Cardiomyocytes Expressing SOX10 are Vital to Zebrafish Heart Regeneration

A few higher animal species, such as salamanders and zebrafish, are capable of regeneration of limbs and internal organs, regrowing lost and injured tissue without scarring or loss of function. Numerous research groups are engaged in investigating the biochemistry of proficient regeneration, attempting to find the specific differences between species that might explain how it happens and why adult mammals are largely incapable of such feats of regrowth. Today's open access research is an example of the type, in which the authors narrow down on a specific cell population that appear in zebrafish hearts during regeneration, but not in human tissues.

It may be the case that the mechanisms and capacity for adult regeneration do still exist in mammals, but are suppressed in some way, as suggested by the fact that the human ARF gene can shut down zebrafish regeneration. After all, we all managed to undertake the process of growing organ tissue during embryonic development. Alternatively perhaps a single crucial part of the adult regeneration mechanisms was lost over evolutionary time, and thus there is an opportunity to reinsert it into mammalian tissues via gene therapy or some other form of modern biotechnology. It still remains to be seen as to whether there are simple paths towards enabling greater adult mammalian regeneration, or, as seems equally likely, the situation is a complex mess that will take decades to decipher, and offers no easy path to therapy.

Special cells contribute to regenerate the heart in Zebrafish

In mammals, including humans, the heart muscle has a very limited capacity to recover after injury. After an acute myocardial infarction, millions of cardiac muscle cells, named cardiomyocytes, die, and are replaced by a scar. Unlike mammals, other vertebrates can recover much better from a cardiac damage. This is the case of some fish, including the zebrafish, a well-established animal model in biomedical research which shares with humans most of its genes.

Zebrafish are extremely well suited to study organ regeneration. After heart injury, zebrafish cardiomyocytes can divide and the scar is replaced by new cardiac muscle. Now the researchers show that not all cardiomyocytes in the zebrafish heart contribute equally to regenerate the lost muscle, but that there is a specific subset of cardiomyocytes with enhanced regenerative capacity.

A small subset of cardiomyocytes in the zebrafish heart, marked by sox10 gene expression, expanded more than the rest of myocardial cells in response to injury. These cells differed from the rest of the myocardium also in their gene expression profile, suggesting that they represented a particular cell subset. Furthermore, experimental erasure of this small cell population, impaired heart regeneration. The researchers want to find out whether the absence of such a sox10 cell population in mammals could explain why their heart does not regenerate well. If this is the case, the researchers believe that this finding could be of great importance in stimulating the repair process in the human heart.

Adult sox10+ Cardiomyocytes Contribute to Myocardial Regeneration in the Zebrafish

Like mammals, zebrafish cardiomyocytes (CMs) derive from first and second heart field progenitors. However, in the zebrafish, the neural crest represents a third progenitor population that contributes to the developing heart. Cell transplantation and fluorescent dye tracing experiments suggested that cardiac neural crest cells incorporate not only into the areas of the outflow tract, as in mammals and birds, but also into the atrium and ventricle. Moreover, genetic lineage tracing using sox10 as a neural crest cell marker revealed a cellular contribution of sox10+ cells to the zebrafish heart and suggested that sox10-derived CMs are necessary for correct heart development. Noteworthy, it is still unclear if a sox10+ neural crest population differentiates into CMs or if alternatively, a sox10+ CM subset is relevant for heart development.

Here, we assessed the contribution of sox10-derived cells to the adult zebrafish heart. We found that embryonic sox10-derived cells contributed to significant portions of the adult heart. We also identified adult sox10+ CMs that expanded to a higher degree upon injury than other CMs and significantly contributed to cardiac regeneration. Their transcriptome differed from other CMs in the heart, and their genetic ablation impaired recovery from ventricular injury.

Comments

I am afraid there is no simple fix to unleash the regeneration for the humans, and even mammals. However, there might be a series of small hacks that can enhance what we already have.

Regrowing a lost limb or organ, however, will require many advances. By then we might be able to print organs. There could be some shortcuts, however. For example if mixing human and zebra fish or salamander cells along with regeneration promoting factors and write scaffolds might actually be doable and enable in- body tissue regrowth. In some cases the tissue doesn't have to be perfect to help with debilitating conditions (nerves, muscles, tendons, etc

Posted by: Cuberat at November 7th, 2019 2:51 PM

This either conflicts with or supplements findings that the small molecule drug MSI-1436 regenerates injured heart (and other) tissues in both zebra fish and mice, as mentioned in the April 2019 Scientific American article "A Shot at Regeneration".
(Some discussion can be found in the side bar discussion at URL -
http://file.magzdb.org/ul/2490/Scientific%20American%202019%2008.pdf)

MSI-1436 blocks the protein tyrosine phosphatase 1B enzyme (PTP1B), and is being developed as "trodusquamine" by Novo Biosciences -
https://cannels.com/ghana/novo-biosciences-brings-important-milestone-in-new-drug-to-treat-heart-disease-and-dmd/

Posted by: L Pagnucco at November 7th, 2019 3:09 PM

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