Migration of cardiomyocytes is essential for heart regeneration in zebrafish

Abstract

SUMMARYAdult zebrafish possess a significant ability to regenerate injured heart tissue through proliferation of pre-existing cardiomyocytes, which contrasts with the inability of mammals to do so after the immediate postnatal period. Zebrafish therefore provide a model system in which to study how an injured heart can be repaired. However, it remains unknown what important processes cardiomyocytes are involved in other than partial de-differentiation and proliferation. Here we show that migration of cardiomyocytes to the injury site is essential for heart regeneration. Ventricular amputation induced expression of cxcl12a and cxcr4b, genes encoding a chemokine ligand and its receptor. We found that cxcl12a was expressed in the epicardial tissue and that Cxcr4 was expressed in cardiomyocytes. We show that pharmacological blocking of Cxcr4 function as well as genetic loss of cxcr4b function causes failure to regenerate the heart after ventricular resection. Cardiomyocyte proliferation was not affected but a large portion of proliferating cardiomyocytes remained localized outside the injury site. A photoconvertible fluorescent reporter-based cardiomyocyte-tracing assay demonstrates that cardiomyocytes migrated into the injury site in control hearts but that migration was inhibited in the Cxcr4-blocked hearts. By contrast, the epicardial cells and vascular endothelial cells were not affected by blocking Cxcr4 function. Our data show that the migration of cardiomyocytes into the injury site is regulated independently of proliferation, and that coordination of both processes is necessary for heart regeneration.

Notch signalling restricts inflammation and serpine1 expression in the dynamic endocardium of the regenerating zebrafish heart

“…1J, 1 mpci; Fig. S1E, 3 mpci), consistent with published data (Chablais et al, 2011;Itou et al, 2012). Analysis of optical sections in 1 mpci hearts revealed that regions still lacking cardiomyocytes were filled with endocardial cells (Fig.…”

Chemokine signaling in development and disease

“…Cells migrating singly, such as primordial germ cells (PGCs) Doitsidou et al, 2002;Knaut et al, 2003;Molyneaux et al, 2003), lymphocytes (Bleul et al, 1996a,b;Ma et al, 1998;Nagasawa et al, 1996;Zou et al, 1998), gonadotropin-releasing hormone (GnRH) neurons (Schwarting, 2006), endothelial precursor cells (Li et al, 2012), cardiomyocytes during heart regeneration (Itou et al, 2012), interneurons (Li et al, 2008;López-Bendito et al, 2008;Stumm et al, 2003;Tiveron et al, 2006), granule cells in the cerebellum and dentate gyrus (Bagri et al, 2002;Lu et al, 2002;Ma et al, 1998;Reiss et al, 2002;Zhu et al, 2002;Zou et al, 1998) and hematopoietic stem cells (HSCs) (Kawabata et al, 1999;Nie et al, 2008;Peled, 1999;Sugiyama et al, 2006;Tzeng et al, 2011), rely on CXCL12 to reach their target or remain at a distinct location. Similarly, cells migrating in small groups or as tissues, such as trigeminal sensory neurons (Knaut et al, 2005), sprouting blood vessels (Bussmann et al, 2011;Siekmann et al, 2009), the posterior lateral line primordium ( pLLP) (David et al, 2002), the endoderm (Mizoguchi et al, 2008;Nair and Schilling, 2008) and some cancer cells, also use CXCL12 for guidance (Müller et al, 2001).…”

Fanning the flames to regenerate the heart

“…Additionally, the mechanisms used by the P1 regenerative macrophage subset to promote regeneration are unclear, although a proangiogenesis function was implicated. It is possible that regenerative macrophages act on resident fibroblast and myofibroblast populations, which mediate fibrosis and scarring adult zebrafish, which are able to regenerate heart tissue, other organ-wide events, including epicardial activation and cardiomyocyte proliferation, are observed during heart repair (12,13). The significance of an organ-wide macrophage response to injury in the murine neonatal heart and the molecular cues that instruct localization to remote myocardium are unclear.…”

“…In summary, the study by Kim et al (13) provides new insights into the fundamental role of NRF2 in regulating the hematopoietic response to ionizing radiation. Of equal importance, NRF2 represents a new mechanistic target for the development of therapeutics to accelerate hematopoietic reconstitution both in victims of acute Damage to the adult mammalian heart is irreversible, and lost cells are not replaced through regeneration.…”