But a new study, by scientists from Oxford University and the University of Coimbra in Portugal, might have put us a step closer to heart regeneration with the discovery of the key molecule controlling the development of several heart and blood vessels’ tissues in the zebrafish embryo. The molecule, called Fibroblast growth factor (FGF) works like a “switch”, inhibiting and activating the genes for the different tissues in order to develop a balanced heart. But scientists also found that manipulation of FGF levels allows to control which tissue(s) forms, what could be the first step towards treatments able to create heart or blood vessels tissues according to the patient’ specific needs. The study, out in the journal Development(1), is on zebrafish, but FGF is known to affect also the human heart development, even promoting the growth of new blood vessels.
One other interesting aspect of the study – because it might explain a key steppingstone of evolution – is the fact that high levels of FGF lead to more cardiac muscle and bigger hearts. This – says Filipa Simões, one of the first authors of the study – could have been the mechanism behind the appearance of the 4-chambered hearts (zebrafish has only 2), which, more energetically efficient, allowed warmed-blooded animals and changed Earth’s landscape forever.
CVD are the number one cause of death in the world, killing as much as 17 millions of people every year. Death tends to happen by loss of the cardiac muscle (the myocardium) following cut of its blood supply after, for example, a heart attack. Even if the patient survives, the rigid scar tissue that forms unbalances the pumping organ, overworking the remaining muscle and increasing susceptibility to new episodes. And the human heart capacity to regeneration is so low that only in 2009 – when radioactive isotopes released into the atmosphere by above-ground nuclear testing during the Cold War, were found in the heart of people born before the tests (proving that those cells were new) – was categorically proved. This lack of self repair together with a CVD epidemic that is now spreading to developing countries, no effective treatments available and stem cells still to live up to their hype, makes research into new approaches to heart regeneration crucial.
In this sense, a population of progenitor cells called haemangioblasts found in embryos of animals with 2-chambered hearts is particularly promising. Progenitor cells are “precursors” like stem cells just more differentiated, and as such tend to only be able to develop one type of tissue. But haemangioblasts, not only form two tissues – blood and endothelial – but also seem to have the potential to develop a third – the myocardium Additionally, they seem to be the evolutionary precursors of the 2nd heart field – an embryonic area of 4 chambered heart animals (during evolution there was an increase of chambers and complexity in the heart culminating with the mammals and birds’ 4 chambers) that develops most of their myocardium (so most of the organ per se). The 2nd heart field is also home to another curious population of progenitor cells that is able to form many heart tissues (like haemangioblasts?).This genetic/evolutionary link, together with haemangioblasts’ “multi-tissue capacity” suggested that their study could give us important clues on our own heart.
It is in “this state of affairs” that Filipa Simões, Tessa Peterkin and Roger Patient used zebrafish (that have 2-chambered hearts) to look at the effects of FGF on the heart region and haemangioblasts, which are located next to each other in the embryo, during development. FGF is known to be important for heart development, including our own, although the exact effects and the mechanisms behind them are still unclear.
Normally in zebrafish the heart field area develops the myocardium, while haemangioblasts form endothelial tissue (that is part of both the heart and the blood vessels) and blood cells. Simões and Peterkin started by inhibiting FGF in the embryos and to their surprise, with FGF levels reduced, the heart field no longer had cardiac markers ((markers are genes/molecules linked to a specific development) but instead activated genes typical of endothelial/blood cells, which markers were also increased. This was not a transitory effect as it was still seen on differentiated cells. This showed that FGF had been inhibiting the endothelial/blood program. As there was no change in the total of number of cells in the two areas, and the FGF effects occurred simultaneous on both of them, the cells in the heart field were apparently changing their development, turning from myocardium to blood/endothelial tissues.
When the opposite was done, and a molecule that promotes cardiac development (and is induced by FGF) was introduced in the embryos in high quantities they found that it was now haemangioblasts “losing their path” by developing cardiac markers while the heart field increased their levels as well. This showed that FGF not only inhibited the haemangioblasts program (so “switched off” the expression of blood and endothelial genes) but also “switched on” the myocardium genes.
The last clue was the fact that haemangioblasts development (which is the first to be activated in the embryo) is known to inhibit that of the heart field.
So what seems to happen is that FGF inhibits the endothelial/blood genes to keep their tissue development and inhibition over the cardiac tissue under control while also activates the development of the myocardium. This will assure the development of a balanced heart. But if FGF levels change, the results become very different – increased FGF leads to expansion of the myocardium as the endothelial/blood program is totally inhibited, while reduced quantities of FGF, no longer able to stop the endothelial/blood growth sees these tissues taking over both embryonic regions.
An implication of these results is that it gives support to the idea that haemangioblasts are in fact the evolutionary precursors of the mammals’ 2nd heart field by providing a mechanism for this to happen. As FGF levels increase, cardiac genes are activated both in the heart field and in the haemangioblasts, expanding the myocardium and forming larger hearts with more chambers. Interestingly, amphibian, found in the evolution tree between fish and mammals, have 3–chambered hearts and a residual population of haemangioblasts in what could be seen as an intermediate stage.
But can this work help to regenerate our own heart? First it will be necessary to show that FGF has a similar effect in humans. We already know that this molecule promotes the growth of new blood vessels on the human heart, and if haemangioblasts have in fact an evolutionary (genetic) link with the 2nd heart field (what seems very probable) other similarities will exist. It would be interesting, for example, to look at FGF effects on that 2nd heart field’s population of heart progenitors that seems similar to haemangioblasts. Therapies that can deliver specific tissue according to need – instead of, for example, stem cells, which are now seen as the big therapeutic bet – could be, not only more efficient, as stem cells can be sometimes problematic to produce enough tissue, but would also avoid dangers such as teratomas – a potential malign tumour linked to stem cells.
It could be interesting as well to investigate a possible link between FGF and congenital heart defects – which are still the most common problem in newborns and the number one cause of death in the 1st year of life – as many seem to derive from problems in the definition of the heart tissues.
There is something else of note in this new study – the fact that it gives support to the theory that all heart tissues come from a common precursor cell (like blood cells) since all the progenitors studied have the potential to develop more than one heart tissue. This is interesting because it would mean a change of paradigm and, inevitably, a different approach to the development of new biologic therapies for the heart.