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

Nevin Witman, Chikai Zhou, Timm Häneke, Yao Xiao, Xiaoting Huang, Eduarde Rohner, Jesper Sohlmér, Niels Grote Beverborg, Miia L. Lehtinen, Kenneth R. Chien () and Makoto Sahara ()
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Nevin Witman: Karolinska Institutet
Chikai Zhou: Karolinska Institutet
Timm Häneke: Karolinska Institutet
Yao Xiao: Karolinska Institutet
Xiaoting Huang: Karolinska Institutet
Eduarde Rohner: Karolinska Institutet
Jesper Sohlmér: Karolinska Institutet
Niels Grote Beverborg: Karolinska Institutet
Miia L. Lehtinen: Karolinska Institutet
Kenneth R. Chien: Karolinska Institutet
Makoto Sahara: Karolinska Institutet

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Cardiogenic growth factors play important roles in heart development. Placental growth factor (PLGF) has previously been reported to have angiogenic effects; however, its potential role in cardiogenesis has not yet been determined. We analyze single-cell RNA-sequencing data derived from human and primate embryonic hearts and find PLGF shows a biphasic expression pattern, as it is expressed specifically on ISL1+ second heart field progenitors at an earlier stage and on vascular smooth muscle cells (SMCs) and endothelial cells (ECs) at later stages. Using chemically modified mRNAs (modRNAs), we generate a panel of cardiogenic growth factors and test their effects on enhancing cardiomyocyte (CM) and EC induction during different stages of human embryonic stem cell (hESC) differentiations. We discover that only the application of PLGF modRNA at early time points of hESC-CM differentiation can increase both CM and EC production. Conversely, genetic deletion of PLGF reduces generation of CMs, SMCs and ECs in vitro. We also confirm in vivo beneficial effects of PLGF modRNA for development of human heart progenitor-derived cardiac muscle grafts on murine kidney capsules. Further, we identify the previously unrecognized PLGF-related transcriptional networks driven by EOMES and SOX17. These results shed light on the dual cardiomyogenic and vasculogenic effects of PLGF during heart development.

Date: 2023
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DOI: 10.1038/s41467-023-41305-7

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