Fight Aging!

The mammalian heart regenerates very poorly, which is one of the reasons why cardiovascular disease kills so many of us. In the research noted below scientists investigate a possible reason as to why this is the case, uncovering what they believe to be a meaningful difference in the structure of heart cells when compared with those of non-mammalian species in which the heart is capable of regrowth. A cell structure known as the centrosome, important in cellular replication, is lost in heart cells early on in mammalian development, but retained in other species known for the regenerative prowess, such as salamanders and zebrafish.

You might consider this a sort of regenerative research, but quite different in focus from work on stem cells and signals intended to spur heart tissue to regenerate where it would not normally do so. In this case it is suggested that perhaps it might be possible alter heart cells to be more like other muscle cells, more capable of ongoing self-repair. This is of course much more speculative than stem cell therapies at this stage, but all new medicine must start somewhere.

Heart cells are generated early in life and there is little turnover or reconstruction following injury in comparison to other tissues. Looking at other species, the hearts of zebrafish and salamanders regenerate exceptionally well over the whole life span. Remove a whole chunk of heart tissue and it will grow back. Is this a matter of signal environments, as is presently thought to be the case, or is it differences in the complex relationship between the immune system and tissues in regulation of healing, which is looking likely based on salamander studies, or is it inherent in the internal state of the cells themselves? Or all of the above?

Why the human heart cannot regenerate

Heart failure is the most common cause of death worldwide. The main reason for this is that damage to the human heart causes cardiac muscle cells to die, which in turn leads to reduced heart function and death. However, this is not the case for zebrafish or amphibians. If their hearts become damaged and cardiac muscle cells die, their remaining cardiac muscle cells can reproduce, allowing the heart to regenerate. The ability of most cardiac muscle cells to reproduce disappears in humans and all other mammals shortly after birth. What remains unclear, however, is how this happens and whether it is possible to restore this ability and therefore to regenerate the heart.

'In our study we discovered that the centrosome in cardiac muscle cells undergoes a process of disassembly which is completed shortly after birth. This disassembly process proceeds by some proteins leaving the centrosome and relocating to the membrane of the cell nucleus in which the DNA is stored. This process causes the centrosome to break down into the two centrioles of which it is composed, and this causes the cell to lose its ability to reproduce.' The centrosome is an organelle found in almost every cell. In recent years, experiments have shown that if the centrosome is not intact, the cell can no longer reproduce. This raised the key question to what extent centrosome integrity could be manipulated - such as in cancer where cells reproduce at an uncontrolled rate. 'We were incredibly surprised to discover that the centrosome in the cardiac muscle cells of zebrafish and amphibians remains intact into adulthood. For the first time, we have discovered a significant difference between the cardiac muscle cells of mammals and those of zebrafish and amphibians that presents a possible explanation as to why the human heart cannot regenerate.'

Developmental alterations in centrosome integrity contribute to the post-mitotic state of mammalian cardiomyocytes

Increasing evidence supports the requirement of a functional centrosome for cellular proliferative potential. Centrosome disassembly appears to be a very effective way to achieve a post-mitotic state. But why do cardiomyocytes disassemble their centrosomes? Upon birth, the neonatal heart, and the cardiomyocytes therein, undergo increased hemodynamic stress. Effective cardiomyocyte function in response to increased hemodynamic stress may require a cytoskeletal architecture more conducive to handling postnatal physical stresses. Thus, centrosome disassembly may be a result of cytoskeletal reorganization. In this scenario, proliferative potential might be sacrificed for postnatal function.

The ability of zebrafish and newts to regenerate their heart has gained extensive interest in recent years. One major question is what distinguishes mammalian cardiomyocytes from those of zebrafish and newts with regards to their proliferative potential. Our data demonstrate that the state of cellular differentiation of cardiomyocytes from various species is not evolutionary conserved. The fact that adult zebrafish and newt cardiomyocytes maintain their centrosome integrity indicates that factors promoting adult zebrafish cardiomyocyte proliferation might not necessarily induce adult mammalian cardiomyocyte proliferation.

Collectively, our data provide a novel mechanism underlying the post-mitotic state of mammalian cardiomyocytes as well as a potential explanation for why zebrafish and newts, but not mammals, can regenerate their heart.