Biomedical subjects

Marion J Gijbels

Publications and source records attributed to Marion J Gijbels.

4 recordsLinked to original sources

PubMed2026

Atherosclerotic plaque fibroblasts derive from adventitial and medial Pdgfra-lineage-positive cells and predominantly maintain fibroblast identity.

AIMS: Fibroblasts are mesenchymal cells in the healthy vascular adventitia. In atherosclerosis, single-cell sequencing datasets suggest fibroblasts are abundant in plaques. However, their identity, origin, and fate during plaque progression remain unclear, which we aim to unravel here. APPROACH AND RESULTS: To robustly define fibroblast identity, origin, and fate, we employed meta-analyses of 54 single-cell RNA sequencing libraries, including murine smooth muscle cell (Myh11) and endothelial cell (EC) (Cdh5) lineage reporter mice with and without atherosclerosis; human control and atherosclerotic arteries; and murine adventitia and atherosclerotic plaques processed separately from low-density lipoprotein (LDL) receptor knockout (Ldlr-/-) mice. These meta-analyses showed that murine and human plaque fibroblast identity was robustly defined by Pdgfra, Pi16, Cygb, and Serpinf1 mRNA. Ninety-five percent of plaque fibroblasts do not derive from the Myh11 lineage, while no Cdh5-lineage-positive cells were present in the fibroblast cluster. We identified five murine arterial fibroblast subsets in atherosclerotic murine aorta: progenitor fibroblasts, matrix fibroblasts, inflammatory fibroblasts, an EC-like fibroblast subset, detected in both adventitia and plaques, and Col5a3+ fibroblasts, unique to the adventitia. We next studied fibroblast identity, origin, and fate using pseudotime analysis and Pdgfra-CreERT2/tdTomato lineage reporter mice (Pdgfra Lin+). Healthy Pdgfra Lin+ reporter mice showed predominant adventitial tdTomato expression, and infrequent medial and intimal Pdgfra Lin+ cells co-expressing MYH11 and PECAM1, respectively. The Pdgfra Lin+ plaque area increased with diet duration. Pdgfra Lin+ cells largely maintain fibroblast identity in the plaque, while <10% co-express SMC markers (MYH11, SM22α), or contribute to ACTA2+ cap cells. ECs gaining mesenchymal markers are transcriptionally distinct from Cdh5-lineage-negative fibroblasts gaining EC markers. Plaque-resident EC-like fibroblasts displayed a mesenchymal-to-endothelial transition transcriptome, which was induced in human primary fibroblasts in vitro by starvation, and dampened or reversed by IL1B, TGFB1, TGFB3, and oxidized LDL. Cross-species integration showed that all murine plaque fibroblasts were conserved in human atherosclerosis, with one additional subset partially resembling murine subsets, and three human-specific subsets. Importantly, human fibroblast subsets differentially correlated to human plaque traits, with EC-like fibroblasts correlating to plaque instability. CONCLUSION: Our results indicate that 95% of plaque-residing fibroblasts are Myh11 Lin- Plaque fibroblasts have a dual origin, predominantly adventitial Pdgfra Lin+ progenitor fibroblasts, with a minor contribution from medial Pdgfra Lin+  Myh11+ SMCs. Most plaque fibroblasts maintain fibroblast identity. Murine plaque fibroblast subsets were conserved in human atherosclerosis. EC-like fibroblasts are linked to human plaque instability. Intervening in progenitor-to-specific fibroblast transitions could present a new avenue to promote plaque stability in atherosclerosis.

Atherosclerosis↗

PubMed2005

Early diet-induced non-alcoholic steatohepatitis in APOE2 knock-in mice and its prevention by fibrates.

BACKGROUND/AIMS: The molecular mechanisms leading to Non-Alcoholic Steatohepatitis (NASH) are not fully understood. In mice, NASH can be inhibited by fenofibrate, a synthetic agonist for the nuclear receptor peroxisome proliferator activated receptor alpha, which regulates hepatic triglyceride metabolism. This study aimed to elucidate the relation between steatosis and inflammation in NASH in a human-like hyperlipidemic mouse model. METHODS: Liver phenotype and gene expression were assessed in APOE2 knock-in mice that were fed a western-type high fat diet with or without co-administration of fenofibrate. RESULTS: In response to a western diet, APOE2 knock-in mice developed NASH characterized by steatosis and inflammation. Strikingly, macrophage accumulation in the liver preceded the steatosis during progression of the disease. This phenotype was in line with gene expression patterns, which showed regulation of two major groups of genes, i.e. inflammatory and lipid genes. Fenofibrate treatment decreased hepatic macrophage accumulation and abolished steatosis. Moreover, a marked reduction in the expression of inflammatory genes occurred immediately after fenofibrate treatment. CONCLUSIONS: These data indicate that inflammation might play an instrumental role during the development of NASH in this mouse model. Inhibition of NASH by fenofibrate may be due, at least in part, to its inhibitory effect on pro-inflammatory genes.

ATP-Binding Cassette Transporters↗

PubMed2005

Hydrophobicity as a design criterion for polymer scaffolds in bone tissue engineering.

Porous polymeric scaffolds play a key role in most tissue-engineering strategies. A series of non-degrading porous scaffolds was prepared, based on bulk-copolymerisation of 1-vinyl-2-pyrrolidinone (NVP) and n-butyl methacrylate (BMA), followed by a particulate-leaching step to generate porosity. Biocompatibility of these scaffolds was evaluated in vitro and in vivo. Furthermore, the scaffold materials were studied using the so-called demineralised bone matrix (DBM) as an evaluation system in vivo. The DBM, which is essentially a part of a rat femoral bone after processing with mineral acid, provides a suitable environment for ectopic bone formation, provided that the cavity of the DBM is filled with bone marrow prior to subcutaneous implantation in the thoracic region of rats. Various scaffold materials, differing with respect to composition and, hence, hydrophilicity, were introduced into the centre of DBMs. The ends were closed with rat bone marrow, and ectopic bone formation was monitored after 4, 6, and 8 weeks, both through X-ray microradiography and histology. The 50:50 scaffold particles were found to readily accommodate formation of bone tissue within their pores, whereas this was much less the case for the more hydrophilic 70:30 counterpart scaffolds. New healthy bone tissue was encountered inside the pores of the 50:50 scaffold material, not only at the periphery of the constructs but also in the center. Active osteoblast cells were found at the bone-biomaterial interfaces. These data indicate that the hydrophobicity of the biomaterial is, most likely, an important design criterion for polymeric scaffolds which should promote the healing of bone defects. Furthermore, it is argued that stable, non-degrading porous biomaterials, like those used in this study, provide an important tool to expand our comprehension of the role of biomaterials in scaffold-based tissue engineering approaches.

3T3 Cells↗

PubMed2003

Atherosclerotic plaque rupture: local or systemic process?

It is generally established that the unstable plaque is the major cause of acute clinical sequelae of atherosclerosis. Unfortunately, terms indicating lesions prone to plaque instability, such as "vulnerable plaque," and the different phenotypes of unstable plaques, such as plaque rupture, plaque fissuring, intraplaque hemorrhage, and erosion, are often used interchangeably. Moreover, the different phenotypes of the unstable plaque are mostly referred to as plaque rupture. In the first part of this review, we will focus on the definition of true plaque rupture and the definitions of other phenotypes of plaque instability, especially on intraplaque hemorrhage, and discuss the phenotypes of available animal models of plaque instability. The second part of this review will address the pathogenesis of plaque rupture from a local and a systemic perspective. Plaque rupture is thought to occur because of changes in the plaque itself or systemic changes in the patient. Interestingly, contributing factors seem to overlap to a great extent and might even be interrelated. Finally, we will propose an integrative view on the pathogenesis of plaque rupture.

Animals↗