Proper heart development all about timing

Much like babies at birth, stem cells harbor the magic of possibility. A stem cell has the potential to become a multitude of different adult cells within the body. It could eventually mature—or differentiate—into a fat cell or heart cell or nerve cell, for example.

Cells in transition between a stem cell and adult cell are known as progenitors. Some progenitors are maintained within the body and used throughout a person’s life to repair and replenish organs and tissues. Others complete differentiation into mature cells during embryonic development, forming essential components of an embryo’s organs, including the heart.

Ivan Moskowitz, MD, PhD, professor of pediatrics, pathology, and human genetics, and his team of researchers at the University of Chicago are interested in the timing of differentiation—why some progenitors differentiate quickly whereas others are maintained as progenitors for much longer. They have studied this in the context of heart development and have found that issues with timing can lead to congenital heart defects (CHD)—also known as congenital heart disease—which affect about one in 100 babies born each year.

“Since the introduction of genetics to the field of developmental biology, researchers have been focused on the process of specification—what tells a stem cell to become either a heart cell or a fat cell, for example,” says Megan Rowton, PhD, postdoctoral scholar in the Moskowitz lab. “They haven’t really been focused as much on the timing of that process—when or what controls the timing of progenitor differentiation.”

A game of telephone

So, what keeps a cell in the progenitor stage until it is time for it to fully mature?

The Moskowitz lab discovered that a pathway called Hedgehog signaling controls differentiation timing. A signaling pathway is a group of molecules that are sent from one cell to another, and that tell the receiving cell how to behave. Like a flowchart, information is transmitted in a step-by-step process. Like a game of telephone, disrupt the flow of information and things can go awry.

The heart, for example, forms from two distinct groups of progenitor cells. The first group differentiates early and forms a primitive heart tube. The second group waits nearby and then migrates into the heart tube before differentiating into structures such as the pulmonary artery and atrial septum. Rowton and Moskowitz have found that Hedgehog signaling dictates when the second group differentiates—it’s all about timing.

“The way it seems to be working is when the Hedgehog signaling pathway is active in progenitors, then you have a delay in differentiation,” Rowton says. “Once the pathway is removed, however, the cells are released to finish the process of differentiation. If you don’t hold those cells back from differentiating, then you don’t end up creating very important parts of the heart. So, proper control of the timing of differentiation is really important.”

For example, common CHDs called atrioventricular septal defects, where there are holes between the chambers of the right and left sides of the heart, can form when the Hedgehog pathway is shut down and cells are allowed to differentiate too early. In such cases, they differentiate before they have migrated into the heart and, therefore, remain outside of the heart.

Rowton and colleagues in the Moskowitz lab are studying the downstream effect of Hedgehog signaling disruption. What happens to the genes within a cell’s nucleus at the end of a pathway when something goes wrong at the beginning? They are specifically focused on transcription—the process whereby certain proteins, called transcription factors, go into the cell’s nucleus and either turn on or turn off target genes.

“If you think about the signaling pathway as a flowchart, any of those steps along the way can be disrupted,” she says. “We are particularly interested in the endpoint of that flowchart, the transcription factors in the nucleus. And we’re really interested in what happens when their function is either activated too much or too little. What genes get turned on or turned off inappropriately due to the activity of these transcription factors, and how does this lead to CHD?”

Effects on more than just congenital heart disease

Interestingly, Hedgehog signaling is not only active in heart development, but also in the developing face, brain, limbs, and other organs.

One famous example of Hedgehog signaling gone wrong is a case from 1957 where sheep on an Idaho ranch were being born with a head and brain deformity that gave them one cyclops-like eye. After a decade of research, scientists discovered that the sheep’s diet of corn lily was to blame. The plant contains a naturally occurring chemical, dubbed cyclopamine, that interrupts Hedgehog signaling. However, why this disruption caused the malformations is still not well understood.

“We have a hunch that perhaps Hedgehog signaling is needed to keep many different types of progenitors from differentiating too early in the embryo,” Moskowitz said. “If Hedgehog signaling doesn’t work properly, we suspect that progenitors in many organs prematurely differentiate, depleting the progenitor pool required for an organ’s normal development and resulting in a malformation.”

Conversely, the Moskowitz lab predicts that keeping Hedgehog signaling active too long would inappropriately maintain a progenitor pool, which may cause a tumor or contribute to cancer. Too much Hedgehog signaling can lead to conditions like Gorlin syndrome, where various cancerous and noncancerous tumors can form uncontrollably all over the skin.

Moskowitz and his team hope to eventually translate their findings into improved diagnostic and treatment approaches for patients with CHD, as well as other disease types influenced by Hedgehog signaling.

“It is currently a very exciting stage in our studies,” Moskowitz said. “These findings have implications for understanding the cause of CHD, but may also illuminate birth defects of many other organs. The ability of Hedgehog signaling to control progenitor differentiation timing may also explain its implication in some adult degenerative diseases and cancers. Understanding the role of Hedgehog signaling in these processes in more detail may allow us to intervene, to ensure that organs develop normally and are maintained properly in adulthood.”

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