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Updated: May 8, 2026
Generation of First Heart Field-like Cardiac Progenitors and Ventricular-like Cardiomyocytes from Human Pluripotent Stem Cells
Published on: June 19, 2018
Driving vascular endothelial cell fate of human multipotent Isl1+ heart progenitors with VEGF modified mRNA
Kathy O Lui1, Lior Zangi, Eduardo A Silva
11] Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA [2] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 01238, USA [3] Stem Cell and Regenerative Medicine Consortium, LKS Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong SAR, China.
Insights
Vascular endothelial growth factor-A (VEGF-A) drives endothelial cell fate in heart progenitors. This discovery enables enhanced vascular regeneration strategies for the heart using stem cell-derived endothelial cells.
Area of Science:
- Cardiovascular Biology
- Stem Cell Biology
- Regenerative Medicine
Background:
- Multipotent heart progenitors generate diverse cardiac lineages during mammalian cardiogenesis.
- Identifying paracrine signals and delivery methods is key for regenerative therapies.
- Human cardiac endothelial intermediates (OFT-ECs) coexpress Isl1 and CD144/vWF.
Purpose of the Study:
- Identify paracrine signals regulating cell-fate decisions of heart progenitors.
- Develop novel in vivo methods for delivering these signals.
- Investigate VEGF-A's role in endothelial specification and therapeutic potential.
Main Methods:
- Identified human outflow tract endothelial cells (OFT-ECs) expressing Isl1 and CD144/vWF.
- Compared angiocrine factors from OFT-ECs and non-cardiac ECs.
- Utilized clonal assays and chemically modified mRNA for VEGF-A delivery.
- Differentiated human embryonic stem cell (ESC)-derived Isl1+ progenitors into human Isl1-ECs.
Main Results:
- VEGF-A was the most abundant factor expressed by OFT-ECs.
- VEGF-A drives endothelial specification of ESC-derived Isl1+ progenitors via VEGF receptor.
- Human Isl1-ECs exhibit organ specificity, resembling OFT-ECs.
- VEGF-A overexpression promotes endothelial specification, engraftment, proliferation, and survival of Isl1+ progenitors in vivo.
Conclusions:
- VEGF-A acts as an in vivo cell-fate switch for human ESC-derived Isl1+ progenitors.
- Chemically modified mRNA enables efficient transient expression of paracrine factors.
- Large-scale derivation of cardiac-specific Isl1-ECs offers a novel strategy for cardiac vascular regeneration.
Abstract:
Distinct families of multipotent heart progenitors play a central role in the generation of diverse cardiac, smooth muscle and endothelial cell lineages during mammalian cardiogenesis. The identification of precise paracrine signals that drive the cell-fate decision of these multipotent progenitors, and the development of novel approaches to deliver these signals in vivo, are critical steps towards unlocking their regenerative therapeutic potential. Herein, we have identified a family of human cardiac endothelial intermediates located in outflow tract of the early human fetal hearts (OFT-ECs), characterized by coexpression of Isl1 and CD144/vWF. By comparing angiocrine factors expressed by the human OFT-ECs and non-cardiac ECs, vascular endothelial growth factor (VEGF)-A was identified as the most abundantly expressed factor, and clonal assays documented its ability to drive endothelial specification of human embryonic stem cell (ESC)-derived Isl1+ progenitors in a VEGF receptor-dependent manner. Human Isl1-ECs (endothelial cells differentiated from hESC-derived ISL1+ progenitors) resemble OFT-ECs in terms of expression of the cardiac endothelial progenitor- and endocardial cell-specific genes, confirming their organ specificity. To determine whether VEGF-A might serve as an in vivo cell-fate switch for human ESC-derived Isl1-ECs, we established a novel approach using chemically modified mRNA as a platform for transient, yet highly efficient expression of paracrine factors in cardiovascular progenitors. Overexpression of VEGF-A promotes not only the endothelial specification but also engraftment, proliferation and survival (reduced apoptosis) of the human Isl1+ progenitors in vivo. The large-scale derivation of cardiac-specific human Isl1-ECs from human pluripotent stem cells, coupled with the ability to drive endothelial specification, engraftment, and survival following transplantation, suggest a novel strategy for vascular regeneration in the heart.
