In This Article
- Massachusetts General Hospital cardiology researchers have created a complex cellular map of the heart
- The study utilized a novel method of single nucleus testing to analyze RNA in individual nuclei of cardiac cells
- The researchers found more cellular diversity and specificity than expected: a healthy heart has nine major cell types and more than 20 other subclusters, and cells may behave differently depending on their chamber location
- Investigators are now examining genetic data and comparing their map to cells from common cardiovascular diseases to identify potential drug targets
A research team led by a Massachusetts General Hospital cardiologist has developed a comprehensive cellular map of the healthy human heart, revealing surprising cell diversity and specificity by chamber. The baseline information about normal cardiac tissue will help the investigators and others answer essential questions about cardiac pathology.
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The research, conducted with the Precision Cardiology Laboratory (PCL) at the Broad Institute of MIT and Harvard, was published in Circulation and is the largest study to date using a new method called single nucleus sequencing on the human heart. The method has uncovered several new cell types, differences in cell behavior by heart chamber and a variety of gene expression patterns.
"Ultimately, the findings will help facilitate the development of new cardiovascular disease therapies," says Patrick T. Ellinor, MD, PhD, senior author on the study, director of the Telemachus & Irene Demoulas Family Foundation Center for Cardiac Arrhythmias at the Mass General Corrigan Minehan Heart Center, and director of the PCL.
Single Nucleus Sequencing Profiles Cells with Precision
Originally, the researchers wanted to understand the genetics of heart failure. "That condition has been somewhat more elusive than other types of heart disease because it's a more heterogeneous disorder," says Dr. Ellinor, who led the study. "However, before we began studying any specific disease, we thought it was important to define what's normal."
Studying heart tissue can be challenging, even with modern single-cell sequencing. Cardiomyocytes are too large to be processed by standard devices and methods.
"If you just take a piece of heart tissue, the largest mass of it is made up of heart muscle cells. They're the biggest cells by volume, and they dwarf every other cell," Dr. Ellinor says.
So the research team, in a partnership with Bayer, utilized single nucleus sequencing. The new approach breaks up cells and analyzes RNA in individual nuclei rather than in whole cells. Single nucleus sequencing allowed the investigators to see the individual components of each individual cell type at a very high resolution.
"The beauty of single-cell sequencing is that it gives us the transcriptional profile for each individual cell," Dr. Ellinor says.
The researchers applied the new single nucleus technique on tissues from each heart chamber in seven human donors with no overt cardiac disease. They then performed single-cell nuclear RNA sequencing to profile 287,269 individual nuclei.
Results Reveal Diverse Cellular Map of the Heart
The findings defy the perception that the heart is a homogeneous organ. The study identified nine major cell types within the human heart. Within those major types were more than 20 additional subclusters of cell types, including two distinct groups of resident macrophages, four endothelial subtypes and two fibroblast subsets.
"There was a lot more diversity of cell types than you would see if you just looked at them in aggregate," Dr. Ellinor says of the results. "Furthermore, there was a surprising amount of diversity in the other cell types between the different chambers of the heart."
Dr. Ellinor says that when researchers develop further studies or therapies, they will need to understand not only the type of cells they examine but the behavior of those cells based on chamber location due to this newly elucidated complexity.
Map Helps Locate Therapeutic Targets in Cardiovascular Disease
The investigators also applied other human genetics data to identify gene expression patterns in different parts of the heart. They anticipate that the information will help researchers more efficiently find potential targets for future treatments.
"In the case of atrial fibrillation (AFib), for example, you might have a region strongly associated with the disease, but in that region, you might have 10 genes. You can't study all 10 of them, and you don't know which one is the causative gene for AFib. And you can't afford to spend years and millions of dollars working on the wrong gene," Dr. Ellinor says. "But if you have data from many cell types in the heart, you can quickly narrow down a disease associated gene that would be a potential therapeutic target."
Dr. Ellinor's team started by looking for cardiac cell types that express genes with known links to cardiovascular disease. That information will help drug developers narrow down specific therapeutic targets, he says. They found that most genes already associated with disease were expressed in three specific cardiac cell types: fibroblasts, cardiomyocytes and fat cells.
Navigating From Data to Disease
With a reference map of the healthy human heart, researchers can begin to better understand what goes wrong in disease. For example, Dr. Ellinor's team will take individual cells from patients with certain cardiac conditions and compare them to the cells from healthy cardiac tissue. Among the first diseases they are already examining include dilated and hypertrophic cardiomyopathy, ischemic myopathy and AFib.
In another recent paper in Circulation, the team examined SARS-CoV-2 and other coronaviruses to determine how they may affect the heart with late-stage complications. They have shared their map with the larger scientific community so that other research groups may use it to generate more data and identify therapeutic targets.
Learn more about the Telemachus & Irene Demoulas Family Foundation Center for Cardiac Arrhythmias
Refer a patient to the Corrigan Minehan Heart Center