Cellular and Molecular Mechanism of Cardiac Regeneration: A Comparison of Newts, Zebrafish, and Mammals

Figures

• 

  Figure 1. Cardiac regeneration in newts, zebrafish and mammals (mice and human). Upon partial resection of the heart, newts and zebrafish show the development of a blood clot to stop the bleeding. Their cardiomyocytes start to dedifferentiate and immune cells, especially macrophages, infiltrate the injured area. The blood clot will gradually become a fibrin clot. Simultaneously, the dedifferentiated cardiomyocytes will start proliferating to replace the fibrin clot. After a few days, the resected tissue will be fully replaced by functional heart tissue. Adult mammals, like mouse and human, on the other hand, cannot regenerate their hearts after myocardial injury. They show high levels of cardiomyocyte cell death, necrosis, and apoptosis, and infiltration of neutrophils into the injured area. Some cardiomyocytes will show signs of partial, pathological dedifferentiation, but adult mammalian cardiomyocytes cannot proliferate in response to injury. Ultimately, a collagen-rich scar will be formed. The picture is created with BioRender.com.

• 

  Figure 2. Total DNA content per cardiomyocyte in relation to their proliferative capacity. Newt and zebrafish cardiomyocytes stay mononucleated, diploid, and proliferative their whole life. Newborn mouse and human cardiomyocytes have similar characteristics as newt and zebrafish, but the mouse cardiomyocytes become binucleated and human cardiomyocytes become tetraploid when they become adults. Simultaneously, these cardiomyocytes lose the ability to proliferate.

• 

  Figure 3. Four processes model of cardiac regeneration. A. Dedifferentiation. cardiac regeneration begins with dedifferentiation of preexisting differentiated cardiomyocytes after injury. It can be induced by hypoxia as well as OSM. B. Proliferation. After dedifferentiation, cardiomyocyte can start proliferation, which can be greatly enhanced by growth factors and cytokines as well as Hippo-YAP signaling pathway. C. Migration. Cardiac injury induce chemokine Cxcl12a expression and cardiomyocytes in the epicardium start to express its receptor Cxcr4b. Damage area enriched Cxcl12a expression stimulates the migration of cardiomyocytes toward the damaged area. D. Redifferentiation. When the newly formed cardiomyocytes arrive at the damaged area, they need to re-differentiate and become electrically coupled with the preexisting cardiomyocytes. OSM: Oncostain M; RA: Retinoic acid; IGF: Insulin-like growth factor; FGF1: fibroblast growth factor one; NRG1: Neuregulin 1.

• 

  Figure 4. A simplified overview of the classic Hippo-YAP signaling pathway. The core of this Hippo-YAP is a cascade of kinase activation. When the Hippo pathway is activated by cell-cell contact, cytokine or mechanical stress, LATS1/2 and MST1/2 are recruited to the plasma membrane by NF-2 and scaffold protein Salvador (Sav) respectively. MST then activates LATS by phosphorylation. Active LATS then phosphorylates YAP and its binding protein angiomotin protein (AMOT) to inhibit nuclear localization of YAP. Phosphorylated AMOT, bound to YAP, dissociates from F-actin and translocates to the cytoplasm, where the complex will be degraded via the ubiquitin–proteasome system. Upon inactivation, YAP is dephosphorylated and translocated to the nucleus, where it interacts with TEAD transcription factors to promote cell cycle and anti-apoptosis gene transcription. Nuclear YAP can also enhance Wnt/β-catenin signaling by binding to b-Catenin/TCF transcription activation complex. NF-2: Neurofibromin 2; YAP: yes-associated protein 1; LATS1/2: Large tumor suppressor kinase ½; TEAD: TEA domain family member. The picture is created with BioRender.com.