Tissue microenvironment dictates the state of human iPSC-derived endothelial cells of distinct developmental origin in 3D cardiac microtissues

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Xu Cao - , Leiden University Medical Centre (LUMC) (Author)
  • Maria Mircea - , Leiden University (Author)
  • Sara Cascione - , Leiden University Medical Centre (LUMC) (Author)
  • Atoosa Amel - , Leiden University Medical Centre (LUMC) (Author)
  • Theano Tsikari - , Leiden University Medical Centre (LUMC) (Author)
  • Francijna E van den Hil - , Leiden University Medical Centre (LUMC) (Author)
  • Hailiang Mei - , Leiden University Medical Centre (LUMC) (Author)
  • Katrin Neumann - , Genetic Engineering of Stem Cells (Research Group) (Author)
  • Anna Alemany - , Leiden University Medical Centre (LUMC) (Author)
  • Konstantinos Anastassiadis - , Genetic Engineering of Stem Cells (Research Group) (Author)
  • Christine L Mummery - , Leiden University Medical Centre (LUMC) (Author)
  • Stefan Semrau - , Leiden University (Author)
  • Valeria V Orlova - , Leiden University Medical Centre (LUMC) (Author)

Abstract

Each tissue and organ in the body has its own type of vasculature. Here, we demonstrate that organotypic vasculature for the heart can be recreated in a three-dimensional cardiac microtissue (MT) model composed of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs), cardiac fibroblasts (CFs), and endothelial cells (ECs). ECs in cardiac MTs upregulated expression of markers enriched in human intramyocardial ECs, including CD36, CLDN5, APLNR, NOTCH4, IGFBP3, and ARHGAP18. We further show that the local microenvironment largely dictates the organ-specific identity of hiPSC-derived ECs: we compared ECs derived from cardiac and paraxial mesoderm and found that, regardless of origin, they acquired similar identities upon integration into cardiac MTs. Overall, the results indicated that while the initial gene profile of ECs was dictated by developmental origin, this could be modified by the local tissue environment. This developmental "plasticity" in ECs has implications for multiple pathological and disease states.

Details

Original languageEnglish
Article number113611
JournaliScience
Volume28
Issue number10
Publication statusPublished - 17 Oct 2025
Peer-reviewedYes

External IDs

PubMedCentral PMC12546991
Scopus 105017881651

Keywords

DFG Classification of Subject Areas according to Review Boards

Sustainable Development Goals

Keywords

  • Developmental biology, Transcriptomics, Stem cells research