Biology subjects

Rydbirk, R.

Publications and source records attributed to Rydbirk, R..

5 recordsLinked to original sources

bioRxiv2025

Adipose tissue cell states linked to progression and clinical subtypes of MASLD in human obesity

Adipose tissue dysfunction is a key determinant of inter-individual variability in obesity-associated comorbidities, yet the underlying tissue-level mechanisms linking adipose remodeling to progression of metabolic dysfunction-associated steatotic liver disease (MASLD) remain poorly defined. We applied single-nucleus RNA sequencing to abdominal subcutaneous adipose tissue (SAT) from individuals with severe obesity, stratified by histologically defined MASLD stage, and integrated these data with bulk RNA-seq from [~]200 individuals. MASLD was associated with adipocyte hypertrophy and near-depletion of an ADH1BHI adipocyte subset linked to improved lipid buffering and systemic metabolic health. Conversely, lipid-associated macrophages (LAMs) expanded in MASLD, coordinating lipid-handling and inflammatory programs in the myeloid compartment. In advanced metabolic dysfunction-associated steatohepatitis (MASH), we identified a senescence-associated PLAUHI progenitor subpopulation with pro-inflammatory signaling potential. Whereas LAMs were broadly enriched in MASLD subtypes, PLAUHI progenitors specifically marked a cardiometabolic MASLD endotype, characterized by type 2 diabetes and cardiovascular disease. These findings highlight cellular remodeling of adipose tissue as a potential driver of MASLD heterogeneity and progression.

cell biology↗

bioRxiv2025

Single cell-resolved transcriptional dynamics of human subcutaneous adipose tissue during lifestyle- and bariatric surgery-induced weight loss

During sustained weight gain, human white adipose tissue undergoes dramatic remodeling that may compromise adipose tissue function and lead to obesity comorbidities such as cardiometabolic disease. These comorbidities can be at least partially reversed by weight loss; however, the degree to which human adipose tissue is remodeled during weight loss is currently unclear. Here, we have used snRNA-seq combined with bulk RNA-seq and 3D light microscopy to investigate the cellular and transcriptional alterations in abdominal subcutaneous adipose tissue (ASAT) from a unique cohort of obese individuals undergoing initially modest (8-10%) lifestyle-induced weight loss followed by a more dramatic (20-45%) bariatric surgery-induced weight loss. We show that in response to this weight loss, ASAT in both males and females underwent dramatic compositional and transcriptional remodeling. Most notably, surgery-indued weight loss led to an increase in the adipose vascular compartment, a dramatic reduction in proinflammatory immune cells, and a tissue-wide reduction in inflammatory gene signatures. In response to modest weight loss, we observed an increase in specific progenitor populations and an induction of proadipogenic genes, indicating that this process is important for the early adaptation of AT to weight loss that might contribute to the early overall beneficial effects on insulin sensitivity and systemic inflammation.

cell biology↗

bioRxiv2024

Single-cell profiling of cortical tubers in tuberous sclerosis complex shows molecular structure preservation and massive reorganization of metabolism

Tuberous sclerosis complex (TSC) is a multisystemic genetic disorder associated with loss-of-function mutations in the TSC1 or TSC2 gene, which lead mTOR pathway hyperactivation and epileptogenesis. Cortical tubers are the hallmark of TSC and represent disorganized cortical structure underlying the generation of focal seizures. Here, we report single-nucleus RNA sequencing in resected cortical tubers vs matched pediatric controls. Strikingly, in spite of severe cortical disorganization, we found that cortical tubers preserve all neuronal subtypes, even the rarest ones. Moreover, we showed that principal neurons largely preserve spatial position based on transcriptional signatures. Principal neurons and layer 1-2 GABAergic neurons that modulate upper cortical circuits exhibited the largest gene expression changes. Interestingly, multiple mTOR pathway gene expression changes in TSC counteracted mTOR hyperactivation. TSC neuronal, but not glial, networks exhibited massive metabolic reorganization with a reduction in mitochondrial respiration and a concomitant switch to fatty acid metabolism. Finally, we show that neuron-specific AMPA receptor signaling might underlie epileptogenesis in TSC and could represent a potential candidate for therapeutic targeting.

neuroscience↗

bioRxiv2022

Case-control analysis of single-cell RNA-seq studies

Single-cell RNA-seq (scRNA-seq) assays are being increasingly utilized to investigate specific hypotheses in both basic biology and clinically-applied studies. The design of most such studies can be often reduced to a comparison between two or more groups of samples, such as disease cases and healthy controls, or treatment and placebo. Comparative analysis between groups of scRNA-seq samples brings additional statistical considerations, and currently there is a lack of tools to address this common scenario. Based on our experience with comparative designs, here we present a computational suite (Cacoa - case-control analysis) to carry out statistical tests, exploration, and visualization of scRNA-seq sample cohorts. Using multiple example datasets, we demonstrate how application of these techniques can provide additional insights, and avoid issues stemming from inter-individual variability, limited sample size, and high dimensionality of the data.

bioinformatics↗

bioRxiv2020

Selective vulnerability of supragranular layer neurons in schizophrenia

Schizophrenia is one of the most wide-spread mental brain disorders with complex and largely unknown etiology. To characterize the impact of schizophrenia at a cellular level, we performed single nucleus RNA sequencing of >190,000 neurons from the dorsolateral prefrontal cortex of patients with schizophrenia and matched controls (7 vs 11, respectively). In addition, to correlate data with cortical anatomy, >100,000 neurons were analyzed topographically by immunohistochemistry in an extended cohort of cases with schizophrenia and controls (10 vs 10). Compositional analysis of RNA sequencing data revealed reduction in relative abundance across all families of GABAergic neurons and a concomitant increase in principal neurons, which was most pronounced for supragranular subtypes (layers 2-3). Moreover, supragranular subtypes of GABAergic interneurons showed most dramatic transcriptomic changes. These results were substantiated by histological analysis, which revealed a reduction in the density of calretinin, calbindin and parvalbumin GABAergic interneurons particularly in layer 2. Common effect of schizophrenia on supragranular neuronal networks was underlined by downregulation of protein processing genes and upregulation of neuronal development/plasticity genes across supragranular subtypes of principal neurons and GABAergic interneurons. In situ hybridization and spatial transcriptomics further confirmed supragranular layer neuron vulnerability, revealing complexity of schizophrenia-affected cortical circuits. These point towards general network impairment within supragranular layers being a core substrate associated with schizophrenia symptomatology.

neuroscience↗