Stem cells reveal how hearts are made – and broken

Australian scientists have induced about 40,000 skin-derived human pluripotent stem cells to develop into cardiomyocytes – heart cells – in order to map the intricate interplay of the 1700 genes that influence the development of the organ.

The result – an extraordinary mat of rhythmically beating tissue – represents the most in-depth study ever completed into the genetic forces that govern heart development.

In a paper published in the journal Cell Stem Cell, researchers led by Nathan Palpant from the Institute for Molecular Bioscience at the University of Queensland, reveal detailed single-cell RNA sequencing to map how the stem cells gradually morphed into mature cardiomyocytes.

The researchers hope that the work will illuminate avenues to overcome the human heart’s greatest weakness. Unlike those found in other parts of the body, such as limbs, the skin and liver, cells in the heart lack the capacity to self-repair once they have been damaged – which is one of the reasons that heart disease is the leading cause of death around the world.

“The big challenge, as we see it, is to uncover new approaches and new insights into ways to help the heart repair itself,” explains Palpant.  

“We think the answers to heart repair almost certainly lie in understanding heart development. If we can get to grips with the complex choreography of how the heart builds itself in the first place, we’re well placed to find new approaches to helping it rebuild after damage.”

The work is already paying dividends. Palpant and colleagues discovered that one particular gene, known as HOPX, acts like a switch, making heart cells shift from an immature phase – during which they are still capable of dividing – into a large, more stable and non-divisible form. If HOPX malfunctions, the result is an abnormally large heart, a condition known as hypertrophy.

Learning how to control the gene, thus, will be a crucial step in accurately controlling the growth of lab-based, stem-cell derived heart cells.

“The development of the heart is like an intricate dance,” says co-author Joseph Powell of the Garvan-Weizmann Centre for Cellular Genomics in Melbourne, Australia.  

“Each cell goes through its own series of complex, nuanced changes. They are all different, and changes in one cell affect the activity of other cells. By tracking those changes across the different stages of development, we can learn a huge amount about how different subtypes of heart cells are controlled, and how they work together to build the heart.”