‘ A broken heart is beyond repair ‘, we have heard such expressions used quite often by poets, heroes of our favorite movies and many characters of well loved literature. Is this infact true? Philosophically, I can’t say, but science sure has a different story to tell.
Even from our lower classes, we have heard that the heart is one of the most important organ and pumps blood to the nook and corner of our body, which in turn carries nutrients and oxygen to sustain life. The cells of these tirelessly working organs do not divide like the rest of our cells and a heart cell once dead cannot be replaced. Again, ‘a broken heart is beyond repair’. But, this is only partly true. Even though the adult human heart does not have the regenerative capacity, this was not always the case. The human heart had regenerative potential during its fetal stage and early neonatal period which was lost during maturation. Is there a way to reverse this once lost regenerative capacity? If so, wouldn't it provide a solution to many acquired and congenital heart defects?
This is where Zebrafish ( Danio rerio ), which have regenerative capacity throughout their life, has been gaining importance over the last decade as a model organism for cardiac studies.
The genome of zebrafish, which has almost entirely been sequenced shows great genetic similarity with humans and is highly conserved. Moreover, whole-genome forward genetic studies done for identifying novel genes required for cardiovascular development and various reverse genetic techniques and phenotypic expression studies for identifying unknown genes can be easily carried out in a zebrafish. Besides the ease of carrying out genetic studies, the transparency of its embryos makes visualization of early development easier and their fast and short life cycle makes them a useful vertebrate model.
The studies conducted by Poss on zebrafish have shown that new myocardium generated during regeneration was from differentiated cardiomyocytes and that they showed distinct molecular signatures that were absent in non-regenerating cardiomyocytes. Further studies by Zhang and Han on another mutant strain showed that atrial-to-ventricular transdifferentiation is responsible for ventricular heart muscle regeneration and through gene expression analysis found that the ventricular muscle depletion activates re-expression of Notch pathway genes which indirectly regulate transdifferentiation. These molecular mechanisms underlying transdifferentiation is thought to be conserved in mammals and has been addressed in many studies. Studies conducted by Aguirre focused on finding such conserved mechanisms and investigated upon miRNAs. They identified two such miRNA families, miR-99/100 and let-7a/c and their results showed that the miR-99/100 pathway is dormant in the mammalian heart and can be reactivated through forceful downregulation to induce regeneration.
All the above studies put forwards a concept of possible mammalian adult heart regeneration, whose mechanisms are yet to be deciphered. But with zebrafish as a promising model, further understanding of the cellular and molecular regulation of cardiac regeneration can be deduced and this will probably provide an insight into how human heart regeneration can be triggered effectively. This will give rise to novel therapeutic strategies and aid in developing techniques to tackle cardiac diseases like myocardial infarction, aortic valve stenosis, atherosclerosis, and many more common congenital heart diseases.
And yes, a broken heart is not beyond repair.
References:
Aguirre, A., Montserrat, N., Zacchigna, S., Nivet, E., Hishida, T., Krause, M. N., Izpisua Belmonte, J. C. In vivo activation of a conserved microRNA program induces mammalian heart regeneration (2014).
Anita Dittrich, Henrik Lauridsen.Myocardial infarction and the immune response - Scarring or regeneration? A comparative look at mammals and popular regenerating animal models (2019).
Juan Manuel González-Rosa1,Caroline E. Burns1,C. Geoffrey Burns1.Zebrafish heart regeneration: 15 years of discoveries (2017).
Poss, K. D. Advances in understanding tissue regenerative capacity and mechanisms in animals.(2010).
Ruilin Zhang, Peidong Han, Hongbo Yang, Kunfu Ouyang, Derek Lee, Yi-Fan Lin, Karen Ocorr, Guson Kang, Ju Chen, Didier Y.R. Stainier,Deborah Yelon, and Neil C. Chi1. In Vivo Cardiac Reprogramming Contributes to Zebrafish Heart Regeneration (2013).
Zak, R.Cell proliferation during cardiac growth(1973).
Date: Oct 30, 2020
Author: Malavika Saji
Malavika is a postgrad student of Biochemistry and Molecular Biology at Pondecherry University. SciArt and illustrations are an integral part of effective Scicomm and she loves making illustrations and art that makes visualization of science effective.
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