Biology subjects

Lo Sardo, V.

Publications and source records attributed to Lo Sardo, V..

4 recordsLinked to original sources

bioRxiv2026

Genome-wide cell type-specific and sex-specific transcriptional dysregulation in the islet of Langerhans underlies islet dysfunction in Down syndrome-related diabetes

Individuals with Down syndrome (trisomy of human chromosome 21) are at a significantly higher risk of developing type 2 diabetes (T2D) than the general population. Systemic metabolic defects in Down syndrome have been linked to gene expression dysregulation in peripheral tissues like the liver, muscle, brain, and adipose. However, the contribution of gene expression dysregulation in the islets of Langerhans to the increased risk of T2D in Down syndrome has not been explored. Here we show that trisomic Ts65Dn mice, a common Down syndrome mouse model, are glucose intolerant and display reduced {beta}-to- cell ratio compared to disomic controls. Using single cell RNA sequencing on islets from Ts65Dn mice we found genome-wide, cell type-specific, and sex-specific transcriptional dysregulation in trisomic islets compared to controls. The Down syndrome-associated transcriptional signature revealed important islet defects, both at the cell autonomous level and at the whole-islet level, increasing T2D susceptibility. Our results put forth innate islet defects as a central underlying cause of Down syndrome-related T2D, warranting additional studies.

developmental biology↗

bioRxiv2026

Allelic Variation at 9p21.3 Orchestrates Widespread RNA Splicing Shifts Governing Vascular Smooth Muscle Cell Plasticity

Genetic risk for coronary artery disease (CAD) has been linked to variants across more than 300 genomic loci. Whether and how these loci interface with RNA processing to drive disease-relevant cellular phenotypes remains unknown. Here, we applied haplotype-biased genome editing in induced pluripotent stem cells (iPSCs), followed by differentiation into vascular smooth muscle cells (VSMCs), to address how genetic variation at the strongest CAD locus - the 9p21.3 CAD risk locus - affects RNA processing and alternative splicing genome-wide. Using long-read RNA sequencing, we identified distinct allele-specific transcriptional programs driven by the two major haplotypes at 9p21.3, risk and non-risk. We unravel extensive reprogramming of mRNA splicing across the transcriptome, which leads to VSMC aberrant phenotypic modulation. The 9p21.3 risk haplotype disrupts transcript isoform expression and usage across multiple genomic loci implicated in diverse stages of atherosclerotic plaque development. We prioritized DDX5, previously implicated in CAD through GWAS. Isoform-specific modulation of DDX5 in VSMCs was sufficient to mitigate the 9p21.3 risk-associated molecular signature. Together, this work provides the first comprehensive isoform-level transcriptomic comparison of the two major haplotypes at the 9p21.3 locus and identifies a 9p21.3-DDX5 axis as a key regulator of VSMC phenotypic plasticity. These findings uncover allele-specific reprogramming of RNA splicing as a previously unrecognized mechanism underlying cardiovascular disease susceptibility and present a resource of targetable transcripts with potential relevance across vascular pathologies.

genetics↗

bioRxiv2025

White and Brown Adipose Tissue Share a Common Fibro-Adipogenic Progenitor Population

Adipose tissue heterogeneity has emerged as a central factor in regulating adipose tissue function in physiology and pathophysiology, yet tools to model and study this diversity in vitro remain limited. Here, we performed single-cell RNA sequencing on cultured primary white and brown preadipocytes to assess how in vitro conditions impact progenitor identity. We identified two major subpopulations in both depots: committed adipogenic precursors (CAPs) and fibro-adipogenic progenitor-like cells (FAPLs). Remarkably, FAPLs were also present in brown adipose tissue, expanding the known landscape of progenitor populations in this depot. Trajectory and regulon analyses revealed that both white and brown FAPLs exhibit similar pro-fibrotic, stress-responsive signatures and diverge early from proliferating progenitor states. Integration of datasets showed that FAPLs from both depots cluster together, emphasizing their conserved identity, while CAPs remain depot-specific. Comparison to previously published in vivo single-cell datasets revealed that these in vitro populations, including brown adipose FAPLs, correspond to adipose-resident progenitor subtypes, validating the physiological relevance of this model for studying adipose tissue heterogeneity and development.

physiology↗

bioRxiv2024

The 9p21.3 coronary artery disease risk locus drives vascular smooth muscle cells to osteo-chondrogenic state

BackgroundGenome-wide association studies have identified common genetic variants at [~]300 human genomic loci linked to coronary artery disease (CAD) susceptibility. Among these genomic regions, the most impactful is the 9p21.3 CAD risk locus, which spans a 60 kb gene desert and encompasses [~]80 SNPs in high linkage disequilibrium. Despite nearly two decades since its discovery, the role of the 9p21.3 locus in cells of the vasculature remains incompletely resolved. MethodsWe differentiated induced pluripotent stem cells (iPSCs) from risk and non-risk donors at 9p21.3 into vascular smooth muscle cells. We performed single-cell transcriptomic profiling, including co-embedding and comparison with publicly available human arterial datasets. We conducted functional characterization using migration and calcification assays and confirmed our findings on iPSC-VSMCs derived from additional donors. Finally, we used overexpression of ANRIL followed by gene expression analysis. ResultsWe demonstrated that iPSC-VSMCs harboring the 9p21.3 risk haplotype preferentially adopt an osteochondrogenic state and show remarkable similarity to fibrochondrocytes from human artery tissue. The transcriptional profile and functional assessment of migration and calcification capacity across iPSC-VSMCs lines from multiple donors concordantly resemble an osteochondrogenic state. Importantly, we identified numerous transcription factors driving different VSMC state trajectories. Additionally, we prioritized LIMCH1 and CRABP1 as signature genes critical for defining the risk transcriptional program. Finally, overexpression of a short isoform of ANRIL in non-risk cells was sufficient to induce the osteochondrogenic transcriptional signature. ConclusionsOur study provides new insights into the mechanism of the 9p21.3 risk locus and defines its previously undescribed role in driving a disease-prone transcriptional and functional state in VSMCs concordant with an osteochondrogenic-like state. Our data suggest that the 9p21.3 risk haplotype likely promotes arterial calcification, through altered expression of ANRIL, in a cell-type specific and cell-autonomous manner, providing insight into potential risk assessment and treatment for carriers. HighlightsThe 9p21.3 CAD risk locus promotes the transition of iPSC-derived Vascular Smooth Muscle Cells (iPSC-VSMCs) to an osteochondrogenic phenotype, both transcriptionally and functionally. iPSC-VSMCs carrying the risk haplotype at 9p21.3 display a distinct transcriptomic signature, including osteochondrogenic markers SOX9 and COL2A1, along with two novel markers: LIMCH1 and CRABP1. Knockout of the entire haplotype reverts this signature to a non-risk state, demonstrating a clear genotype-to-phenotype causal effect of the risk allele. Short isoform 12 of the lncRNA ANRIL, which partially overlaps the 9p21.3 locus, is sufficient to induce this transcriptional signature. The iPSC-VSMC transcriptional profile strongly resembles that of ex-vivo human arterial VSMCs, providing a human-specific model to study VSMC phenotypic alterations and investigate the effects of large CAD haplotypes on vascular wall cells.

cell biology↗