Biology subjects

Moles, A.

Publications and source records attributed to Moles, A..

4 recordsLinked to original sources

bioRxiv2025

Patient-derived liver biopsy organoids enable precision alcohol-associated liver disease modeling

Background & AimsAlcohol-associated liver disease (ALD) is a major cause of liver disease worldwide with scarce therapeutic options. Animal models poorly recapitulate advanced ALD precluding the development of new treatments. Organoids have emerged as a powerful human-based preclinical tool. However, current patient-derived liver organoids fail to recapitulate the epithelial heterogeneity and its generation requires liver surgical resections, thus limiting personalized disease modeling. Here, we report the development of organoids from liver needle biopsies (b-Orgs) from patients with ALD. Methodsb-Orgs were generated from tru-cut biopsies from patients at early (n=28) and advanced (n=34) stages of ALD. b-Orgs were characterized by immunofluorescence, bulk and single cell RNA-sequencing and compared to parental tissues. b-Orgs were used to model ALD progression, identify pathogenic drivers, induce alcohol-associated hepatitis (AH) and evaluate response to prednisolone. ResultsPhenotypic and functional analysis of b-Orgs showed hepatocyte- enriched features. Single-cell RNA-sequencing revealed a heterogeneous cell composition comprising hepatocyte, biliary and progenitor populations, mirroring the epithelial landscape found in patients with advanced ALD. Moreover, b-Orgs preserved disease-stage features and allowed to identify the association of ELF3 with cell plasticity and disease progression. Finally, stimulation of b-Orgs with drivers of ALD induced pathophysiological features of alcohol-associated hepatitis, including ROS production, lipid accumulation, inflammation and decreased cell proliferation, which were mitigated in response to prednisolone. Conclusions Overall, we provide a human-based model that recapitulates epithelial complexity and patient specific features, allowing to identify drivers of cell plasticity and expanding organoid-based liver disease modeling for personalized medicine. Impact and implications Here, we describe the generation of biopsy-derived organoids (b-Orgs) from patients with liver disease. b-Orgs reproduce the liver epithelial cell composition found in patients liver tissue and are efficiently generated from different stages of the disease, providing a platform for patient- tailored disease modeling and drug testing.

cell biology↗

bioRxiv2024

Structural variants underlie parallel adaptation following global invasion

Rapid adaptation during invasion has historically been considered limited and unpredictable. We leverage whole-genome sequencing of >2600 plants across six continents to investigate the relative roles of colonization history and adaptation during the worldwide invasion of Trifolium repens. Introduced populations contain high levels of genetic variation with independent colonization histories evident on different continents. Five large structural variants on three chromosomes exist as standing genetic variation within the native range, and exhibit strong signatures of parallel climate-associated adaptation across continents. Common gardens in the native and introduced ranges demonstrate that three structural variants exhibit patterns of selection consistent with local adaptation across each range. Our results provide strong evidence that rapid and parallel adaptation during invasion is caused by large-effect structural variants introduced throughout the world. Significance StatementBiological invasions occur over short timescales and introductions are often hypothesized to include limited genetic diversity, making the role of adaptation in invasion success controversial. We demonstrate that the invasion of a human-commensal species, Trifolium repens, likely stems from multiple, diverse introductions with significant evidence of climate-associated adaptation following introduction. The genetic basis of adaptation is most strongly linked to five chromosomal rearrangements that each span hundreds of genes - matching theoretical predictions that large-effect variants are key to the initial stages of adaptation to novel environments. Chromosomal rearrangements have remarkably parallel signatures of adaptation across different introductions despite initial colonization from different areas of Europe. Our study highlights the impact of globalization and rapid adaptation for the invasion success of human commensal species.

evolutionary biology↗

bioRxiv2024

Trajectory analysis of hepatic stellate cell differentiation reveals metabolic regulation of cell commitment and fibrosis

Defining the trajectory of cells during differentiation and disease offers the possibility to understand the mechanisms driving cell fate and identity. However, trajectories of human cells are largely unexplored. By investigating the proteome trajectory of iPSCs differentiation to hepatic stellate cells (dHSCs), we identified RORA as a key transcription factor governing the metabolic reprogramming of HSCs necessary for HSCs commitment, identity, and activation. Using RORA deficient iPSCs and pharmacologic interventions, we showed that RORA is required for mesoderm differentiation and prevents dHSCs activation by reducing the high energetic state of the cells. While RORA knockout mice had enhanced fibrosis, RORA agonists rescued multi- organ fibrosis in in vivo models. RORA expression was consistently found to be negatively correlated with liver fibrosis and HSCs activation markers in patients with liver disease. This study reveals that RORA regulates cell metabolic plasticity, crucial for mesoderm differentiation, pericyte quiescence, and fibrosis, influencing cell commitment and disease mechanisms. SummaryThis study describes the trajectory of induced pluripotent stem cells (iPSCs) differentiation to hepatic stellate cells (dHSCs). We identify RAR-related orphan receptor alpha (RORA) as a transcription factor essential for mesoderm commitment and dHSCs identity and fibrogenic activation by regulating metabolic plasticity.

cell biology↗

bioRxiv2020

A maternal effect regulates global DNA methylation patterns

Variation in DNA methylation between individuals has been shown to be influenced by both genetic and environmental factors. However, the relative impact of genetic and non-genetic factors on DNA methylation patterns across the mammalian genome has not been systematically studied. We performed whole-genome methylation analysis in two inbred mouse strains, revealing striking differences in the global distribution of DNA methylation. Although global methylation patterns were indistinguishable for most genomic features, a significant increase in the number of unmethylated CpG-island promoters and first exons was observed between strains. Experiments using F1 reciprocal hybrid strains demonstrated that the genotype of the mother dictated global DNA methylation patterns. Cross-fostering experiments ruled out a postnatal maternal effect on these differences and suggested that they were driven by a prenatal maternal effect, possibly via differential deposition of maternal gene products into the oocyte or uterine environment. These data demonstrate that maternal effects have a major impact on global DNA methylation patterns.

genomics↗