Biology subjects

Deelen, L.

Publications and source records attributed to Deelen, L..

3 recordsLinked to original sources

bioRxiv2025

Stem cell-derived cardiomyocyte migration through TGF-β signalling in the context of myocardial infarction

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) hold significant promise for cardiac regeneration therapies. However, the efficacy of such treatments depends on the ability of transplanted cells to migrate and integrate into the damaged myocardium, a process that remains poorly understood. In this study, we investigated the migratory behaviour of hiPSC-CMs using homogenised rat MI tissue to simulate myocardial infarction (MI) in vitro. Transwell migration assays demonstrated a concentration-dependent chemotactic response, with hiPSC-CM migration increasing up to threefold toward MI tissue homogenate. Wound healing assays further confirmed enhanced migration under MI-mimetic conditions. Bulk RNA sequencing revealed activation of the TGF-{beta} signalling pathway as a key regulator of this response. Inhibition of TGF-{beta} signalling, both pharmacologically and through antibody neutralisation, significantly reduced hiPSC-CM migration. These findings uncover a previously underappreciated chemotactic capability of hiPSC-CMs and identify TGF-{beta} signalling as a central mediator, offering new mechanistic insights and potential therapeutic targets to improve the integration and efficacy of hiPSC-CM-based cardiac regeneration strategies.

cell biology↗

bioRxiv2025

Human-specific transposable elements shaped the evolution of craniofacial development through regulation of neural crest migration

Craniofacial development is evolutionarily conserved, yet subtle changes in its regulatory network drive species-specific traits. Transposable elements (TEs) contribute to genome evolution, but their role in cranial neural crest cells (CNCCs) remains unclear. Here, we investigate the domestication of hominoid-specific TEs (LTR5Hs and SVAs) as enhancers during human CNCC specification, a process critical for vertebrate craniofacial development. Using human iPSC-derived CNCCs, we identified [~]550 hominoid-specific TEs functioning as enhancers, including [~]250 human-specific, predominantly LTR5Hs. These elements are enriched for CNCC coordinator motifs, are bound by the CNCC signature factor TWIST1, and their enhancer activity appears largely CNCC-specific. CRISPR-interference targeting [~]75% of these active TEs led to widespread transcriptional dysregulation of genes involved in neural crest migration, and two orthogonal functional assays confirmed that CNCC migration is impaired upon TE repression. Finally, genes near human-specific TEs showed higher expression in human CNCCs compared to chimpanzee CNCCs, but TE repression restored gene expression to chimpanzee levels. These findings highlight how young TEs were domesticated to fine-tune CNCC regulatory networks, potentially contributing to lineage-specific craniofacial evolution.

genomics↗

bioRxiv2025

CHD3 regulates BMP signalling response during cranial neural crest cell specification

CHD3 is a component of the NuRD chromatin remodeling complex. Pathogenic CHD3 variants cause Snijders Blok-Campeau Syndrome, a neurodevelopmental disorder with variable features including developmental delays, intellectual disability, speech/language difficulties, and craniofacial anomalies. To unveil the role of CHD3 in craniofacial development, we differentiated CHD3-KO induced pluripotent stem cells into cranial neural crest cells (CNCCs). CHD3 expression is low in wild-type iPSCs and neuroectoderm, but upregulated during CNCC specification, where it opens the chromatin at BMP-responsive enhancers, to allow binding of DLX5 and other factors. CHD3 loss leads to repression of BMP target genes and an imbalance between BMP and Wnt signalling, ultimately resulting in aberrant mesodermal fate. Consequently, CNCC specification fails, replaced by early-mesoderm identity, which can be partially rescued by titrating Wnt levels. Our findings highlight a novel role for CHD3 as a pivotal regulator of BMP signalling, essential for proper neural crest specification and craniofacial development.

developmental biology↗