Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, UMR7104, INSERM U964, Université de Strasbourg, Illkirch, France
Department of Medicine, Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, United States
Caroline E Burns
Department of Medicine, Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, United States
Juan C del Álamo
Mechanical and Aerospace Engineering Department, University of California, San Diego, La Jolla, United States; Institute for Engineering in Medicine, University of California, San Diego, La Jolla, United States
Department of Medicine, Division of Cardiology, University of California, San Diego, La Jolla, United States; Institute for Engineering in Medicine, University of California, San Diego, La Jolla, United States; Institute of Genomic Medicine, University of California, San Diego, La Jolla, United States
Lower vertebrate and neonatal mammalian hearts exhibit the remarkable capacity to regenerate through the reprogramming of pre-existing cardiomyocytes. However, how cardiac injury initiates signaling pathways controlling this regenerative reprogramming remains to be defined. Here, we utilize in vivo biophysical and genetic fate mapping zebrafish studies to reveal that altered hemodynamic forces due to cardiac injury activate a sequential endocardial-myocardial signaling cascade to direct cardiomyocyte reprogramming and heart regeneration. Specifically, these altered forces are sensed by the endocardium through the mechanosensitive channel Trpv4 to control Klf2a transcription factor expression. Consequently, Klf2a then activates endocardial Notch signaling which results in the non-cell autonomous initiation of myocardial Erbb2 and BMP signaling to promote cardiomyocyte reprogramming and heart regeneration. Overall, these findings not only reveal how the heart senses and adaptively responds to environmental changes due to cardiac injury, but also provide insight into how flow-mediated mechanisms may regulate cardiomyocyte reprogramming and heart regeneration.
