023-06-21 | GSE210680 | GEO
Project description:To date, no immunotherapy approaches have managed to fully overcome T-cell exhaustion, which remains a mandatory fate for chronically activated effector cells and a major therapeutic challenge. Understanding how to reprogram CD8+ TILs away from exhausted effector states remains an elusive goal. Our work provides for the first-time evidence that orthogonal gene-engineering of T cells to secrete an IL-2-variant binding the IL-2R and the alarmin IL-33 reprogrammed adoptively transferred T cells to acquire a novel, synthetic state, which deviated from canonical exhaustion and displayed superior effector functions. These cells successfully overcame homeostatic barriers in the host, and led – in the absence of lymphodepletion or exogenous cytokine support – to high levels of engraftment and tumor regression. Our work unlocks the novel opportunity of rationally engineering synthetic CD8+ T-cell states endowed with the ability to avoid exhaustion and control advanced solid tumors.
2022-04-12 | GSE200535 | GEO
Project description:A Repressive Type of TEAD4 Condensation and Engineering a Glue Peptide Therapy Against Cancer
| PRJNA1022819 | ENA
Project description:Engineering CAR T cells expressing specific chimeric cytokine receptors that signal independently from the presence of an exogenous cytokine can significantly impact cancer cellular therapy by improving : i) trafficking and expansion of the adoptive cells therapy product post-infusion, ii) extended persistence of the modified T cells post tumour eradication. Altogether, these features will allow lifelong tumour protection. Furthermore, the technology here illustrated holds the potential to reduce the dose required to reach therapeutic efficacy, greatly reducing the overall manufacturing cost. Finally, the generalisability of the architecture described holds the potential to tailor a specific cytokine signal to a particular type of cell that the developed therapy is based upon.
2023-04-01 | GSE227161 | GEO
Project description:The ability to endow constitutively active proteins with synthetic allostery is a central objective of Synthetic Biology, mostly focused on the creation of protein biosensors – artificial sensing proteins with easily quantifiable outputs. Here we hypothesize that circular permutation of proteins increases the probability of functional coupling of new N- and C- terminal sequences with the active center of the protein through increased local structural disorder. We test this by constructing a synthetically allosteric version of circular permutated NanoLuc luciferase, activated through ligand-induced intramolecular non-covalent cyclisation. The developed biosensors cover a range of emission wavelengths and display sensitivity as low as 50 pM and dynamic range as high as 16-fold and could quantify their cognate ligand in human fluids such as saliva, serum and lysed blood. We apply hydrogen exchange kinetic mass spectrometry to analyze time resolved structural changes in the developed biosensors and observed ligand-mediated folding of newly created termini. While a large study is required for determining how frequent synthetic allostery emerges following circular permutation and what types of protein folds are susceptible to it, this study provides motivation and justification for such efforts.
2022-02-10 | PXD031169 | Pride