Getting to the heart of the matter
What if humans could grow new hearts?
Dr Chi Chung Wu (Croucher Fellowship 2018), of Germany’s Max Planck Institute for Heart and Lung Research, is determined to find out how to make this a reality – by turning the clock back on the heart muscle cell to the start of mammalian life.
Heart disease is the number one cause of death globally. Nearly one-third of all deaths worldwide are due to cardiovascular disease, according to the World Health Organisation, and 75 per cent of these involve heart attacks or strokes.
“Theoretically, understanding how cardiomyocytes fail cell division during the early postnatal stage could have an impact on finding therapeutics that we can use after heart attacks to promote cardiomyocyte proliferation for regeneration,” Wu said.
But this is a long-term project. “My primary interest is basic science; I just want to know how things work,” he said.
Wu has nursed a passion for biology since high school and completed his bachelor’s and MPhil degrees in molecular biotechnology at The Chinese University of Hong Kong before moving to Germany for further studies. Now, at the Max Planck Institute in Bad Nauheim, he is pursuing research into heart muscle cells – also known as cardiomyocytes.
The mechanics behind the regeneration of these cells remain poorly understood. “Cardiomyocytes are the heart cells that are important for the contractile function of the heart to pump blood,” Wu explained.
“The problem with mammalian hearts like ours is that after injuries like heart attacks we cannot regenerate our heart cells. A scar will form and the heart function will be compromised.” This is why heart attacks are so damaging to the vital organ and often reduce the heart’s ability to pump blood effectively.
“What is interesting about mammalian cardiomyocytes is that in the embryonic stage, all the cardiomyocytes are mononuclear, meaning they have one nucleus and are highly proliferative,” Wu explained.
“But shortly after birth, rodent cardiomyocytes lose the ability to undergo cytokinesis (cell division), the last step of the cell cycle, so instead of dividing into two cells they will become a single cell with two nuclei. This transition greatly reduced their proliferative and regenerative capacity. However, the underlying mechanisms are poorly understood.”
Mammalian organs retain some limited regenerative capabilities. For instance, our livers can regrow fairly well. “In mouse models, for instance, after a significant loss of hepatocytes, they are able to proliferate and regenerate, unlike cardiomyocytes,” Wu said.
This is a useful trait, but it pales in comparison to the regenerative abilities of other members of the animal kingdom that far surpass our own. “For mammals – mice, rats, humans – the regenerative capacity is extremely low for most, if not all, of the organs,” he explained. “But for lower vertebrates like zebrafish and axolotl, these animals have much higher regenerative capabilities in their heart, in their appendages, and so on.”
Zebrafish in particular are considered the standard regenerative model for cardiac repair research. Studying for his PhD at a Max Planck Institute in Dresden and later Ulm University, the fish’s tiny hearts played an outsized role in his work, thanks to their unique properties. “Within 30 to 60 days, zebrafish hearts are completely healed. It is like nothing happened to them,” he said.
Why can’t most human cells regenerate like axolotl and zebrafish? “That’s the million dollar question,” Wu said. “People have been working on this for decades and we don’t know, but probably during evolution we lost this capability to regenerate organs.”
Mammals, like many of their aquatic and amphibious kin, begin life with mononuclear cardiomyocytes that are able to regenerate. Yet in the days, weeks, and for humans, years after birth, mammalian cardiomyocytes stall during mitosis and/or cytokinesis, causing polyploidisation – meaning the cells have more than two paired sets of chromosomes.
Wu and other scientists in his field perform tests on the cells of new-born rats and mice to better understand the poor regenerative capabilities of mammal cardiomyocytes compared with other types of animals.
“The primary goal is to understand what promotes the binucleation of cardiomyocytes,” Wu said. “My postdoc work focuses on understanding [the role of] other cell types in the heart in terms of the cardiomyocytes’ transition from cell division to binucleation.
“I found that postnatal cardiac fibroblasts promote cardiomyocyte binucleation through modulating the extracellular matrix. I also identified two embryonic extracellular matrix proteins that are able to promote cardiomyocyte cytokinesis.”
Wu also pointed out: “Each and every cell type behaves differently in different situations.” This can make it difficult to find patterns of cell behaviour, but means this research could yield results outside the realm of expectation.
So, don’t expect to see humans growing second hearts anytime soon. But 30 years in the future, it could be happening.
Dr Chi Chung Wu received his BSc in Molecular Biotechnology at the Chinese University of Hong Kong in 2008 and his MPhil in 2010. He joined the International Max Planck Research School for Cell, Developmental and Systems Biology in Dresden, Germany, for his doctoral studies under the supervision of Professor Gilbert Weidinger to study heart regeneration in zebrafish and received his PhD in 2016. Currently, he is a postdoctoral fellow in the laboratory of Professor Didier Stainier in the Max Planck Institute of Heart and Lung Research.
To view Dr Wu’s Croucher profile please click here.