Healthy tissue atlases play a vital role in biomedical research by serving as a reference that can be compared with diseased samples.. These atlases can help scientists understand what goes wrong before a disease progresses, knowledge that, in parallel, can provide key information on the development of treatments for the early stages of pathology.
In this line of knowledge, Nature publishes three studies in which the reference cell maps for the human intestine, the kidney and the maternal-fetal interface (an element in which the placenta and maternal cells coexist) are presented.. These reports are part of a larger package of articles from the Human BioMolecular Atlas Program (HuBMAP), a consortium of more than 400 scientists from more than 40 global institutions.
The works uncover new information about how cell types are organized and how they interact in different human tissues and organs: how the individual cells of the organism live and work together in what are called 'cellular neighbourhoods', information that becomes a resource indispensable for studying biology and human disease.
Through tools -developed by the HuBMAP consortium, founded by the National Institutes of Health (NIH)- that allow to assemble spatial maps of cellular molecular components, including RNA, proteins and metabolites, within tissues and organs at the single cell level , reference cell atlases have been generated for human intestine, kidney, and placenta-connected tissues.
“The three HuBMAP atlases have the potential to advance our understanding of pathology by defining the spatial location of disease-linked cellular states,” Roser Vento-Tormo and Roser Vilarrasa-Blasi note in an accompanying News & Views article, of Nature. “They anticipate the generation of more atlases in other tissues, but note that further testing needs to be done in more samples to establish robust associations between cellular organization and function in health and disease.”
The intestinal 'neighborhood'
In one of the three works, the team led by Michael Snyder, Garry Nolan and William Greenleaf, from Stanford University in California, United States, have studied the human intestine, a complex organ with many different structures and functions, from digestion to support for the immune system, developing, “for the first time, a spatial map of this organ at the level of a single cell”, according to Synder, co-author of the research and director of Genetics at the aforementioned university.
To map the intestine, the scientists examined eight regions of the small and large intestine from nine deceased donors, identifying 20 distinct cellular 'neighborhoods' based on the relative abundance of each cell.. Additional molecular analysis of RNA and chromosomal material from some of the samples provided an even greater level of detail within each cell type; In short, there are radical variations in cell composition in different regions.
For Snyder, the new maps his team has developed “are intended to be a benchmark for a healthy gut, against which we can compare everything from irritable bowel disease to early-stage colon cancer.”. This will be critical to our understanding of all sorts of digestive diseases, as it is possible to identify where each type of cell is found and what other cells they associate with.”
Thus, new epithelial cell subtypes have been identified and different cell types have been found to form 'neighborhoods', some of which are specifically primed to mediate immune responses.
The findings reveal the complex and varied cellular composition that contributes to the functioning of this organ.. For example, in studying how the organization of healthy tissue changes throughout the digestive tract, from closer to the stomach to closer to the rectum, variations have been observed.
“Some 'neighborhoods,' such as those dominated by smooth muscle cells (which control involuntary movements) became more common toward the end of the colon, while other 'neighborhoods' made up primarily of immune cells became less common,” John says. Hickey , of Stanford's Department of Microbiology and Immunology, and first author of the paper, who adds that “what is normal in one region may be a sign of disease in another.”
The new maps have also offered some interesting clinical connections.. For example, people with a higher body mass index have been found to have much higher numbers of M1 macrophages, a type of immune cell associated with inflammation.
In addition, people with a history of high blood pressure also had fewer CD8 T cells, which play a role in finding and destroying potential cancer cells.. Using the spatial map, the researchers were able to see that CD8 T cells were missing from a particular 'neighborhood' within the epithelial cells lining the intestine.
“This was an unexpected but important result because we know that the immune system plays a role in preventing cancer by killing off malignant cells.. If you have fewer CD8 T cells, you may be at higher risk of cancer,” Hickey says.. In fact, research has shown that patients with hypertension are more likely to develop colorectal cancer.
New resources for renal pathology
In another of the articles collected by Nature, the single-cell atlas of the human kidney is presented, which provides new resources for studying and understanding kidney disease, with a starting question: why do some people with a sudden decrease in kidney function develop pathology? kidney disease while others recover?
Sanjay Jain, Matthias Kretzler, Kun Zhang, Tarek M.. El-Achkar, Pierre C. Dagher, y Michal T. Eadon, of the Universities of California and the Institute of Sciences, San Diego, Washington, Indiana, and Michigan, all in the United States, have provided detailed information, in individual cells, on the underlying factors contributing to these results that divergent results.
To do this, the researchers built the largest single-cell atlas of the human kidney to date that maps the states of healthy and diseased cells in more than 90 patients..
To build the atlas, more than 400,000 cells and nuclei were analyzed from a wide range of kidney samples from 45 people with healthy kidneys and 48 diseased ones: acute kidney injury and chronic kidney disease.
With single-cell and single-nucleus sequencing technologies to generate RNA expression and using gene expression profiles of cells, a single-cell and spatial atlas could be established by identifying 51 different populations of major cell types in different regions of the world. kidney. Cellular states and 'neighbourhoods' of renal epithelial, stromal and immune cells that are altered by acute or chronic injury have also been identified, including states related to whether repair pathways are successful or faulty, as well as 28 of these types. of cells are altered in acute kidney injury.
When kidney cells are injured they normally go into a state of repair, making new copies of themselves and releasing signals that recruit immune cells and fibroblasts to heal the injured area.. Subsequently, they return to their normal cellular state.
According to team member Blue Lake of the UC San Diego Department of Bioengineering, “These states of repair are important for healing, but they can become maladaptive.. If they persist or are constantly stimulated, the kidney will continue to be in a diseased state.”
The researchers found that these altered cell types, in the so-called 'maladaptive repair state', live in two areas of the nephrons, which are the main filtration units of the kidney.. The first area is called the proximal tubule, which is known from previous studies in mice.. This new study reveals that a second area in the nephrons, called the thick ascending limb, is also home to these altered cell types.
Maternal-fetal interactions through the placenta
The third of the investigations published in Nature on new human maps also comes from Stanford; this time the one related to the changing placenta.
Michael Angelo's team, from Stanford Medical School's Department of Pathology, which also includes Shirley Greenbaum, mapped the human placenta during the first half of pregnancy, providing the most detailed description to date of how Genetically mismatched maternal and fetal cells cooperate to restructure the uterine arteries.
“We mapped the intricate and highly coordinated dance between cells called trophoblasts, which originate on the fetal side of the placenta and send signals that coordinate artery remodeling, and the mother's immune system, which adapts to accommodate these changes. unknown cells as the placenta forms,” says Angelo.
For this, they analyzed around 500,000 cells and 588 arteries from 66 samples from the human maternal-fetal interface, an area where maternal and placental cells cooperate to support the fetus.. What the researchers make clear is that the maternal immune system is performing an activation function of the entire process of artery remodeling..
The findings, according to the work, can serve as a springboard to unravel medical problems in pregnancy, such as infertility or preeclampsia, going through organ transplantation to even cancer.
Angelo suggests that the data may help explain and lead to treatments for certain types of infertility, as previous research suggests that some miscarriages occur because the immune system fails to accommodate enough development of the placenta to maintain the pregnancy.. “Recruiting maternal-fetal tolerance around the second or third month of pregnancy is critical to getting through the first trimester.”
Too small a change in immune tolerance could also explain the poor remodeling of the arteries found in pre-eclampsia, and try to anticipate who is at risk and provide some kind of preparation for the immune system before pregnancy.”.
The cancer connection
When it comes to organ transplants, the researcher notes that “by looking at tolerance in the context of pregnancy, we might find better ways to address long-term organ tolerance in transplantation.”. And about the potential to better understand the development of certain types of cancer, scientists suspect the two traits are connected: that tumors take unfair advantage of the immune flexibility that allows the formation of a healthy placenta..
Some of the new study's findings support this idea, including the overlap the researchers saw between the genetic pathways that activate trophoblasts and previously identified cancer pathways..
“Increased placental invasiveness comes at a cost,” says Angelo, who stresses that “we believe that the cracks in the immune system's armor that allow us to thrive in the womb become a vulnerability to cancer later on.”
