All animals have evolved strategies to deal with damage due to injury or disease, but the ability to regenerate lost or damaged organs and appendages varies greatly in different species. Unfortunately, humans and other mammals are quite poor at regenerating, while other vertebrates, like salamanders and fish, can efficiently re-grow lost limbs/fins and regenerate many internal organs including their hearts. Currently it is a mystery why mammals can’t do what these lower vertebrates achieve. We hope that elucidating the mechanisms that zebrafish use to regulate regeneration will one day result in therapies aimed at activating regenerative potential in human organs.

Adult zebrafish efficiently regenerate many organs and structures after injury.

1. Mechanisms of zebrafish fin and bone regeneration

 

Unlike mammals, zebrafish can completely and repeatedly regenerate lost appendages, that is their fins. This occurs via formation of a population of progenitor cells, the blastema, which contains the precursors of the regenerating tissue. How the blastema forms is a central question in regeneration research. In particular it has been unclear whether the blastema forms from activated adult stem cells or from differentiated mature cells through a process of dedifferentiation. We take advantage of the ease with which transgenic zebrafish can be established to address these questions. Intriguingly, we have found that mature osteoblasts dedifferentiate and give rise to blastema cells after fin injury. Currently, we aim to elucidate the molecular mechanisms regulating this cellular plasticity.

 

In addition, we are interested in understanding the molecular pathways regulating regenerative growth and patterning. We have found that Wnt/beta-catenin signaling is required for formation and proliferation of the blastema; intriguingly however, it acts largely indirectly and orchestrates regenerative growth via secondary signals. Currently, we aim to elucidate how Wnt signaling sets up orgnaizing centers within the blastema. Furthermore, we use gene expression profiling to identify and characterize other important gene regulatory networks controlling fin regeneration. Recently, we have also found that Notch signaling acts to maintain blastema cells in an undifferentiated, proliferative state.

Selected first or last author publications of our group related to fin & bone regeneration:

Wehner et al. 2015, JoVE
Wehner et al. 2015, Trends in Genetics
Geurtzen et al 2015, Development
Wehner et al. 2014, Cell Reports
Grotek et al. 2013, Development
Azevedo et al. 2011, PLOS One
Knopf et al. 2011, Dev. Cell
Stoick-Cooper et al. 2007, Genes Dev.
Stoick-Cooper et al. 2007, Development

Our work on bone regeneration is embedded in the Collaborative Research Center (SFB) 1149:  "Danger Response, Disturbance Factors and Regenerative Potential after Acute Trauma".

2. Mechanisms of zebrafish heart regeneration

 

Heart damage, usually caused by infarction, is a leading cause of death in humans. After cardiomyocyte loss the damaged part of the myocardium in humans undergoes extensive scarring and fibrosis, and only few new cardiomyocytes are produced. Thus, infarction results in permanent damage to the heart. In contrast, zebrafish are able to regenerate their hearts after amputation of the tip of the ventricle without scarring. We have found that injuries causing necrotic death of the myocardium, which are more similar to human heart infarction, are likewise efficiently regenerated.

 

Regeneration involves the proliferation of differentiated cardiomyocytes and the coordinated growth of myocardium, endocardium and epicardium. Currently, the molecular mechanisms regulating these processes are only beginning to emerge. We have been identifying genes expressed during heart regeneration and are studying their role in heart repair and development.

Recently, we found that BMP signaling is essential for heart regeneration. Interestingly, it promotes cardiomyocyte proliferation during regeneration, but is not required for physiological cardiomyocyte proliferation. In addition, BMP signaling has also been reported to be active in mammalian hearts after injury, but there it plays a detrimental role, promoting cardiomyocyte apoptosis. Thus, our findings indicate that the differential capacity of zebrafish and mammals to regenerate the heart depends, at least in part, on different responses of cardiomyocytes to the same conserved signaling pathway, namely BMP signaling. We currently aim to elucidate how BMP signaling promotes regeneration in zebrafish and why it does not in mammals.

Selected first or last author publications of our group related to heart regeneration:

Wu et al., 2016, Dev. Cell
Wu and Weidinger 2014, Curr. Pathobiol. Reports
Schnabel et al. 2011, PLOS One
Knopf et al. 2010, PNAS
Nemtsas et al. 2010, J Mol Cell Cardiol
Ueno et al. 2007, PNAS

3. Regulation of Wnt signaling pathways

 

Wnt signaling does not only have essential functions during organ regeneration, but plays important roles in regulating cell fate, cell proliferation, cell polarity and migration in many tissues during embryonic development and in adult homeostasis. Tight regulation of Wnt signaling is essential, in particular of the Wnt/beta-catenin pathway, since misregulation causes disease, most prominently cancer. We have aimed at identifying novel feedback regulators of Wnt signaling by screening for universal Wnt target genes during zebrafish embryogenesis.

This work has resulted in identification of Wnt activated inhibitory factor 1 (Waif1), which inhibits Wnt/beta-catenin signaling during mesoderm and neuroectoderm patterning and uses an intriguing novel mechanism to interfere with beta-catenin signaling, namely by blocking Wnt-mediated internalization of the Wnt co-receptor LRP6 (Kagermeier-Schenk et al. 2011 Dev. Cell). At the same time, Waif1 enhances beta-catenin independent Wnt signaling, suggesting that it is involved in regulating which pathway a cell activates in response to Wnt ligands.

We have also found that lypd6, a gene identified in the same screen, codes for a positive regulator of Wnt/beta-catenin signaling. Lypd6 is a GPI-anchored plasma membrane protein that enhances Wnt signaling by ensuring that LRP6 is phosphorylated in raft plasma membrane subdomains (Özhan et al. 2013 Dev Cell). When Lypd6 is mislocalized to non-raft domains or when it is knocked down, LRP6 is inappropriately activated in non-rafts, from where signaling cannot be transmitted to the interior of the cell.

 

Selected first or last author publications of our group related to the regulation of Wnt signaling:

Özhan et al. 2013, Dev. Cell
Kagermeier-Schenk et al. 2011, Dev. Cell
Nakamura et al. 2007, J Clin Invest.