Migratory and anti-fibrotic programmes define the regenerative potential of human cardiac progenitors
Poch CM, Foo KS, De Angelis MT, Jennbacken K, Santamaria G, Baehr A, Wang QD, Reiter F, Hornaschewitz N, Zawada D, Bozoglu T, My I, Meier A, Dorn T, Hege S, Lehtinen ML, Tsoi YL, Hovdal D, Hyllner J, Schwarz S, Sudhop S, Jurisch V, Sini M, Fellows MD, Cummings M, Clarke J, Baptista R, Eroglu E, Wolf E, Klymiuk N, Lu K, Tomasi R, Dendorfer A, Gaspari M, Parrotta E, Cuda G, Krane M, Sinnecker D, Hoppmann P, Kupatt C, Fritsche-Danielson R, Moretti A, Chien KR, Laugwitz KL (2022)
Publication Type: Journal article
Publication year: 2022
Journal
Book Volume: 24
Pages Range: 659-671
Journal Issue: 5
DOI: 10.1038/s41556-022-00899-8
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.
Involved external institutions
Technische Universität München (TUM)
Germany (DE)
Karolinska Institute
Sweden (SE)
AstraZeneca UK Limited
United Kingdom (GB)
Hochschule für angewandte Wissenschaften München
Germany (DE)
Western Michigan University (WMU)
United States (USA) (US)
Procella Therapeutics AB
Sweden (SE)
Ludwig-Maximilians-Universität (LMU)
Germany (DE)
Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK e.V.)
Germany (DE)
Magna Græcia University of Catanzaro / Università degli studi Magna Græcia di Catanzaro
Italy (IT)
Germany (DE)
Karolinska Institute
Sweden (SE)
AstraZeneca UK Limited
United Kingdom (GB)
Hochschule für angewandte Wissenschaften München
Germany (DE)
Western Michigan University (WMU)
United States (USA) (US)
Procella Therapeutics AB
Sweden (SE)
Ludwig-Maximilians-Universität (LMU)
Germany (DE)
Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK e.V.)
Germany (DE)
Magna Græcia University of Catanzaro / Università degli studi Magna Græcia di Catanzaro
Italy (IT)
How to cite
APA:
Poch, C.M., Foo, K.S., De Angelis, M.T., Jennbacken, K., Santamaria, G., Baehr, A.,... Laugwitz, K.-L. (2022). Migratory and anti-fibrotic programmes define the regenerative potential of human cardiac progenitors. Nature Cell Biology, 24(5), 659-671. https://dx.doi.org/10.1038/s41556-022-00899-8
MLA:
Poch, Christine M., et al. "Migratory and anti-fibrotic programmes define the regenerative potential of human cardiac progenitors." Nature Cell Biology 24.5 (2022): 659-671.
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