Publications

Nature Immunology | November, 2023

Dual targeting of cancer metabolome and stress antigens affects transcriptomic heterogeneity and efficacy of engineered T cells

The authors combined a cancer metabolome targeting strategy, mediated by a γ9δ2TCR, with a stress ligand sensing system using chimeric co-stimulatory receptors to target both solid or hematological tumors. SCD perfromed SORT-Seq experiments to explore how the different chimeras impacted transcriptomic signatures and T cell phenotypes. The results showed that γ9δ2 TCRs and CAR-like co-stimulation allows to tweak transcriptomic heterogeneity toward a more favorable transcriptomic profile for CD4+, which displayed more proliferative and cytotoxic transcriptional signatures and less exhaustion signatures. Additionally, the researchers observed a beneficial activation of the NF-κB pathway when using a particular co-stimulatory signaling domain within their chimera designs.

SORT-seq Mouse Tumor tissue

Cancer Research Communications | October, 2023

Ewing sarcoma single-cell transcriptome analysis reveals functionally impaired antigen-presenting cells

In this work, the Clevers group characterized the immune microenvironment of Ewing sarcoma biopsies to better guide novel immuno-therapies. SCD supported the research by profiling the immune population using SORT-Seq. Researchers found that tumour cells promote a switch of the immune microenvironment into an immunosuppressive niche, explained by dysfunctional T cells and antigen presenting cells.

SORT-seq Human Tumor tissue

Scientific Reports | October, 2023

Exploring intrinsic variability between cultured nasal and bronchial epithelia in cystic fibrosis

The nasal and bronchial epithelium are integral parts of the respiratory tract, impacted in the monogenic disorder cystic fibrosis (CF). Recent studies reveal intrinsic variability in nasal and bronchial tissues, including differences in mucociliary cell composition and expression of unique transcriptional regulatory proteins. The authors investigate if these intrinsic differences between nasal and bronchial epithelial cells persist in culture and affect their functioning in CF. Bulk RNA sequencing performed by SCD identified cell type-specific signature transcription factors, some of which were poised for expression in basal progenitor cells. Notably, differentiated nasal and bronchial epithelial 3D organoids exhibited varying capacities for fluid secretion, associated with differences in ciliated cell differentiation. These unique features in cell culture models can inform investigations into tissue-specific effects on upper and lower respiratory disease development in CF.

Bulk RNA sequencing Human Organoids

Nature Communications | October, 2023

Interferon-γ couples CD8+ T cell avidity and differentiation during infection

Effective responses to intracellular pathogens involve T cell clones with a broad affinity range for their cognate peptide and diverse functional phenotypes. However, how T cell clones are selected throughout the response to maintain a breadth of avidities remains unclear. In this study, the authors demonstrate that direct sensing of the cytokine IFN-γ by CD8+ T cells coordinates avidity and differentiation during infection. Here, IFN-γ promotes the expansion of low-avidity T cells and reinforces high-avidity T cell entry into the memory pool. Notably, 10x Genomics based single cell RNA sequencing performed by SCD reveals that IFN-γ in this context is mainly provided by virtual memory T cells—an antigen-inexperienced subset with memory features. Overall, authors propose that IFN-γ and virtual memory T cells fulfill a critical immunoregulatory role by enabling the coordination of T cell avidity and fate

10x Genomics Mouse Primary cells Spleen

PLOS Biology | October, 2023

Identification of the regulatory circuit governing corneal epithelial fate determination and disease

Limbal stem cells (LSCs) play a crucial role in maintaining the transparent corneal epithelium, while epidermal keratinocytes are responsible for renewing the nontransparent epidermis. To understand the specific cell faits of the two cell types, researchers employed a comprehensive multi-omics analysis, including SORT-seq single cell RNA sequencing performed by SCD, and identified shared and cell type-specific transcription factors (TFs) that define specific cell destinies. Notably, some of these TFs are associated with corneal opacity. The study sheds light on the regulatory circuitry governing LSC fate and its connection to corneal diseases.

SORT-seq Human Primary cells

Cell Reports | January, 2024

Tubuloid differentiation to model the human distal nephron and collecting duct in health and disease

In the realm of renal research, tubuloid organoids had emerged as a valuable tool for long-term expansion of primary human renal epithelium. However, this expansion often comes at the cost of limited differentiation. To address this, researchers have devised niche-inspired culture conditions. By examining a single cell atlas, they discovered that differentiation primarily leads to the formation of ascending limb of Henle and principal cells. Leveraging these differentiated tubuloids, they successfully modeled lithium nephropathy in vitro. Through single-cell RNA sequencing performed by SCD, they explored the transcriptional effects induced by lithium. Notably, lithium was found to suppress electrolyte and solute transporters across various cell types, while also inducing a progenitor state within kidney tubuloids

10x Genomics Human Organoids

Cell Stem Cell | January, 2024

Human conjunctiva organoids to study ocular surface homeostasis and disease

In this study, authors establish and characterize long-term expanding organoids and air-liquid interface representing human and mouse conjunctiva. PAX6, a critical transcription factor, plays a central role in eye development and continues to be expressed in the conjunctiva during adulthood. In specific conjunctival pathologies like pterygium and pinguecula, PAX6 expression is reduced. To investigate the impact of PAX6 loss of function, the authors employed CRISPR-Cas9 to mutate the Pax6 gene in mouse conjunctival organoids and analyze the effect through Bulk RNA sequencing performed by SCD. Absence of PAX6 leads to undifferentiated basal-like phenotype similar to one in pterygia.

Bulk RNA sequencing Mouse Organoids

BioRxiv | January, 2024

Targeted CRISPR-Cas9 screening identifies transcription factor network controlling murine haemato-endothelial fate commitment

Hematopoiesis is the process by which the body creates and maintains all blood cells. It begins during development in the yolk sac, where haemato-endothelial mesoderm differentiates into hematopoietic progenitors. In this study authors use SORT-seq – single cell RNA sequencing method performed by SCD on a mouse embryonic stem cell model. This data was used to construct developmental trajectory of mesodermal populations and resulted in identification of key regulators, including Etv2, Smad1, Ldb1, Six4, and Zbtb7b, which drive or repress mesodermal commitment. These factors play a precise role in shaping the gene expression signature of developing mesoderm, leading to distinct lineage differentiation biases for endothelial and hematopoietic cells.

SORT-seq Mouse Cell culture Stem cells

BioRxiv preprint | January, 2024

Neutrophil immune profile controls spinal cord regeneration in zebrafish

In this study, authors use regenerative zebrafish model to elucidate the role of neutrophils in spinal cord injury. While neutrophil recruitment to the site of injury is necessary for the macrophage recruitment, resolving the neutrophil mediated inflammation through reverse migration is equally important for the tissue regeneration. Neutrophil-specific Bulk RNA-sequencing based on CEL-seq protocol performed by SCD reveals that accelerating the resolution of neutrophil mediated inflammation via Cxcr4 inhibition improves the regenerative process through transient increased expression of tnf-a in macrophages and microglia.

Bulk RNA sequencing Zebrafish Spinal cord

Cancer Immunology, Immunotherapy |

Leukocyte-associated immunoglobulin-like receptor-1 blockade in combination with programmed death-ligand 1 targeting therapy mediates increased tumour control in mice

Collagen expression and structure in the tumor microenvironment play a crucial role in tumor development and therapy response. Leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is a widely expressed inhibitory collagen receptor, a promising target in cancer therapy. With the help of SCD & CEL-seq protocol for Bulk RNA sequencing, authors confirm inactivation of lymphocyte immunity and increased cell adhesion due to activity of LAIR-1.

Bulk RNA sequencing Mouse Cell culture Spleen

Acta Neuropathologica | February, 2024

Astroglial calcium signaling and homeostasis in tuberous sclerosis complex

Tuberous Sclerosis Complex (TSC) is a genetic disorder characterized by benign tumors in various organs, including the brain. It often leads to epilepsy, intellectual disability, and autism. TSC involves hyperactivation of the mTOR pathway, affecting cortical development and astrocyte metabolism. Dysregulated calcium channels contribute to seizure activity. Authors use 10x Genomics Flex single cell RNA-seq performed by SCD to study TSC astrocytes and report altered Ca2+ dynamics, reduced responsiveness, and mitochondrial abnormalities. These factors play a role in TSC-related conditions.

10x Genomics Flex Human Brain

Biomedicines | November, 2023

Levamisole Modulation of Podocytes’ Actin Cytoskeleton in Nephrotic Syndrome

The researcher investigated the molceular mechanisms behind the benefitial effects of levamisole for the treatment of ideopathic nephrotic syndrome. SCD performed RNA Bulk-Seq analysis on podocytes treated with levamisole. The results show that levamisole significantly modulates podocyte actin dynamic, which in functional experiments restored the actin cytoskeleton derangement, reduced cell motility, and impaired cellular adhesion present in nephrotic syndrome patients.

Bulk RNA sequencing Human Cell culture Kidney

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