When you think of your ideal neighborhood, maybe you think of tree-lined streets or a tight-knit community that helps each other. You may not think about your digestive system, but maybe you should. According to a team of scientists led by researchers at Stanford University School of Medicine, "neighborhoods" of different types of cells do exist that work together to digest food, protect you from infection, and more.
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The images were produced using advanced imaging techniques that allow us to study cells in the human gut. Using a combination of microscopy and robotics, these scientific visuals provide a window into the intricate world of cellular diversity. The various colors in the image represent specific molecules expressed in different cell types. These molecules, such as proteins, play a crucial role in determining the identity and function of every cell in the gut. By "painting" or "labeling" specific cells with different colors, we can gain insight into the complex interactions and structures within the gut. In this particular image, each color corresponds to a specific molecule, providing information about the presence and distribution of different cell types or structures. Image credit: Stanford University School of Medicine/Snyder Laboratory/Nolan Laboratory/Greenleaf Laboratory
Just as human communities have common elements such as streets, restaurants and houses, cellular communities are made up of varying numbers of cell types with specific functions. By combining several new imaging and sequencing technologies, the researchers were able to map these neighborhoods down to the level of individual cells.
"This is the first time anyone has mapped the gut space at the single-cell level," said Dr. Michael Snyder, professor and chair of genetics and co-first author of the study, which was published July 19 in the journal Nature. "It's a bit like exploring a new planet because we don't know exactly what cell types we'll find or how they're organized."
Draw a diagram of the intestines
Researchers from multiple laboratories at Stanford University School of Medicine and other institutions participated in the new mapping effort, which is part of the Human BioMolecular Atlas Program sponsored by the National Institutes of Health. Scientists on the project aim to create a comprehensive cellular map of the human body.
To map the gut, the scientists examined eight regions of the small and large intestines of nine deceased donors. The researchers used a technique called Co-indexed Detection (CODEX), which repeatedly stains and washes tissue with fluorescent antibodies (substances that bind to and image certain proteins), to identify 20 distinct cell neighborhoods based on the relative abundance of each cell type.
Additional molecular analysis of RNA and chromosomal material in some samples provided more detail in each cell type.
"Our atlas is intended to serve as a reference for a healthy gut that we can use to compare conditions ranging from irritable bowel syndrome to early colon cancer," said Snyder, the W. Ascherman, MD, FACS Professor of Genetics at Stanford University. "This will lay the foundation for our understanding of various digestive disorders."
The intestines are approximately 20 feet long and absorb nutrients from food and protect the body from microbial invasion while maintaining a healthy balance of good bacteria that aid digestion.
To accomplish these tasks, the intestine uses many types of cells, including epithelial cells, connective tissue cells, nerve cells, and immune cells that make up the intestinal lining. With the new map, scientists can determine where each cell type is located and which other cells they are related to. How cells fit together determines their function.
Snyder, director of the Center for Genomics and Personalized Medicine, and William Greenleaf, Ph.D., professor of genetics, co-led the study.
The researchers also wanted to observe how the organization of healthy tissue changes throughout the digestive tract, from near the stomach to near the rectum. "What's normal in one area may be a sign of disease in another area," said Dr. John Hickey, a postdoctoral fellow in microbiology and immunology and first author of the paper.
Some neighborhoods, such as those dominated by smooth muscle cells (which control involuntary movements), became more common at the end of the colon, while other neighborhoods composed mostly of immune cells became less common.
Relationship to body mass index and hypertension
In addition to providing a reference for health organizations, the new map also reveals some interesting clinical connections. For example, the researchers found that donors with a higher body mass index had significantly increased numbers of M1 macrophages, a type of immune cell associated with inflammation.
"People with a higher body mass index, especially above a certain level, are at higher risk for gastrointestinal disease," Hickey said. "Many of these diseases are associated with chronic inflammation. Although these donors had no history of gastrointestinal disease, the increase in macrophages may be an indicator of pre-disease processes."
Donors with a history of high blood pressure also had fewer of another type of immune cell called CD8 T cells, which play a role in finding and destroying possible cancer cells. Using spatial mapping, the researchers found that CD8 T cells were missing from a specific neighborhood of epithelial cells lining the gut.
"This is an unexpected but important result because we know that the immune system plays a role in preventing cancer by pruning out malignant cells," Hickey said. "If you have fewer CD8 T cells, the risk of cancer may be higher. In fact, studies have shown that people with high blood pressure are more likely to develop colorectal cancer."
future direction
In this study, all nine samples were from adult donors, and most were white and male. "One of our biggest goals next is to increase the diversity of our sample and get a more comprehensive representation of individuals, including a variety of ethnic backgrounds and age groups," Snyder said.
The scientists also hope to create a three-dimensional map of the gut, which will help them better observe the network of nerves and blood vessels in a healthy gut.