Cardioids reveal self-organizing principles of human cardiogenesis

Cell. 2021 Jun 10;184(12):3299-3317.e22. doi: 10.1016/j.cell.2021.04.034. Epub 2021 May 20.

Abstract

Organoids capable of forming tissue-like structures have transformed our ability to model human development and disease. With the notable exception of the human heart, lineage-specific self-organizing organoids have been reported for all major organs. Here, we established self-organizing cardioids from human pluripotent stem cells that intrinsically specify, pattern, and morph into chamber-like structures containing a cavity. Cardioid complexity can be controlled by signaling that instructs the separation of cardiomyocyte and endothelial layers and by directing epicardial spreading, inward migration, and differentiation. We find that cavity morphogenesis is governed by a mesodermal WNT-BMP signaling axis and requires its target HAND1, a transcription factor linked to developmental heart chamber defects. Upon cryoinjury, cardioids initiated a cell-type-dependent accumulation of extracellular matrix, an early hallmark of both regeneration and heart disease. Thus, human cardioids represent a powerful platform to mechanistically dissect self-organization, congenital heart defects and serve as a foundation for future translational research.

Keywords: cardiac injury model; cardiac organoid; cardioids; congenital heart defects; heart development; heart organoid; human pluripotent stem cells; mesoderm; self-organization; self-organizing organoids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activins / metabolism
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Bone Morphogenetic Proteins / metabolism
  • Calcium / metabolism
  • Cell Line
  • Cell Lineage
  • Chickens
  • Endothelial Cells / cytology
  • Extracellular Matrix Proteins / metabolism
  • Female
  • Fibroblasts / cytology
  • Heart / embryology*
  • Homeobox Protein Nkx-2.5 / metabolism
  • Humans
  • Male
  • Mesoderm / embryology
  • Models, Biological
  • Myocardium / metabolism
  • Organogenesis*
  • Organoids / embryology*
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / metabolism
  • Vascular Endothelial Growth Factor A / metabolism
  • Wnt Proteins / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Bone Morphogenetic Proteins
  • Extracellular Matrix Proteins
  • Homeobox Protein Nkx-2.5
  • NKX2-5 protein, human
  • Vascular Endothelial Growth Factor A
  • Wnt Proteins
  • helix-loop-helix protein, eHAND
  • Activins
  • Calcium