Migratory and anti-fibrotic programmes define the regenerative potential of human cardiac progenitors
Christine M Poch, Kylie S. Foo, Maria Teresa De Angelis, Karin Jennbacken, Gianluca Santamaria, Andrea Bähr, Qing‐Dong Wang, Franziska Reiter, Nadja Hornaschewitz, Dorota Zawada, Tarik Bozoglu, Ilaria My, Anna B. Meier, Tatjana Dorn, Simon Hege, Miia Lehtinen, Yat Long Tsoi, Daniel Hovdal, Johan Hyllner, Sascha Schwarz, Stefanie Sudhop, Victoria Jurisch, Marcella Sini, Mick D. Fellows, Matthew J. Cummings, Jonathan Clarke, Ricardo Baptista, Elif Eroğlu, Eckhard Wolf, Nikolai Klymiuk, Kun Lü, Roland Tomasi, Andreas Dendorfer, Marco Gaspari, Elvira Immacolata Parrotta, Giovanni Cuda, Markus Krane, Daniel Sinnecker, Petra Hoppmann, Christian Kupatt, Regina Fritsche‐Danielson, Alessandra Moretti, Kenneth R. Chien, Karl‐Ludwig Laugwitz
Abstract
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.