Biology subjects

Visser, N.

Publications and source records attributed to Visser, N..

5 recordsLinked to original sources

bioRxiv2024

Phthalate monoesters affect membrane fluidity and cell-cell contacts in endometrial stromal cell lines

Phthalate monoesters have been identified as endocrine disruptors in a variety of models, yet understanding of their exact mechanisms of action and molecular targets in cells remains incomplete. Here, we set to determine whether epidemiologically relevant mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) can affect biological processes by altering cell plasma membrane fluidity or formation of cell-cell contacts. As a model system, we chose endometrial stromal cell lines, one of which was previously used in a transcriptomic study with MEHHP or MEHHP-containing mixtures. A short-term exposure (1 h) of membrane preparations to endocrine disruptors was sufficient to induce changes in membrane fluidity/rigidity, whereas different mixtures showed different effects at various depths of the bilayer. A longer exposure (96 h) affected the ability of cells to form spheroids and highlighted issues with membrane integrity in loosely assembled spheroids. Finally, in spheroids assembled from T-HESC cells, MEHHP interfered with the formation of tight junctions as indicated by the immunostaining of zonula occludens 1 protein. Overall, this study emphasized the need to consider plasma membrane, membrane-bound organelles, and secretory vesicles as possible biological targets of endocrine disruptors and offered an explanation for a multitude of endocrine disruptor roles documented earlier.

pharmacology and toxicology↗

bioRxiv2023

Galectin-9 has non-apoptotic cytotoxic activity towards Acute Myeloid Leukemia independent of cytarabine resistance

Acute myeloid leukemia (AML) is a malignancy still associated with poor survival rates, among others due to frequent occurrence of therapy-resistant relapse after standard-of-care treatment with cytarabine (AraC). AraC triggers apoptotic cell death, a type of cell death to which AML cells often become resistant. Therefore, therapeutic options that trigger an alternate type of cell death are of particular interest. We previously identified that the glycan-binding protein Galectin-9 (Gal-9) has tumor-selective and non-apoptotic cytotoxicity towards various types of cancer, which depended on autophagy inhibition. Thus, Gal-9 could be of therapeutic interest for (AraC-resistant) AML. In the current study, treatment with Gal-9 was cytotoxic for AML cells, including for CD34+ patient-derived AML stem cells, but not for healthy cord blood-derived CD34+ stem cells. This Gal-9-mediated cytotoxicity did not rely on apoptosis but negatively associated with autophagic flux. Importantly, both AraC-sensitive and -resistant AML cell lines as well as AML patient samples were sensitive to single agent treatment with Gal-9. Additionally, Gal-9 potentiated the cytotoxic effect of DNA demethylase inhibitor Azacytidine (Aza), a drug that is clinically used for patients that are not eligible for intensive AraC treatment. Thus, Gal-9 is a potential therapeutic agent for the treatment of AML, including AraC resistant AML, by inducing caspase-independent cell death.

cancer biology↗

bioRxiv2022

Human commensal Candida albicans strains demonstrate substantial within-host diversity and retained pathogenic potential

Candida albicans is a frequent colonizer of human mucosal surfaces as well as an opportunistic pathogen. C. albicans is remarkably versatile in its ability to colonize diverse host sites with differences in oxygen and nutrient availability, pH, immune responses, and resident microbes, among other cues. It is unclear how the genetic background of a commensal colonizing population can influence the shift to pathogenicity. Therefore, we undertook an examination of commensal isolates from healthy donors with a goal of identifying site-specific phenotypic adaptation and genetic variation associated with these phenotypes. We demonstrate that healthy people are reservoirs for genotypically and phenotypically diverse C. albicans strains, and that this genetic diversity includes both SNVs and structural rearrangements. Using limited diversity exploitation, we identified a single nucleotide change in the uncharacterized ZMS1 transcription factor that was sufficient to drive hyper invasion into agar. However, our commensal strains retained the capacity to cause disease in systemic models of infection, including outcompeting the SC5314 reference strain during systemic competition assays. This study provides a global view of commensal strain variation and within-host strain diversity of C. albicans and suggests that selection for commensalism in humans does not result in a fitness cost for invasive disease.

microbiology↗

bioRxiv2022

M2-polarized macrophages control LSC fate by enhancing stemness, homing, immune evasion and metabolic reprogramming

While it is increasingly becoming clear that cancers are a symbiosis of diverse cell types and tumor clones, the tumor microenvironment (TME) in acute myeloid leukemias (AML) remains poorly understood. Here, we uncover the functional and prognostic relevance of an M2-polarized macrophage compartment. Intra bone marrow co-injection of M2d-macrophages together with leukemic blasts that fail to engraft on their own now induce fatal leukemia in mice. Even a short-term two-day in vitro exposure to M2d macrophages can "train" leukemic blasts after which cells are protected against phagocytosis, display increased mitochondrial metabolism and improved in vivo homing, resulting in full-blown leukemia. Single-cell RNAseq analysis of AML associated macrophages revealed metabolic-related pathways such as Fatty Acid Oxidation and NAD+ generation as therapeutical targetable vulnerabilities. Our study provides insight into the mechanisms by which the immune landscape contributes to aggressive leukemia development and provides alternatives for effective targeting strategies.

cancer biology↗

bioRxiv2019

Regulation of heterotopic ossification through local inflammatory monocytes in a mouse model of aberrant wound healing

Heterotopic ossification (HO) is an aberrant regenerative process with ectopic bone induction in response to musculoskeletal trauma, in which mesenchymal stem cells (MSC) differentiate into osteochondrogenic cells instead of myocytes or tenocytes. Despite frequent cases of hospitalized musculoskeletal trauma, the inflammatory responses and cell population dynamics that regulate subsequent wound healing and tissue regeneration are still unclear. Here we examine, using a mouse model of trauma-induced HO, the local microenvironment of the initial post-injury inflammatory response. Single cell transcriptome analyses identify distinct monocyte/macrophage populations at the injury site, with their dynamic changes over time elucidated using trajectory analyses. Mechanistically, transforming growth factor beta-1 (TGF{beta}1)-producing monocytes/macrophages are associated with HO and aberrant chondrogenic progenitor cell differentiation, while CD47-activating peptides that reduce systemic TGF{beta} levels help ameliorate HO. Our data thus implicate CD47 activation as a novel therapeutic approach for modulating monocyte/macrophage phenotypes, MSC differentiation and HO formation during wound healing.

immunology↗