Biology subjects

Goumans, M.-J.

Publications and source records attributed to Goumans, M.-J..

3 recordsLinked to original sources

bioRxiv2025

Multi-omics reveals global signaling rewiring and identifies Activin A-induced dysregulation of FOS/Activator Protein 1 as a novel target in Fibrodysplasia ossificans progressiva

BackgroundFibrodysplasia ossificans progressiva (FOP) is caused by an activating mutation (p.R206H) in the type I BMP receptor ALK2, leading to heterotopic ossification (HO) in soft connective tissues. While aberrant Activin A-induced SMAD signaling is central in FOP pathogenesis, global signaling alterations remain poorly understood. MethodsWe performed phosphoproteomics, transcriptomics and biochemical analyses in mesenchymal cells (MSCs) overexpressing wild-type ALK2WT or mutant ALK2R206H receptors and in induced-MSCs derived from FOP patient iPSCs. Findings were validated in vivo using FOP-like mouse models and in vitro via pharmacological interventions. ResultsMulti-omics analyses revealed previously unrecognized signaling networks in ALK2R206H cells, including enhanced MAPK, mTOR, RUNX2 and RHO-mediated mechanotransduction pathways. Notably, we identified dysregulated Activator Protein-1 (AP-1) expression and function as a novel contributor to FOP. AP-1 factors were highly enriched in HO lesions in FOP-like animals. Pharmacological inhibition of AP-1 significantly reduced osteochondrogenic differentiation in vitro. ConclusionThis study highlights global signaling dysregulation in FOP and identifies AP-1 as a critical driver and potential therapeutic target for FOP.

molecular biology↗

bioRxiv2025

The Brugada syndrome associated gene WT1 impacts on SCN5A expression and cardiac conduction

Brugada syndrome (BrS) is an inherited cardiac arrhythmic disorder caused by conduction slowing primarily affecting the right ventricular (RV) outflow tract (RVOT). A recent genome-wide association study (GWAS) implicated a genomic region in chromosome 11, overlapping the transcription factor WT1, in BrS susceptibility. Here, we investigated the role of WT1 on cardiac conduction using a heterozygous knockout mouse model (Wt1+/-). Transcriptomic analysis revealed increased Scn5a predominantly in Wt1+/- cardiomyocytes located subepicardially in the RV and RVOT without any changes in electrical properties. To unmask an effect on cardiac conduction, we performed optical mapping in a severely challenged setting offered by Scn5a haploinsufficiency, ageing, and exposure to the sodium channel blocker ajmaline and found that diminished Wt1 improved the observed slowed conduction. Examination of human single-nuclei cardiac datasets indicated a strong negative correlation between WT1 and SCN5A expression. In line with this observation, cardiac samples from patients carrying mutations in SCN5A showed increased WT1 protein abundance in histological sections, suggesting that increased WT1, and not loss, is associated with BrS pathophysiology. By deleting the mouse orthologue of a BrS-associated noncoding region (RE) harboring a candidate regulatory element, we established that this RE controls expression of Wt1 specifically in the (sub)epicardium of the RV. Lastly, transient overexpression of WT1 in hiPSC-derived cardiomyocytes resulted in notably reduced sodium current density. Our study thereby identifies the transcription factor WT1 as a novel contributor to the pathophysiology of BrS, at least in part, through SCN5A.

genetics↗

bioRxiv2020

Prrx1b directs pro-regenerative fibroblasts during zebrafish heart regeneration

RationaleThe human heart loses millions of cardiomyocytes after an ischemic injury, but is unable to regenerate the lost tissue. Instead, the injured human heart is repaired by pro-fibrotic fibroblasts that form a large permanent scar. In contrast, the injured zebrafish heart regenerates efficiently without the formation of a permanent scar. While fibroblasts have been shown to be indispensable for zebrafish heart regeneration, very little is known about the mechanisms balancing the fibrotic and regenerative response. A better understanding of these mechanisms could lead to the discovery of novel therapeutic strategies to reduce fibrosis and promote heart regeneration. ObjectiveTo identify novel mechanisms that regulate the balance between cardiac fibrosis and scar-free regeneration. Methods and ResultsUsing a genetic approach, we first show that zebrafish prrx1b loss-of-function mutants display reduced cardiomyocyte proliferation and impaired heart regeneration. Using a lineage tracing approach, we show that Prrx1b is expressed in tcf21+ epicardial-derived cells localizing around and inside the injured area. Next, we used a single cell RNA-sequencing approach on sorted tcf21+ cells isolated from injured prrx1b-/- and wild-type hearts and identified two distinct fibroblast populations. With combined bioinformatic and histological analysis we found that prrx1b-/- hearts contain an excess of pro-fibrotic fibroblasts that produce TGF-{beta} ligands and collagens, while fewer pro-regenerative Nrg1-expressing fibroblasts are formed. Furthermore, by injecting recombinant NRG1 in prrx1b-/- fish we were able to rescue their cardiomyocyte proliferation defect. Finally, using cultured human fetal epicardial cells and siRNA mediated knock-down of PRRX1 we found that PRRX1 is required for NRG1 induction in human epicardial-derived cells. ConclusionsPrrx1b in the injured heart restricts fibrosis and stimulates regeneration by directing epicardial-derived cells towards a pro-regenerative Nrg1-producing fibroblast state.

developmental biology↗