The findings could pave the way for better predicting lymphatic complications in children with single-ventricle heart disease.
Researchers at Children’s Hospital Los Angeles have uncovered molecular signals that shape a little-understood network of vessels in the heart, offering new insight into both its normal formation and its response to injury.
The study, published in Nature Communications – Opens in a new window, showed how two genes work together to regulate the development of cardiac lymphatic vessels, which remove excess fluid and immune cells from the heart. The research was led by senior author Ching-Ling (Ellen) Lien, PhD, an investigator in the Heart Institute at CHLA, and first author Xidi Feng.
These cardiac lymphatic vessels use the same key signaling molecules as the lymphatics throughout the body. The discovery might open the door to better understanding why some children with single-ventricle heart disease develop serious lymphatic complications. Children’s Hospital Los Angeles treats more children with single-ventricle heart defects than almost any other center in the world.
“Compared with cardiac muscle cells and blood vessels, we know relatively little about the heart’s lymphatic vessels,” Dr. Lien says. “Learning how these vessels develop is an important first step in uncovering what happens when they do not function properly.”
A delicate balance shapes lymphatic vessel growth
The researchers studied cardiac lymphatic vessels in zebrafish, an established model for heart development and regeneration. They found that two genes, adma and ackr3a, work together to regulate the growth of these vessels.
The adma gene produces a signaling molecule that promotes this growth, while ackr3a encodes a receptor that limits how much of the signal is available.
When the researchers disrupted adma, the vessels were abnormally patterned, with fewer sprouts and abnormally enlarged vessels. Disrupting ackr3a produced the opposite effect: increased lymphatic cell budding.
“These genes appear to work together to maintain the right balance,” Dr. Lien says. “Too much or too little of the signal can alter how these vessels develop.”
The genes also affected the vessels’ ability to clear immune cells after heart injury. But while disrupting ackr3a accelerated that clearance, it did not improve heart muscle regeneration or scar resolution, Dr. Lien notes.
In addition, researchers identified several distinct populations of lymphatic cells, suggesting that these cells may perform different functions in the heart.
Novel method reveals hard-to-see cells
Cardiac lymphatic cells have been challenging to study because they are relatively few in number and are difficult to distinguish from surrounding tissue.
To overcome this issue, the researchers worked with CHLA’s Spatial Biology and Genomics Core to apply an advanced single-cell spatial transcriptomics method called seqFISH.
Using this technology, the team could examine which genes were expressed in individual cells while preserving each cell’s location in the heart.
“That allowed us to see how lymphatic cells interact with the surrounding tissue and helped us identify signals that would otherwise be difficult to detect,” Dr. Lien says.
Looking for patterns in single-ventricle hearts
Dr. Lien’s team will next work with CHLA cardiac surgeons to study tissue removed from children with single-ventricle heart disease as part of clinically necessary procedures.
The researchers will examine the tissue to look for abnormal patterns in these genes. One goal is to see whether those patterns might serve as biomarkers to predict patients’ risk for lymphatic complications, which can cause fluid buildup in the lungs and other organs.
That’s important because clinicians cannot currently predict which patients with single-ventricle heart defects will develop these complications, which can sometimes be life-threatening.
“The goal is to eventually recognize which children are at risk before they develop a lymphatic complication,” Dr. Lien says. “That could allow physicians to intervene earlier and ultimately improve outcomes. We also hope to further determine whether the candidate genes we identified can be therapeutic targets.”
Learn more about the Heart Institute at CHLA.