How stem cells know the right way to make a heart . And what goes wrong when they don’t

Gladstone scientists Deepak Srivastava (left), Yvanka De Soysa (center), and Casey Gifford (right) publish a complete catalog of the cells involved in heart development.

The invention of GPS navigation systems has made finding your way around so much easier, providing simple instructions on how to get from point A to point B. Now, a new study shows that our bodies have their own internal navigation system that helps stem cells know where to go, and when, in order to build a human heart. And the study also shows what can go wrong when even a few cells fail to follow directions.

In this CIRM-supported study, a team of researchers at the Gladstone Institutes in San Francisco, used a new technique called single cell RNA sequencing to study what happens in a developing heart. Single cell RNA sequencing basically takes a snapshot photo of all the gene activity in a single cell at one precise moment. Using this the researchers were able to follow the activity of tens of thousands of cells as a human heart was being formed.

In a story in Science and Research Technology News, Casey Gifford, a senior author on the study, said this approach helps pinpoint genetic variants that might be causing problems.

“This sequencing technique allowed us to see all the different types of cells present at various stages of heart development and helped us identify which genes are activated and suppressed along the way. We were not only able to uncover the existence of unknown cell types, but we also gained a better understanding of the function and behavior of individual cells—information we could never access before.”

Then they partnered with a team at Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg which ran a computational analysis to identify which genes were involved in creating different cell types. This highlighted one specific gene, called Hand2, that controls the activity of thousands of other genes. They found that a lack of Hand2 in mice led to an inability to form one of the heart’s chambers, which in turn led to impaired blood flow to the lungs. The embryo was creating the cells needed to form the chamber, but not a critical pathway that would allow those cells to get where they were needed when they were needed.

Gifford says this has given us a deeper insight into how cells are formed, knowledge we didn’t have before.

“Single-cell technologies can inform us about how organs form in ways we couldn’t understand before and can provide the underlying cause of disease associated with genetic variations. We revealed subtle differences in very, very small subsets of cells that actually have catastrophic consequences and could easily have been overlooked in the past. This is the first step toward devising new therapies.”

These therapies are needed to help treat congenital heart defects, which are the most common and deadly birth defects. There are more than 2.5 million Americans with these defects. Deepak Srivastava, President of Gladstone and the leader of the study, said the knowledge gained in this study could help developed strategies to help address that.

“We’re beginning to see the long-term consequences in adults, and right now, we don’t really have any way to treat them. My hope is that if we can understand the genetic causes and the cell types affected, we could potentially intervene soon after birth to prevent the worsening of their state over time.

The study is published in the journal Nature.

Sequencing data helps us understand the genes involved in heart cell development

skin cells to beating heart

Human heart cells generated in the laboratory. Image courtesy of Nathan Palapant at the University of Queensland

Heart disease is the leading cause of death for both men and women in the United States and is estimated to be responsible for 31% of all deaths globally. This disease encompasses a wide variety of conditions that all effect how well your heart is able to pump blood to the rest of your body. One of the reasons that heart disease is so devastating is because, unlike many other organs in our bodies, heart tissue is not able to repair itself once it is damaged. Now scientists at the Institute for Molecular Bioscience at the University of Queensland and the Garvan Institute for Medical Research in Australia have conducted a tour de force study to exquisitely understand the genes involved in heart development.

The findings of the study are published in the journal Cell Stem Cell. in a press release, Dr. Nathan Palapant, one of the the lead authors, says this type of research could pay dividends for heart disease treatment because:

“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.”

To determine which genes are involved in heart cell development, the investigators use a method called single cell RNA sequencing. This technique allowed them to measure how 17,000 genes (almost every gene that is active in the heart) were being turned on and off during various stages of heart cell development in 40,000 human pluripotent stem cells (stem cells that are capable of becoming any other cell type) experimentally induced to turn into heart cells.  This data set, the first of its kind, is a critical new resource for all scientists studying heart development and disease.

Interestingly, this study also addressed a commonly present, but rarely discussed issue with scientific studies: how applicable are results generated in vitro (in the lab) rather than the body, in the context of human health and disease? It is well known that heart cells generated in the lab do not have the exact same characteristics as mature heart cells found in our bodies, but the extent and precise nature of those discrepancies is not well understood. These scientists find that a gene called HOPX, which is one of earliest markers of heart cell development, is not always expressed when it should be during in vitro cardiac cell development, which, in turn, affects expression of other genes that are downstream of HOPX later on in development. Therefore, these scientists suggest that mis-expression of HOPX  might be one reason why in vitro heart cells express different genes and are distinct from heart cells in humans.

The scientists also learned that HOPX is responsible for controlling whether the developing heart cell moves past the “immature” dividing phase to the mature phase where cells grow bigger, but do not divide. This finding shows that this data set is powerful both for determining differences between laboratory grown cells versus mature human cells, but also provides critical biological information about heart cell development.

Joseph Powell, another lead author of this research, further explains how this work contributes to the important fundamentals of heart cell development:

“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 sub-types of heart cells are controlled, and how they work together to build the heart.”