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Cardiogenesis is a highly dynamic process relying on the precise spatiotemporal coordination of progenitor cell populations. Understanding the specification of these progenitors during early human development is crucial for advancing our knowledge of congenital cardiac malformations. Here, we used a combination of genetic labeling, cell sorting, and bulk and single-cell transcriptional profiling to thoroughly characterize various mesodermal progenitor pools and their definitive progenies emerging during cardiac differentiation of human pluripotent stem cells., Die Herzentwicklung ist ein hochdynamischer Prozess, der auf der präzisen räumlich-zeitlichen Koordinierung von Vorläuferzellen beruht. Um unser Wissen über angeborene Herzfehler zu erweitern ist es entscheidend die Entwicklung dieser Vorläuferzellen zu verstehen. In dieser Arbeit wurden verschiedene kardiale Vorläuferpopulationen aus humanen pluripotenten Stammzellen generiert und mittels einer Kombination aus genetischer Markierung, Zellsortierung, und Analyse des Transkriptoms detailliert analysiert.

Heart regeneration is an unmet clinical need, hampered by limited renewal of adult cardiomyocytes and fibrotic scarring. Pluripotent stem cell-based strategies are emerging, but unravelling cellular dynamics of host–graft crosstalk remains elusive. Here, by combining lineage tracing and single-cell transcriptomics in injured non-human primate heart biomimics, we uncover the coordinated action modes of human progenitor-mediated muscle repair. Chemoattraction via CXCL12/CXCR4 directs cellular migration to injury sites. Activated fibroblast repulsion targets fibrosis by SLIT2/ROBO1 guidance in organizing cytoskeletal dynamics. Ultimately, differentiation and electromechanical integration lead to functional restoration of damaged heart muscle. In vivo transplantation into acutely and chronically injured porcine hearts illustrated CXCR4-dependent homing, de novo formation of heart muscle, scar-volume reduction and prevention of heart failure progression. Concurrent endothelial differentiation contributed to graft neovascularization. Our study demonstrates that inherent developmental programmes within cardiac progenitors are sequentially activated in disease, enabling the cells to sense and counteract acute and chronic injury.

Heart regeneration is an unmet clinical need, hampered by limited renewal of adult cardiomyocytes and fibrotic scarring. Pluripotent stem cell-based strategies are emerging, but unravelling cellular dynamics of host-graft crosstalk remains elusive. Here, by combining lineage tracing and single-cell transcriptomics in injured non-human primate heart biomimics, we uncover the coordinated action modes of human progenitor-mediated muscle repair. Chemoattraction via CXCL12/CXCR4 directs cellular migration to injury sites. Activated fibroblast repulsion targets fibrosis by SLIT2/ROBO1 guidance in organizing cytoskeletal dynamics. Ultimately, differentiation and electromechanical integration lead to functional restoration of damaged heart muscle. In vivo transplantation into acutely and chronically injured porcine hearts illustrated CXCR4-dependent homing, de novo formation of heart muscle, scar-volume reduction and prevention of heart failure progression. Concurrent endothelial differentiation contributed to graft neovascularization. Our study demonstrates that inherent developmental programmes within cardiac progenitors are sequentially activated in disease, enabling the cells to sense and counteract acute and chronic injury. In this study, the authors report that pluripotent stem cell-derived ventricular progenitors target loss of myocardium and fibrotic scarring to promote heart regeneration, thus offering new potential therapeutic strategies for heart injury., Funding Agencies|European Research Council (ERC) under the European Union [743225, 788381, 101021043]; German Research Foundation, Transregio Research Unit 152; German Research Foundation, Transregio Research Unit 267; Swedish Research Council Distinguish Professor Grant; German Centre for Cardiovascular Research (DZHK)