Biology subjects

Veltrop, R. J. A.

Publications and source records attributed to Veltrop, R. J. A..

2 recordsLinked to original sources

bioRxiv2026

Polyploid cardiomyocytes define disease-specific transcriptional states in the mammalian heart

The adult mammalian heart has a limited regenerative capacity. Following injury, cardiomyocytes undergo a hypertrophic response accompanied by polyploidization, which has been described as a barrier to proliferation and regeneration of the heart1,2. However, the unique molecular programs of polyploidy, or genome multiplied cardiomyocytes, and their influence on the disease-related myocardial remodelling process remains unclear. Here, we integrate single-nuclei and high-resolution spatial multi-omics across human, rat, and mouse hearts to define novel cardiac cell states and their tissue niches in ischemic and non-ischemic heart disease. Computational analysis across scales allowed us to generate detailed networks of the cardiac tissue remodelling process as well as tissue and sub-cellular environments uniquely enriched in polyploid cardiomyocytes or their diploid origins. We identify a conserved, dichotomous transcriptional program distinguishing diploid from polyploid cardiomyocytes. Polyploid cardiomyocytes demonstrated rewired metabolic and chromatin-remodeling transcriptional programs and recapitulate the gene signature of immature human fetal cardiomyocytes. Notably, we observe that polyploid cardiomyocytes--rather than the general myocyte population--are the primary sites of enrichment for major heart-failure drug targets, including the mineralocorticoid, {beta}1-adrenergic, and glucagon-like peptide-1 receptors. Based on our cross-species dataset we further identified TNIK, a Wnt-pathway regulator expressed in polyploid cardiomyocytes across species, as a potential therapeutic target and demonstrate that pharmacological TNIK inhibition improves cardiac function after myocardial infarction in rats. Together, this species-spanning, disease-resolved study redefines cardiomyocyte heterogeneity in heart disease and suggests a therapeutic path to heart failure treatment by targeting polyploid cardiomyocytes.

genomics↗

bioRxiv2024

Detailed Colocalization Analysis of A- and B-type Nuclear Lamins: a Workflow Using Super-Resolution STED Microscopy and Deconvolution

The inner nuclear membrane is covered by a filamentous network, the nuclear lamina, consisting of A- and B-type lamins as its major components. The A- and B-type lamins form independent but interacting and partially overlapping networks, as demonstrated by previous super-resolution studies. The nuclear lamina in fibroblast cultures derived from laminopathy patients shows an increased segregation of the A- and B-type lamin networks, which can be quantitatively expressed by the Pearsons Correlation Coefficient (PCC). Blurring and noise (convolution), however, significantly affect the quality of microscopy images, which led us to optimize the deconvolution approach for Confocal Scanning Laser Microscopy (CSLM) and Stimulated Emission Depletion (STED) microscopy images. For that purpose, the differences in using a theoretical, experimental, or semi-experimental Point Spread Function (PSF), an important parameter for deconvolution, was evaluated for its use in deconvolution of CSLM and STED microscopy images of double immunolabeled healthy and laminopathy patient fibroblasts. The semi-experimental is a new PSF introduced in this study, which combines the theoretical and experimental PSF to solve issues that arise from noisy PSF recordings due to very small and thereby low intensity fluorescent beads. From these deconvoluted images, the colocalization of the lamin networks could not only be quantified at the level of the nucleus as a whole, but also at a subnuclear level. The latter was achieved by dividing the nucleus into multiple equal rectangles using a custom-made ImageJ macro in Fiji. In this detailed analysis, we found heterogeneity in the colocalization of lamins A/C and B1 within and between nuclei in both healthy and laminopathy dermal fibroblasts, which cannot be detected in one single analysis for the entire nucleus.

cell biology↗