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Heart Regeneration in zebrafish

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​Anatomy of adult zebrafish heart
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Models of heart injury and regeneration​
The adult mammalian (including human) hearts shows minimal regeneration of new cardiac muscle after ischemic myocardial infarction (MI). Unlike mammals, adult zebrafish possess a remarkable capacity for cardiac regeneration with minimal scarring after injuries removing up to 60% of CMs. Defining regenerative mechanisms in zebrafish will help shape strategies for mammalian heart repair. Zebrafish heart regeneration is achieved through the proliferation of existing CMs, which are quiescent without injury (as in mammalian CMs). CM proliferation is aided by cellular contributions and paracrine effects of non-muscle tissues, such as the epicardium and endocardium. 

The epicardium enveloping the adult heart is a multipotent cardiac progenitor cell population, which is activated after heart injury (expressing developmental genes), proliferates, and supplies paracrine signals and other cell types during cardiac repair or regeneration in both zebrafish and mice. In a previous study, my colleagues and I found that an intact epicardium is required for CM regeneration in zebrafish (Wang and Cao et al., 2015, Nature). This suggests that enhancing the epicardial injury response would benefit CM regeneration. However, how epicardial cells respond to heart injury and further exert effects on muscle regeneration are poorly understood, 
and my recent finding of the cellular heterogeneity of the zebrafish epicardial cells added complexity to this question (Cao et al., 2016, Development). This deficiency of knowledge represents a major barrier for harnessing epicardium for therapeutic goals. To address this, using a combination of zebrafish model, explant tissue culture, high-throughput sequencing, chemical screening, live imaging, and genome editing approaches (such as CRISPR/Cas9), we will dissect how epicardial cell activation, proliferation, and lineage specification are molecularly and genetically regulated to engage in heart muscle regeneration.

Epicardial Regeneration

Epicardial regeneration in an expalnted heart​
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Chemical screens in explant reveal regulators of epicardial regeneration
What mechanisms govern the homeostatic and regenerative activities of an adult tissue is a fundamental question of regenerative biology. To explore this by focusing on the zebrafish heart, I developed a heart explant culture and live imaging platform for mechanistic and large-scale approaches (Cao et al. 2016, Nat. Protoc.). When combined this new technology with the genetic ablation tool, my colleague and I discovered that the epicardium is highly regenerative, and it vigorously regenerates from the ventricular base to apex across the cardiac surface (Wang and Cao et al. 2015, Nature; Cao et al., 2017, Dev. Cell). The epicardial regeneration provides a great model for live surveillance of tissue regeneration. The cell cycle dynamics that occur during epicardial regeneration suggest the regulated presence of molecular factors. Mechanistic studies of these regulators will not only reveal the basis that maintains the regenerative capacity but also uncover mitogens for enhancing tissue regeneration. This study will reveal mechanisms of regenerative capacity that are broadly applicable in tissue repair models.

Polyploidy during tissue regeneration

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Two regions of the regenerating epicardial cell sheet
Mitosis and endoreplication of epicardial cells (FUCCI reporter)
Although polyploidy is known to be involved in tissue repair, the mechanisms dictating polyploidization are poorly understood. By further investigating the mechanism of epicardial regeneration, I discovered that the epicardial regeneration is mediated by two distinct cell subpopulations: large, polyploid leader cells, trailed by much smaller, dividing follower cells. The leader cell population is established and maintained by endoreplication and is eliminated through apoptosis after regeneration, indicating a transient role. The leader cells possess markedly higher mechanical tension than the follower cells which instructed endoreplication in the leader cells.  Both the leader and follower population are independently capable of regeneration, with leaders displaying an enhanced capacity for surface coverage (Cao et al. 2017, Dev. Cell). This finding revealed regional control of cell cycle dynamics during regeneration and brought a new concept of tension-instructed endoreplication. Control of tension to strategically guide cell cycle decisions thus has potential applications in tissue engineering and therapeutic tissue repair. However, it is largely unknown how and why polyploidy arises and how it functions in tissue repair. The regenerative biology of the epicardium is generalizable to many tissues and when combined with the explant culture system, provides a unique platform to address these questions. Understanding polyploidy during tissue regeneration will help us harness its advantages in tissue repair strategies and suppress its disadvantages during diseases.
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