STRA6 is essential for induction of vascular smooth muscle lineages in human embryonic cardiac outflow tract development

Abstract

Aims Retinoic acid (RA) signaling is essential for heart development, and dysregulation of the RA signaling can cause several types of cardiac outflow tract (OFT) defects, the most frequent congenital heart disease (CHD) in humans. Matthew-Wood syndrome is caused by inactivating mutations of a transmembrane protein gene STRA6 that transports vitamin A (retinol) from extracellular into intracellular spaces. This syndrome shows a broad spectrum of malformations including CHD, although murine Stra6-null neonates did not exhibit overt heart defects. Thus, the detailed mechanisms by which STRA6 mutations could lead to cardiac malformations in humans remain unclear. Here, we investigated the role of STRA6 in the context of human cardiogenesis and CHD. Methods and Results To gain molecular signatures in species-specific cardiac development, we first compared single-cell RNA sequencing (RNA-seq) datasets, uniquely obtained from human and murine embryonic hearts. We found that while STRA6 mRNA was much less frequently expressed in murine embryonic heart cells derived from the Mesp1+ lineage tracing mice (Mesp1Cre/+; Rosa26tdTomato), it was expressed predominantly in the OFT region-specific heart progenitors in human developing hearts. Next, we revealed that STRA6-knockout human embryonic stem cells (hESCs) could differentiate into cardiomyocytes similarly to wild-type hESCs, but could not differentiate properly into mesodermal nor neural crest cell-derived smooth muscle cells (SMCs) in vitro. This is supported by the population RNA-seq data showing downregulation of the SMC-related genes in the STRA6-knockout hESC-derived cells. Further, through machinery assays, we identified the previously unrecognized interaction between RA nuclear receptors RARα/RXRα and TBX1, an OFT-specific cardiogenic transcription factor, which would likely act downstream to STRA6-mediated RA signaling in human cardiogenesis. Conclusion Our study highlights a critical role of human-specific STRA6 progenitors for proper induction of vascular SMCs that is essential for normal OFT formation. Thus, these results shed light on novel and human-specific CHD mechanisms, driven by STRA6 mutations. Translational Perspectives Dysregulation of the RA signaling can cause cardiac OFT defects, however, the detailed mechanisms by which STRA6 mutations lead to cardiac malformations have remained unclear. Our study highlights a critical role of human-specific STRA6 progenitors for proper induction of vascular SMCs that is essential for normal OFT formation. These results shed light on novel and human-specific CHD programs, driven by STRA6 mutations. Thus, our study paves the way for further studies of deciphering the origins and the disease mechanisms of a rare genetic disorder Matthew-Wood syndrome, which would help us develop diagnosis, prevention, and novel treatment for the disease.

Placental growth factor exerts a dual function for cardiomyogenesis and vasculogenesis during heart development

“…Therefore, these attempts are still in their infancy and far from clinical application 3 , 4 . On the other hand, recent sophisticated single-cell omics studies of in vitro human embryonic stem cell (hESC)-derived cardiac cells and in vivo human embryonic heart cells have uncovered cellular heterogeneity and molecular signatures, and identified previously unrecognized heart progenitors and cardiogenic molecules that would play certain roles in developing hearts 5 – 7 . In fact, a wide variety of paracrine mediators, such as growth factors, cytokines/chemokines, and secreted proteins, play important roles in heart development through regulating the differentiation and proliferation of cardiac progenitors and their progeny cells 8 , 9 .…”

ZNF714 Supports Pro-Oncogenic Features in Lung Cancer Cells

“…Another upregulated and demethylated gene in H2073 cells, STRA6, was reported as an oncogene [24,25], supporting the maintenance of cancer stem cell characteristics [48]. However, it was also shown to contribute to the p53-dependant apoptosis [26] and retinoic acid-induced differentiation pathways [49][50][51]. Thus, the exact role of STRA6 in cancer and stem cells remains to be fully elucidated.…”

In-Depth Genomic Analysis: The New Challenge in Congenital Heart Disease

“…Additional pathways and gene networks involved in cardiac neural crest differentiation have been discovered. In mice, the normal differentiation of cardiac neural crest cells is prevented in the absence of retinoic acid signalling [63], which can be ameliorated by maternal vitamin A supplementation [64]. This highlights the genotype-environment interactions in CHD.…”