The research projects in Michael Snyder, PhD’s lab at Stanford cover a wide range of interests; COVID-19, the NASA twin study, and personal omics profiling to name some examples. Another interest of Snyder’s is spatial biology. He told GEN earlier this year that uncovering cellular interactions using spatial will be “super cool,” especially since doing so promises to reveal how cells communicate with each other. And, that researchers will be able to uncover biology that nobody has ever been able to get at before.

Now, the Snyder lab—working together with collaborators—has published the first spatial map of the intestine at the single cell level. To map the intestine (which is over 9 m long) scientists examined eight regions of the small and large intestine from nine deceased donors using CODEX (co-detection by indexing) technology which involves staining and washing the tissue repeatedly with fluorescent antibodies. In doing so, the researchers identified 20 distinct cellular neighborhoods based on the relative abundance of each cell type. Additional molecular analysis of RNA and chromosomal material from some of the samples provided an even greater level of detail within each cell type.

spatial map
Spatial image of the intestine [Stanford Medicine/Snyder lab/Greenleaf lab/Nolan lab]
The team found, “cell compositions that differ substantially across regions of the intestine and demonstrate the complexity of epithelial subtypes, and find that the same cell types are organized into distinct neighborhoods and communities, highlighting distinct immunological niches that are present in the intestine.”

The work is published in Nature, in the paper, “Organization of the human intestine at single-cell resolution.

“This is the first time anyone has made a spatial map of the intestine at the single-cell level,” said Snyder, professor and chair of genetics at Stanford School of Medicine. “It was a bit like exploring a new planet, in that we didn’t know exactly what cell types we would find or how they would be organized.”

“Our maps are intended to be a reference for a healthy intestine, with which we can compare everything from irritable bowel disease to early-stage colon cancer,” he continued. “This will be foundational for our understanding of all kinds of digestive diseases.”

The intestine employs a variety of cell types, including epithelial cells that make up the intestinal lining, connective tissue cells, nerve cells, and immune cells. With the new maps, scientists were able to pinpoint not only where each cell type is located, but also which other cells they associate with.

“Looking at the presence or absence of a single cell doesn’t tell you much,” said Garry Nolan, PhD, professor of pathology at Stanford. “It’s how cells are grouped together that defines their functionality.”

The researchers also wanted to investigate the organization of healthy tissue and how it changed throughout the digestive tract. “What’s normal in one region might be a sign of disease in another,” said John Hickey, PhD, a post-doc in the Snyder lab.

Some neighborhoods, such as the one dominated by smooth muscle cells became more common toward the end of the colon, while other neighborhoods composed primarily of immune cells became less common.

In addition to creating a reference for healthy tissue, the new maps revealed some interesting clinical connections. For instance, the researchers found that donors with higher body mass index had a greatly increased number of M1 macrophages, which are associated with inflammation.

“People who have a higher body mass index, especially above certain levels, are known to have higher risk for gastrointestinal disease,” Hickey said. “Many of those diseases are associated with chronic inflammation. Even though these donors didn’t have a history of GI disease, the increase in macrophages could be an indicator of a pre-disease process.”

Donors with a history of hypertension also had fewer CD8 T cells, which play a role in seeking out and destroying possible cancer cells. With the spatial map, the researchers were able to see that the CD8 T cells were missing from one particular region within the epithelial cells lining the intestine.

“This was an unexpected but important result,” Hickey said, “because we know the immune system plays a role in preventing cancer by pruning out malignant cells. If you have fewer CD8 T cells, you might have a higher risk of cancer.”

In this study, all nine samples came from adult donors, and the majority were white and male. “One of our biggest next steps is to increase the diversity of the samples,” Snyder said. “Our goal is to get a much more comprehensive set of individuals, including multiple ethnic backgrounds and age groups.”

The scientists also hope to map the intestine in three dimensions, which will help them better visualize the networks of nerves and blood vessels in the healthy intestine.

“You can’t understand dysfunction until you understand what’s normal,” Nolan said.

spatial map
[Stanford Medicine/Snyder lab/Greenleaf lab/Nolan lab]
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