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Engineering an inducible leukemia-associated transcription factor enables large-scale ex vivo production of functional human phagocytes

ABSTRACT: Engineering an inducible leukemia-associated transcription factor enables large-scale ex vivo production of functional human phagocytes

PROVIDER: PRJNA996892 | ENA |

REPOSITORIES: ENA

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Engineering an inducible leukemia-associated transcription factor enables large-scale ex vivo production of functional human phagocytes

Project description:Ex vivo expansion of human CD34+ hematopoietic stem and progenitor cells remains a challenge due to rapid differentiation after detachment from the bone marrow niche. In this study, we assessed the capacity of an inducible transcription factor to enable sustained ex vivo proliferation of hematopoietic precursors and their capacity to differentiate into functional phagocytes. We fused the coding sequences of an FK506-Binding Protein 12 (FKBP12)-derived destabilization domain (DD) to the myeloid/lymphoid lineage leukemia/eleven nineteen leukemia (MLL-ENL) transcription factor to generate the fusion protein DD-MLL-ENL and retrovirally expressed the protein switch in human CD34+ progenitors. Using Shield1, a chemical inhibitor of DD fusion protein degradation, we established large-scale and long-term expansion of late monocytic precursors. Upon Shield1 removal, the cells lost self-renewal capacity and spontaneously differentiated, even after 2.5 years of continuous ex vivo expansion. In the absence of Shield1, stimulation with IFN-γ, LPS, and GM-CSF triggered terminal differentiation. Gene expression analysis of the obtained phagocytes revealed marked similarity with naïve monocytes. In functional assays, the novel phagocytes migrated towards CCL2, attached to VCAM-1 under shear stress, produced reactive oxygen species, and engulfed bacterial particles, cellular particles and apoptotic cells. Finally, we demonstrated Fcγ receptor recognition and phagocytosis of opsonized lymphoma cells in an antibody-dependent manner. Overall, we have established a novel transcription factor that, as a single factor, is useful for large-scale ex vivo production of human phagocytes. Such adjustable transcription factors have the potential to be applied as molecular tools to produce functional immune cells for cell therapy.

2024-05-22 | GSE237826 | GEO

i-shaped antibody engineering enables conformational tuning of biotherapeutic receptor agonists

Project description:The ability to leverage antibodies to agonize disease relevant biological pathways has the potential to unlock new drug targets for clinical investigation. While antibodies have been successful as antagonists, immune mediators, and targeting agents, they are not readily effective at recapitulating the biological activity of natural ligands. Among the important determinants of antibody agonist activity is the geometry of target receptor engagement. Herein, we describe a novel engineering approach inspired by a naturally occurring Fab-Fab homotypic interaction that constrains IgG in a unique i-shaped conformation. i-shaped antibody (iAb) engineering enables potent intrinsic agonism of five tumor necrosis factor receptor superfamily (TNFRSF) targets. When applied to bispecific antibodies against the heterodimeric IL-2 receptor pair, constrained bispecific IgG formats recapitulate IL-2 agonist activity. Thus, iAb engineering represents a new tool to tune agonist antibody function and this work provides a framework for the development of intrinsic antibody agonists with the potential for generalization across broad receptor classes.

2023-12-18 | GSE246602 | GEO

i-shaped antibody engineering enables conformational tuning of biotherapeutic receptor agonists

Project description:i-shaped antibody engineering enables conformational tuning of biotherapeutic receptor agonists

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Environmental Optimization Enables Maintenance of Quiescent Hematopoietic Stem Cell Ex Vivo

Project description:Environmental Optimization Enables Maintenance of Quiescent Hematopoietic Stem Cell Ex Vivo

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An evolved AAV variant enables efficient genetic engineering of murine T cells

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Sorted Mouse Phagocytes RNAseq

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Expression analysis of purified intestinal phagocytes in Schmidtea mediterranea

Project description:Identification of differentially expressed genes in intestinal phagocytes, compared to non-intestinal cells in Schmidtea mediterranea. Total RNA was isolated from either intestinal phagocytes or non-intestinal cells (control). Four independent biological replicates were conducted with two dye swaps. Labeled targets were hybridized to two oligonucleotide arrays on which 11,521 planarian transcripts were represented.

2012-10-01 | E-GEOD-35565 | biostudies-arrayexpress

RELATe enables genome-scale engineering in fungal genomics.

Project description:CRISPR-Cas9-based screening with single-guide RNA (sgRNA) libraries has emerged as a revolutionary tool for comprehensive analysis of genetic elements. However, genome-scale sgRNA libraries are currently available only in a few model organisms. The traditional approach is to synthesize thousands to tens of thousands of sgRNAs, which is laborious and expensive. We have developed a simple method, RELATe (restriction/ligation coupled with Agrobacterium-mediated transformation), to generate sgRNA libraries from 10 μg of genomic DNA, targeting over 98% of the protein-coding genes in the human fungal pathogen Cryptococcus neoformans Functional screens identified 142 potential C. neoformans genes contributing to blood-brain barrier penetration. We selected two cryptococcal genes, SFP1 and WDR1, for a proof-of-concept demonstration that RELATe-identified genes are relevant to C. neoformans central nervous system infection. Our RELATe method can be used in many other fungal species and is powerful and cost-effective for genome-wide high-throughput screening for elucidating functional genomics.

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Cell Surface Engineering Enables Surfaceome Profiling

Project description:Understanding which proteins are presented at the cell surface is essential for ongoing therapeutic development, and to expand our basic understanding of biology. We envisioned the integration of cell surface engineering with radical-mediated protein biotinylation to profile cell surface proteins (CSPs). This method relies on the pre-functionalization of cells with cholesterol lipid groups, followed by their conjugation with an APEX2 ascorbate peroxidase enzyme. The APEX2 enzyme allows for the covalent conjugation of biotin moieties to nearby residues for subsequent enrichment, and serves as a tool for the enrichment and subsequent MS analysis of CSPs.

2022-05-06 | PXD031845 | Pride

ImmGen ULI: OpenSource Mononuclear Phagocytes Project

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2018-11-03 | GSE122108 | GEO

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