Biology subjects

Quach, S.

Publications and source records attributed to Quach, S..

5 recordsLinked to original sources

bioRxiv2024

Fetal Liver-like Organoids Recapitulate Blood-Liver Niche Development and Multipotent Hematopoiesis from Human Pluripotent Stem Cells

The fetal liver is a hematopoietic organ, hosting a diverse and evolving progenitor population. While human liver organoids derived from pluripotent stem cells (PSCs) mimic aspects of embryonic and fetal development, they typically lack the complex hematopoietic niche and the interaction between hepatic and hematopoietic development. We describe the generation of human Fetal Liver-like Organoids (FLOs), that model human hepato-hematopoietic interactions previously characterized in mouse models. Developing FLOs first integrate a yolk sac-like hemogenic endothelium into hepatic endoderm and mesoderm specification. As the hepatic and hematopoietic lineages differentiate, the FLO culture model establishes an autonomous niche capable of driving subsequent progenitor differentiation without exogenous factors. Consistent with yolk sac-derived waves, hematopoietic progenitor cells (HPCs) within FLOs exhibit multipotency with a preference for myeloid lineage commitment, while retaining fetal B and T cell differentiation potential. We reconstruct in FLOs the embryonic monocyte-to-macrophage and granulocyte immune trajectories within the FLO microenvironment and assess their functional responses in the liver niche. In vivo, FLOs demonstrate a liver engraftment bias of hematopoietic cells, recapitulating a key phenomenon of human hematopoietic ontogeny. Our findings highlight the intrinsic capacity of liver organoids to support hematopoietic development, establishing FLOs as a platform for modeling and manipulating human blood-liver niche interactions during critical stages of development and disease.

developmental biology↗

bioRxiv2024

Dissecting compounded hepatocyte injury in a model of MASLD progression from human induced pluripotent stem cells

Drug discovery for multifactorial diseases like metabolic dysfunction-associated steatotic liver disease (MASLD) remains challenging due to inadequate models and untargeted drug screenings. We combined stem-cell-based modeling with computational drug predictions identifying flavin pathways as therapeutic targets in MASLD. For disease stage-specific discovery, we established a MASLD testing model, compounding metabolic triggers to intensify mitochondrial crisis. In vitro injuries included adipo- and myokines, immune cell co-culture, and genomic risk factors. Benchmarking experiments revealed similarities with advanced human MASLD. To query therapeutic compounds, protein-protein-interaction networks, weighted gene co-expression, and knowledge graph-based analyses independently predicted flavin adenine dinucleotide (FAD) as an anti-MASLD factor. Dysregulated flavoproteomes in vitro and in vivo-in pediatric and adult MASLD patients- supported our flavin network-focused strategy. We established therapeutic FAD concentrations to mitigate metabolic injury and fibro-inflammation in human multicellular liver organoids and other assays. We enhanced therapeutic FAD effects through genetic mitochondrial biogenic augmentation and identified orally available flavo-active compounds--including Aspirin--restoring mitochondrial respiration. Our study demonstrates how integrating stem cell-derived disease modeling with computed drug predictions can expedite therapeutic discovery.

cell biology↗

bioRxiv2023

Memory reactivation of real-world spatial orientation revealed by human electrophysiology.

Memory consolidation relies on the reactivation of previous experiences during sleep. The precise interplay of sleep-related oscillations (slow oscillations, spindles and ripples) is thought to coordinate the information flow between relevant brain areas, with ripples mediating memory reactivation. However, in humans empirical evidence for a role of ripples in memory reactivation is lacking. Here, we investigated the relevance of sleep oscillations and specifically ripples for memory reactivation during human sleep using targeted memory reactivation (TMR). Intracranial electrophysiology in epilepsy patients and scalp EEG in healthy participants revealed that elevated levels of SO-spindle activity promoted the read-out of TMR induced memory reactivation. Importantly, spindle-locked ripples recorded intracranially from the medial temporal lobe were found to be instrumental for memory reactivation to unfold during non-rapid eye movement (NREM) sleep. Our findings establish ripples as key-oscillation in human systems consolidation and emphasize the importance of the coordinated interplay of the cardinal sleep oscillations.

neuroscience↗

bioRxiv2023

Deciphering sources of PET signals in the tumor microenvironment of glioblastoma at cellular resolution

Various cellular sources hamper interpretation of positron-emission-tomography (PET) biomarkers in the tumor microenvironment (TME). We developed immunomagnetic cell sorting after in vivo radiotracer injection (scRadiotracing) in combination with 3D-histology via tissue clearing to dissect the cellular allocation of PET signals in the TME. In SB28 glioblastoma mice, translocator protein (TSPO) radiotracer uptake per tumor cell was higher compared to tumor-associated microglia/macrophages (TAMs). Cellular radiotracer uptake was validated by proteomics and confirmed for in vitro samples of patients with glioblastoma. Regional agreement between PET signals and single cell tracer uptake predicted the individual cell distribution in 3D-histology. In consideration of cellular tracer uptake and cell type abundance, tumor cells were the main contributor to TSPO enrichment in glioblastoma, however proteomics identified potential PET targets highly specific for TAMs. Combining cellular tracer uptake measures with 3D-histology facilitates precise allocation of complex PET signal sources and will serve to validate novel TAM-specific radioligands.

neuroscience↗

bioRxiv2023

Electrophysiological signatures of veridical head direction in humans

Information about heading direction is critical for navigation as it provides the means to orient ourselves in space. However, given that veridical head direction signals require physical rotation of the head and most human neuroimaging experiments depend upon fixing the head in position, little is known about how the human brain is tuned to such heading signals. To address this, we asked fifty-two healthy participants undergoing simultaneous EEG and motion tracking recordings (split into two experiments) and ten patients undergoing simultaneous intracranial EEG and motion tracking recordings to complete a series of orientation tasks in which they made physical head rotations to target positions. We then used a series of forward encoding models and linear mixed-effects models to isolate electrophysiological activity that was specifically tuned to heading direction. We identified a robust posterior central signature that predicts changes in veridical head orientation after regressing out confounds including sensory input and muscular activity. Both source localisation and intracranial analysis implicated the medial temporal lobe as the origin of this effect. Subsequent analyses disentangled head direction signatures from signals relating to head rotation and those reflecting location-specific effects. Lastly, when directly comparing head direction and eye gaze-related tuning, we found that the brain maintains both codes while actively navigating, with stronger tuning to head direction in the medial temporal lobe. Together, these results reveal a taxonomy of population-level head direction signals within the human brain that is reminiscent of those reported in the single units of rodents.

neuroscience↗