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CeMM Principal Investigator

Laura de Rooij

Circulating endothelial cells & vascular aging

Our group aims to combine single-cell omics and functional vascular assays to increase our fundamental understanding of the molecular make-up and function of circulating endothelial cells (CECs). We intend to not only assess their degree of transcriptomic and functional heterogeneity in health, but also in the context of healthy aging and aging-associated disease, with the overarching goal of exploring the translational relevance of CECs for the diagnosis and treatment of vascular aging.

Questions that fuel our research are: What is the degree of CEC heterogeneity in health, and does this change when we age? What marker genes can separate CECs from other cell types in the blood? Does the overall abundance of CEC (subtypes) change over the course of advancing age? How do CECs home to and maintain/repair blood vessels? Are the homing or reparative properties of CECs isolated from young vs. aged individuals altered or impaired, and if so, can we rejuvenate them?

Non-invasive profiling of the aging human vasculature

Endothelial cells (ECs) line the interior surface of all blood vessels, and are essential for regulation of vascular tone, vessel growth, inflammation, permeability, and coagulation. During the process of aging ECs can become dysfunctional, which plays a major role in the etiology of numerous clinical disorders of advancing age. Gaining insight into mechanisms of healthy and pathological vascular aging however requires invasive assessments that are often impractical in humans. In that light, circulating endothelial cells (CECs) in our blood represent an easy-to-access cell population possibly involved in development, repair, regeneration and aging of the vasculature. Ever since their discovery, CECs have however been plagued with controversy as to their identity, functional relevance, and heterogeneity, all precluding their translational use. Our group aspires to deeply characterize the transcriptomic landscape and function of this rare cell population in human blood, to gain a comprehensive understanding of their complexity and abundance in young and aged individuals.

Characterizing circulating endothelial cells one cell at a time

The single-cell era has led to the emergence of a multitude of studies and technologies that revolutionized our understanding of cellular heterogeneity from both a physiological and pathophysiological viewpoint. Recent single-cell omics studies have compellingly revealed that ECs lining blood vessels are transcriptomically heterogeneous, encompassing several subtypes with distinct gene expression profiles related to their tissue-of-origin or disease setting. In line with this, mounting evidence (gathered before the single-cell revolution) also suggests that isolated CEC populations might comprise multiple, related cell types. By taking advantage of both publicly available scRNA-seq studies, as well as the in-house generation of single-cell datasets of unmatched resolution, our group aspires to generate a first-of-its-kind, high-resolution blueprint of the CEC transcriptome in health, aging and aging-associated disease. With these efforts we aim to deepen our understanding of CEC heterogeneity, and to establish robust, CEC-selective signatures that can aid in their prospective purification, allowing us to further characterize/validate their function in health and aging.

In vitro modeling of circulation endothelial cell function

Our group will use various in vitro approaches to study the overall function of freshly isolated CECs, and the possibility of their ex vivo expansion while maintaining their transcriptomic phenotype. Moreover, the usage of 3D (perfusable) in vitro vascular model systems will be explored to functionally characterize the interaction of CECs with blood vessels in a human context. Altogether, we aim to answer several outstanding questions, including if and how CECs home to areas of vessel injury, whether/how they can aid in repair of injured vessels, and whether aging compromises the function or reparative abilities of CECs. 

Biosketch

Laura de Rooij studied Biomedical Sciences at the University of Amsterdam (The Netherlands), during which she investigated the clinical relevance of colon cancer subtype diversity. She then joined the Stem Cell and Cancer Research Institute at McMaster University in Hamilton (Canada), where she studied the role of RNA binding proteins in leukemic stem cells via an in vivo two step CRISPR-Cas9-mediated screening approach. For her post-doctoral studies, she returned to Europe to work under the mentorship of Prof. Carmeliet in the lab of Angiogenesis and Vascular Metabolism at VIB-KU Leuven (Belgium). Here she led and contributed to numerous single-cell transcriptome atlases of endothelial cells, generated from a diverse range of tissues, preclinical models and clinical patient material in health and disease. Her studies have shed new light on the degree of vessel subtype heterogeneity in different tissues, as well as the altered composition and rewired molecular circuitries of endothelial cell subtypes in disease. Moreover, her efforts led to the discovery of previously unknown vascular subtypes and functions, including endothelial cells with a lipid-processing phenotype and a potential prognostic relevance in breast cancer, and endothelial cells with a putative pro-fibrotic function in COVID-19. Laura joined CeMM as principal investigator in September 2022. Her lab focuses on deciphering the transcriptomic landscape and role of circulating endothelial cells in health and aging.

Selected Papers

de Rooij, L.P.M.H.*, Becker, L.M.* et al. The pulmonary vasculature in lethal COVID-19 and idiopathic pulmonary fibrosis at single cell resolution (2022). Cardiovascular Research. Online ahead of print. (abstract)

de Rooij, L.P.M.H., Becker, L.M. & Carmeliet, P. A role for the vascular endothelium in post-acute COVID-19? (2022). Circulation, 145, 1503-1505. (abstract)

Becker, L.M.*, Chen, S.H.*, Rodor, J.*, de Rooij, L.P.M.H.* et al. Deciphering endothelial heterogeneity in health and disease at single cell resolution: progress and perspectives (2022). Cardiovascular Research, cvac018. (abstract

Vujovic, A.*, de Rooij, L.P.M.H.* et al. A two-step in vivo CRISPR-Cas9 screening unveils pervasive RNA-binding protein dependencies for leukemic stem cells and identifies ELAVL1 as a therapeutic target (2022). BioRxiv. (abstract)   

Teuwen, L.A., de Rooij, L.P.M.H. et al. Tumor vessel co-option probed by single-cell analysis (2021). Cell Reports, 35, 109253. (abstract)

Kalucka, J.*, de Rooij, L.P.M.H.*, Goveia, J.* et al. A single cell transcriptome atlas of murine endothelial cells (2020). Cell, 180, 764-779. (abstract)

Goveia, J. et al. An Integrated Gene Expression Landscape Profiling Approach to Identify Lung Tumor Endothelial Cell Heterogeneity and Angiogenic Candidates (2020). Cancer Cell, 37, 21-36. (abstract)

*joint first authorship