Migratory and anti-fibrotic programmes define the regenerative potential of human cardiac progenitors
Author: 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
Department: Inst för cell- och molekylärbiologi / Dept of Cell and Molecular Biology
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.
Institution:
- Medical Department I, Cardiology, Angiology, Pneumology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
- Department of Medicine, Karolinska Institutet, Huddinge, Sweden
- Institute of Regenerative Medicine in Cardiology, Technical University of Munich, Munich, Germany
- Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
- Division of Biotechnology, IFM, Linköping University, Linköping, Sweden
- Center for Applied Tissue Engineering and Regenerative Medicine (CANTER), Munich University of Applied Sciences, Munich, Germany
- Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
- Western Michigan School of Medicine, Kalamazoo, MI, USA
- Procella Therapeutics, Stockholm, Sweden
- Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, Munich, Germany
- DZHK (German Centre of Cardiovascular Research), Munich Heart Alliance, Munich, Germany
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, LMU Munich, Munich, Germany
- Department of Experimental and Clinical Medicine, University of Magna Grecia, Catanzaro, Italy
- Department of Cardiovascular Surgery, INSURE, German Heart Center Munich, Technical University of Munich, Munich, Germany
Citation: Nat Cell Biol. 2022;24(5):659-671.
Citation DOI: 10.1038/s41556-022-00899-8
Citation PMID: 35550611
Publishing journal: Nature Cell Biology
Eprint status: Peer Reviewed
Version: Published
Issue date: 2022-08-02
Sponsorship:
- European Research Council (ERC), AdG 743225, AdG 788381, AdG 101021043
- German Research Foundation (DFG)
- Swedish Research Council Distinguish Professor Grant
- German Centre for Cardiovascular Research (DZHK)
Rights:
CC BY 4.0
Publication year: 2022
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