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Updated: Mar 11, 2026
In Vitro Generation of Heart Field-specific Cardiac Progenitor Cells
Published on: July 3, 2019
Cyp26 Enzymes Facilitate Second Heart Field Progenitor Addition and Maintenance of Ventricular Integrity
Ariel B Rydeen1,2, Joshua S Waxman1
1Molecular Cardiovascular Biology Division and Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
Abstract:
Although retinoic acid (RA) teratogenicity has been investigated for decades, the mechanisms underlying RA-induced outflow tract (OFT) malformations are not understood. Here, we show zebrafish embryos deficient for Cyp26a1 and Cyp26c1 enzymes, which promote RA degradation, have OFT defects resulting from two mechanisms: first, a failure of second heart field (SHF) progenitors to join the OFT, instead contributing to the pharyngeal arch arteries (PAAs), and second, a loss of first heart field (FHF) ventricular cardiomyocytes due to disrupted cell polarity and extrusion from the heart tube. Molecularly, excess RA signaling negatively regulates fibroblast growth factor 8a (fgf8a) expression and positively regulates matrix metalloproteinase 9 (mmp9) expression. Although restoring Fibroblast growth factor (FGF) signaling can partially rescue SHF addition in Cyp26 deficient embryos, attenuating matrix metalloproteinase (MMP) function can rescue both ventricular SHF addition and FHF integrity. These novel findings indicate a primary effect of RA-induced OFT defects is disruption of the extracellular environment, which compromises both SHF recruitment and FHF ventricular integrity.
Insights
Retinoic acid (RA) excess causes heart defects by disrupting the extracellular environment. This impairs progenitor cell addition and heart tube integrity, revealing new mechanisms of RA teratogenicity.
Area of Science:
- Developmental biology
- Cardiovascular research
- Teratology
Background:
- Retinoic acid (RA) teratogenicity is a long-standing concern, but its precise mechanisms causing outflow tract (OFT) malformations remain unclear.
- Understanding RA's impact on early heart development is crucial for identifying potential therapeutic targets.
Purpose of the Study:
- To elucidate the molecular mechanisms by which excess retinoic acid signaling leads to congenital heart defects, specifically OFT malformations.
- To investigate the roles of Cyp26 enzymes, fibroblast growth factor 8a (FGF8a), and matrix metalloproteinase 9 (MMP9) in RA-induced cardiac abnormalities.
Main Methods:
- Utilized zebrafish embryos with deficiencies in Cyp26a1 and Cyp26c1 enzymes to elevate endogenous RA levels.
- Analyzed the contribution of second heart field (SHF) progenitors and the integrity of first heart field (FHF) ventricular cardiomyocytes.
- Investigated the molecular regulation of fgf8a and mmp9 expression in response to altered RA signaling.
Main Results:
- Zebrafish embryos with impaired RA degradation exhibited OFT defects, including failed SHF progenitor addition to the OFT and FHF cardiomyocyte loss.
- Excess RA signaling was found to downregulate fgf8a expression and upregulate mmp9 expression.
- Restoring FGF signaling partially rescued SHF addition, while inhibiting MMP function rescued both SHF addition and FHF integrity.
Conclusions:
- RA-induced OFT defects primarily result from disruption of the extracellular environment.
- This disruption compromises both the recruitment of SHF progenitors and the structural integrity of FHF cardiomyocytes.
- Targeting MMP activity presents a potential strategy to mitigate RA-induced cardiac malformations.
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