The Human Cell Atlas consortium has added important pieces to the creation of the full map of human cells, offering new insights into gene activity in specific cell types and how immune cells behave in various human tissues and organs.
Through four studies simultaneously published in Science, international teams of researchers offered detailed single-cell and single-nucleus transcriptome maps of more than 1 million human cells across 500 cell types in 33 tissues and organs.
They uncovered some unexpected cell features, signaling mechanisms and genetic traits. The publicly available findings could inform the understanding of human health and disease states and aid the development of diagnostics as well as anti-tumor immunotherapies, vaccines and regenerative medicines.
In two studies, scientists from Wellcome Sanger Institute, the University of Cambridge and other collaborators looked at immune cells in the human body, one focused on the early development of the immune cells across several tissues, and the other on immune cells in adults to understand their states in different tissues.
“You can think of it as a Google Map of the human body, and it’s really that street map’s view of the individual cells and where they sit in tissues that we are aiming towards,” Sarah Teichmann, Ph.D., of the Wellcome Sanger Institute and co-corresponding author of both studies, explained during a press conference.
Beyond commonly studied immune cells in the blood, the scientists also examined the tissues that create immune cells, the tissues where immune cells migrate to, such as the skin, gut and lung, and where the immune cells mature, such as lymph node and the spleen, she said.
In one shocking finding, the team tracked blood stem and progenitor cells not only in professional immune tissues—where they’re expected—but also in embryonic gut and skin. Turns out, B-cell progenitors receive input signals for their development from immune cells in the gut in addition to the bone marrow. This finding is important for engineering immune cells outside the body, Teichmann said, because it offers new clues to what signaling should be put in.
Besides, they found that T cells in the thymus are also talking to each other rather than just from their parent thymic epithelial cells during maturation.
In the second study, Teichmann and colleagues sequenced RNA from 330,000 single immune cells from 16 tissue sites across the adult body to understand their specific functions in different tissues. Teichmann described the process as finding “the molecular GPS system for immune cells that locates them to specific organs around the body.”
The team developed a machine-learning algorithm, called CellTypist, to automate cell type identification. Using CellTypist, the researchers created a cross-tissue immune cell atlas that revealed the relationship between immune cells in different tissues.
Analyses showed some immune cells like macrophages share common signatures across tissues, whereas others like memory T cells have “different flavors” depending on which tissues they reside in, Teichmann said.
“Knowing the code of which molecules direct and maintain T cells to specific tissues is important for engineering and targeting cells for cancer therapies,” Teichmann said. With the findings, future researchers could find inspiration to either enhance or suppress specific immune cells to fight disease or help design vaccines, she added.
In the third study led by the Broad Institute of MIT and Harvard, scientists used single-nucleus RNA sequencing to generate a cross-tissue atlas of the nuclei profiles from nearly 210,000 cells.
One of the main applications of a full human cell atlas is to identify the cell types where disease genes act. Identifying the precise cells where disease arises would allow for the development of more precise diagnostic and new treatment, Aviv Regev, Ph.D., of the Broad Institute and currently head of Roche’s Genentech Research and Early Development, said during the press briefing.
For their study, Regev and colleagues compared the cells across tissues. They found that macrophages take on a particular “pair of flavors” in every tissue they looked at, but the flavors arise in different ratios to support different functions.
The researchers also observed a similar phenomenon for fibroblasts, which are connective tissues, as the cells acquire different properties at different locations. In the lungs, fibroblast cells express genes that sense mechanic tensions to help the lung contract, the team found.
Using machine learning algorithms, the team also associated the cells in the atlas with 6,000 single-gene diseases and 2,000 complex genetic diseases involving multiple genes. They identified cell types and genetic signaling that could be implicated in disease, opening new venues for further research into these conditions.
In one example, the team found non-muscle cell types that are implicated in muscular dystrophy. Even though a problematic mutation exists in genes that are not expressed by muscle cells, it’s affecting other cells in muscle tissues that are critical for muscle function to cause muscular dystrophy, Regev explained.
In another finding that emphasizes the potential of the human cell atlas in assisting precision medicine, Regev’s team showed that genes that are associated with the risk of atrial fibrillation are also used by cells in the skeletal muscle of the esophagus and the prostate.
“Now we can try and devise ways to target more specifically to the cells where we want to have an impact but not to target other cells that are also using these genes in a body,” she said.
The fourth study was conducted by the Tabula Spaiens Consortium, a team of more than 160 experts led by scientists at the Chan Zuckerberg Biohub. Led by Stephen Quake, Ph.D., at Stanford University, the team mapped gene expression in nearly 500,000 cells from 24 human tissues and organs with a focus on collecting samples from the same donors, which allowed researchers to screen out certain background variations such as age.
In one unexpected finding, researchers found that sets of housekeeping genes—which have been thought to handle basic functions in much the same way in every cell—likely have many more roles across the body than was previously thought.
The team also showed that the CD47 protein, which is implicated both in cancer and in the buildup of dangerous plaques on artery walls, may differ widely among cells. Once again, the finding could guide the development of more effect drugs with fewer side effects, the researchers argue.
Based on the tissue samples, Quake and colleagues also took the opportunity to look at gut microbiome profiles. After sequencing the bacterial genes and working out their spatial relationships, the team discovered complex structures to the microbiome species as they move through the intestines, Quake said.
Overall, “[t]hese pan-tissue human cell atlases form important reference datasets for understanding and predicting the side effects and safety issues of new medicines,” two researchers from China's Peking University wrote in an accompanying editorial.
In addition, “understanding both shared and tissue-specific features of tumorigenesis is key to the development of histology-agnostic and cancer type-specific therapeutics,” they added.