Biology subjects

Kalucka, J.

Publications and source records attributed to Kalucka, J..

7 recordsLinked to original sources

bioRxiv2026

Sex-specific remodeling of the human adipose tissue vascular niche in obesity

AO_SCPLOWBSTRACTC_SCPLOWObesity remodels the subcutaneous adipose tissue (SAT) vasculature and contributes to cardiometabolic risk, yet potential sex differences in this process remain poorly defined. Here, we integrated single-nucleus transcriptomics and histological analyses of human SAT to reveal pronounced sexual dimorphism within the vascular niche. Obese males exhibit mural cell loss, increased collagen deposition, and inflammatory endothelial activation, including enhanced antigen presentation programs. In contrast, females display preserved mural coverage and increased lipid-handling and redox-adaptive pathways. These coordinated structural and transcriptional differences position the adipose endothelium as a sex-divergent regulator of obesity-associated cardiometabolic vulnerability.

cell biology↗

bioRxiv2025

Uncovering the transcriptional hallmarks of endothelial cell aging via integrated single-cell analysis

Endothelial cells (ECs) are critical regulators of vascular function and exhibit specialized, organ-specific roles across tissues. During aging, these cells become dysfunctional, resulting in increased susceptibility to cardiovascular disease and its associated mortality. While single-cell transcriptomics studies have revealed extensive endothelial heterogeneity across tissues and conditions, a comprehensive atlas of human EC transcriptomes over the course of the adult human lifespan is still lacking. Here, we present the Human Aging Endothelial Cell Atlas (HAECA), a harmonized single-cell transcriptomic compendium of over 375,000 ECs from 12 human tissues throughout adulthood. Using HAECA, we identified age-associated transcriptional shifts, including a decline in angiogenic gene expression in venous ECs and widespread alterations in extracellular matrix (ECM)- and mechanotransduction-associated pathways. We validated these findings in aging human skin and further uncovered a p21-linked transcriptional program in ECs, confirmed in both in vitro and in vivo models and linked to cellular senescence. Together, our study provides a high-resolution transcriptome reference across spatial as well as temporal axes of the human endothelium.

cell biology↗

bioRxiv2025

TWIST1 drives endothelial-to-mesenchymal-transition to stabilize atherosclerotic plaques

Atherosclerosis progresses from fatty streaks to complex plaques, with rupture leading to life-threatening complications. Endothelial-to-mesenchymal transition (EndMT) is associated with advanced atherosclerotic plaques, but its role in plaque progression remains unclear. To investigate this, we analyzed the role of TWIST1, a key EndMT-driving transcription factor, in plaque development. Using single-cell RNA sequencing of atherosclerotic plaques from hypercholesterolemic mice with inducible deletion of Twist1 from endothelial cells (Twist1ECKO ApoE-/-) we demonstrate that Twist1 regulates endothelial cell heterogeneity by promoting cell states expressing EndMT markers. Cell tracking confirmed that Twist1 induces EndMT in advanced plaques. Mechanistically, we found that TWIST1 contributes to EndMT by promoting endothelial migration and proliferation through the transcriptional coactivator PELP1. Additionally, TWIST1 induces AEBP1 transcription, which upregulates COL4A1 to drive endothelial proliferation. Analyses of murine brachiocephalic plaques show that endothelial Twist1 promotes plaque growth, collagen deposition, and ACTA2-positive cell accumulation, hallmarks of plaque stability, while reducing necrosis and macrophage infiltration, features of plaque instability. Moreover, TWIST1 expression was associated with asymptomatic human carotid atherosclerosis and predicts favourable clinical outcomes. These findings challenge the prevailing view that EndMT destabilizes plaques, by suggesting that TWIST1-driven EndMT can promote plaque stability, offering new insights into atherosclerosis pathophysiology and therapeutic potential.

pathology↗

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

Defining the Vascular Niche of Human Adipose Tissue Across Metabolic Conditions

IntroductionAdipose tissue homeostasis depends on a healthy vascular network. Vascular malfunction is a hallmark of obesity1, and vascular endothelial dysfunction, in particular, accelerates metabolic diseases, including obesity and diabetes. Single-cell transcriptomics studies have mapped the cellular landscape of human white adipose tissue (WAT)2-8. However, the vascular niche remains relatively undefined9, especially regarding its heterogeneity, function, and role in metabolic disease. To address this gap, we created a single-cell transcriptome atlas of human subcutaneous adipose tissue (SAT), comprising nearly 70,000 vascular cells from 65 individuals. We characterized seven canonical adipose tissue endothelial cell (AdEC) subtypes and identified a distinct heterogenous population, here referred to as sub-AdECs. Sub-AdECs exhibit gene signatures characteristic of multiple cell types, including mesenchymal, adipocytic, and immune, suggesting they possess diverse properties and identities. Through computational analyses and whole-mount imaging, we validated the occurrence of sub-AdECs and show that these cells likely arise through endothelial-mesenchymal transition (EndMT), the modulation of which limits obesity-associated adipose tissue inflammation and fibrosis. Furthermore, we compared the transcriptomes of vascular cells from individuals living with or without obesity and type 2 diabetes and find metabolic disease-associated inflammatory and fibrotic transcriptomic patterns. The atlas and accompanying analyses establish a solid foundation for investigations into the biology of the adipose tissue vascular niche and its contribution to the pathogenesis of metabolic disease.

cell biology↗

bioRxiv2023

The phosphodiesterase 2A regulates lymphatic endothelial development via cGMP-mediated control of Notch signaling

During vascular development endothelial junctions mature and vessel integrity is established to form the endothelial barrier. The molecular mechanisms by which lymphatic vessels induce cell contact inhibition are not understood. Here, we uncover the cGMP-dependent phosphodiesterase 2A (PDE2A) as a selective regulator of lymphatic, but not blood endothelial contact inhibition. Conditional deletion of Pde2a in mouse embryos reveals severe lymphatic dysplasia, while large blood vessel architecture remains unaltered. In the absence of PDE2A, human lymphatic endothelial cells fail to induce mature junctions and cell cycle arrest, while cGMP levels, but not cAMP levels, are increased. Loss of PDE2A-mediated cGMP hydrolysis leads to downregulation of NOTCH signaling. Vice versa, DLL4-induced NOTCH activation restores junctional maturation in PDE2A-deficient lymphatic endothelial cells. Our data demonstrate that PDE2A selectively modulates a crosstalk between cGMP and NOTCH signaling to finetune lymphatic development and suggest that PDE2A may be a druggable target to control lymphatic leakage and regeneration.

developmental biology↗

bioRxiv2022

TMEM100, a Lung-Specific Endothelium Gene

The heterogeneity of endothelium across different organs was recently explored using single-cell RNA-sequencing analysis. Compared to other organs, the lung exhibits a distinct structure composed of a thin layer of capillary for efficient gas exchange. In this study, we demonstrate that Tmem100 is a lung-specific endothelium gene.

physiology↗