Heart regeneration

There is little natural regeneration of the major structural cells of the adult mammalian heart, the cardiomyocytes, after injury. This regenerative deficiency is highly relevant to human disease, given the high prevalence in the United States of ischemic myocardial infarction and scarring, a major cause of heart failure. Several years ago, we discovered tthat that adult zebrafish regenerate cardiac muscle after removal of 20 percent of the ventricle, with little or no scarring.  How are new cardiac cells created and functionally integrated into an injured, contracting, adult heart?  How and why do zebrafish retain regenerative capacity of the heart as adults, while mammals lose such capacity very early in life?  Our research program addresses these and other important questions.

It has been a primary goal of our work to define the origin and developmental potential of cellular contributors to regenerated cardiac tissue. We showed recently that cardiac regeneration is not based on stem cells, but rather involves activation and proliferation of spared cardiac myocytes.  It is important now to understand at high spatiotemporal resolution how this regenerative source becomes activated by injury.

We also demonstrated new biological relevance for the epicardium, a thin epithelial layer enveloping
the cardiac chambers, and the inner endothelial lining of the chambers called the endocardium. We have found that the adult zebrafish endocardium and epicardium respond rapidly and robustly to injury, and are important for regenerative cardiomyocyte proliferation and neovascularization, respectively. We are exploring several fascinating questions regarding how the non-muscle cells that comprise the cardiac environment respond to injury and facilitate regeneration. These avenues should yield clues to altering the regenerative capacity of the injured mammalian heart.


 
Organ Regeneration in Zebrafish
 

Regeneration in the Zebrafish Model System


Mammalian tissues achieve remarkable feats of regeneration. After removal of more than two-thirds of its mass, the liver rapidly regenerates within several days by hepatocyte proliferation. Multipotent hematopoietic stem cells replenish red and white blood cells, and skin, muscle, and intestine are repaired by tissue-specific stem cells. However, this regenerative capacity is distributed unequally among mammalian organs: limbs, brain, spinal cord, and heart display minimal regeneration after tissue damage or loss. How and why tissue regeneration does (or does not) occur are critical questions; the answers have the potential to impact the clinical outcomes of the many diseases of organ damage, including heart failure, Alzheimer's disease, and diabetes.

 

It has been known for centuries that certain non-mammalian vertebrates, such as urodele amphibians and teleost fish, regenerate complex tissues much more effectively than mammals. Salamanders have long been the central characters employed in vertebrate regeneration studies. Two features make the teleost zebrafish a powerful, complementary model system to study organ regeneration. First, they are highly regenerative, equipped to regrow amputated fins, injured retinae, transected optic nerves and spinal cord, and resected heart muscle. Second, unlike salamanders, they are amenable to both forward and reverse genetic approaches. As is customary with genetic model systems, a wide array of community resources is available for gene discovery and molecular characterization in zebrafish, including mutagenesis screens, transgenesis, microarrays, developmental markers, and genome sequence information.

 

The Poss lab is investigating the biology of spectacular regenerative events in zebrafish to discover new cellular mechanisms, and we are also developing new tools to interrogate regeneration deeply at the molecular level. Over the next several years, we will pursue fundamental aspects of organ regeneration—most importantly, how tissue renewal is stimulated by injury, and how newly created cells recognize position and functionally incorporate into existing tissue.


 

Fin regeneration

Zebrafish fins are transparent, highly organized structures, making them a very tractable system for asking fundamental questions about complex tissue regeneration. Within two weeks after amputation of the caudal fin, a series of healing, proliferation, and patterning events replaces bone, epidermis, blood vessels, nerves, and connective tissue mesenchyme.  A hallmark of limb or fin regeneration is formation of the blastema, a proliferative mass of mesenchymal cells that is maintained as a zone of progenitor tissue for new structures. The central questions are these: (1) What cells give rise to the blastema, and how is its formation activated by injury? (2) How is blastemal activity maintained appropriately throughout regeneration? (3) How is the completion of regeneration remembered and enacted? We are using forward and reverse genetic approaches to identify new regulatory mechanisms critical for appendage regeneration in zebrafish.