Migratory and anti-fibrotic programmes define the regenerative potential of human cardiac progenitors

• Published in: Nature cell biology Vol. 24; no. 5; pp. 659 - 671
• Main Authors: Poch, Christine M., Foo, Kylie S., De Angelis, Maria Teresa, Jennbacken, Karin, Santamaria, Gianluca, Bähr, Andrea, Wang, Qing-Dong, Reiter, Franziska, Hornaschewitz, Nadja, Zawada, Dorota, Bozoglu, Tarik, My, Ilaria, Meier, Anna, Dorn, Tatjana, Hege, Simon, Lehtinen, Miia L., Tsoi, Yat Long, Hovdal, Daniel, Hyllner, Johan, Schwarz, Sascha, Sudhop, Stefanie, Jurisch, Victoria, Sini, Marcella, Fellows, Mick D., Cummings, Matthew, Clarke, Jonathan, Baptista, Ricardo, Eroglu, Elif, Wolf, Eckhard, Klymiuk, Nikolai, Lu, Kun, Tomasi, Roland, Dendorfer, Andreas, Gaspari, Marco, Parrotta, Elvira, Cuda, Giovanni, Krane, Markus, Sinnecker, Daniel, Hoppmann, Petra, Kupatt, Christian, Fritsche-Danielson, Regina, Moretti, Alessandra, Chien, Kenneth R., Laugwitz, Karl-Ludwig
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 2022; Nature Publishing Group
• Subjects: 13/100; 13/106; 13/31; 13/51; 14/1; 14/19; 38/91; 59/57; 631/136/532/489; 631/80/86/2370; 82/58; 96/109; Animals; Biomedical and Life Sciences; Cancer Research; Cardiac muscle; Cardiomyocytes; Cell Biology; Cell Differentiation; Cicatrix - pathology; Cicatrix - prevention & control; Congestive heart failure; Crosstalk; CXCL12 protein; CXCR4 protein; Cytoskeleton; Developmental Biology; Differentiation; Fibrosis; Heart; Homing behavior; Humans; Injuries; Life Sciences; MEDICAL AND HEALTH SCIENCES; MEDICIN OCH HÄLSOVETENSKAP; Muscles; Myocardium; Myocardium - pathology; Myocytes, Cardiac - pathology; Nerve Tissue Proteins; Pluripotency; Pluripotent Stem Cells - pathology; Progenitor cells; Receptors, Immunologic; Regeneration; Scars; Stem Cells; Swine; Transcriptomics; Transplantation; Vascularization; Ventricle
• ISSN: 1465-7392; 1476-4679; 1476-4679
• DOI: 10.1038/s41556-022-00899-8

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.