▲ This achievement is on theThe cover of the latest issue of Science magazine
It is like a set of “Encyclopedia of Human Cells”,The Human Cell Atlas project aims to map every cell type in the human body at the resolution of a single cell, including their molecular characteristics, how they interact with other cells, and more.
In the previous phase of this international project, the scientists mainly focused on gaining insights into the cell types of a single organ or tissue, such as the heart, kidney, thymus, etc.The four studies published this time are all “pan-tissue”, that is, the cellular atlas that integrates multiple organs and tissues of the human body, using a systematic cell nomenclature, can compare the distribution of specific cell types in different tissues, as well as tissue-specific gene expression, revealing new cellular functions.
Such a detailed atlas of human cells will provideUnderstanding common and rare diseases, vaccine development, anti-tumor immunity and regenerative medicine and other important issues related to the health of all human beingsProvide insight.
In the first study, the scientists created the so-called “Tabula Sapiens” dataset as a reference benchmark, creating a comprehensive sketch of the human cell atlas.
From organs donated by multiple human subjects,Researchers collected nearly half a million live cells for single-cell RNA sequencing (scRNA-seq), depicting more than 400 cell types in 24 organ tissues, including epithelial cells, endothelial cells, stromal cells and immune cells.
The research team developed a method to analyze the huge data,Simultaneous analysis of multiple organs from a single donor. Therefore, factors such as genetic background, age, environmental exposure, and epigenetic effects can be avoided when comparing cell types across tissues, and different tissues can be integrated to examine disease-related variants.
▲The Tabula Sapiens dataset contains 24 different tissues and organs, and can also directly sample and analyze the human microbiome of the entire gastrointestinal tract (Image source: Reference [1])
In this sketch,Some new insights into human cell biology have emerged. For example, the same gene is spliced differently in different types of cells to produce proteins, and the researchers were surprised to find that,Cell-specific RNA splicing patterns ‘surprisingly abundant and diverse’.
In the second study, the scientists used the human cell atlasIdentify cell types and genetic variants associated with disease.
To this end, scientists from the Broad Institute and their collaborators used optimized single-cell sequencing technology:Single Nucleus RNA Sequencing (snRNA-seq). The advantage of this technology is that it can be better applied to frozen samples, not necessarily limited to freshly collected tissue samples,And can capture cell types that have been difficult to analyze due to the sample collection process in the past, such asSkeletal muscle cells, fat cells and neurons. This led to the discovery of rare cell types, such as neuroendocrine cells in the prostate and enteric nerves in the esophagus.
In addition to studying healthy humans, with this large-scale analysis, researchers also have the opportunity to analyze in detailStudy tissues of patients with different diseases at the single-cell level.
Researchers make full use of machine learning algorithms,Systematic association of cells in the atlas with 6000 single-gene disorders and 2000 complex genetic disorders, looking for cell types affected by causative genes and disease traits. For example, in a disease that affects nerve-muscle cell signaling, the researchers found that only muscle cells at the nerve-muscle junction were enriched for genes associated with the disease.
▲The study collected and analyzed the cell types of 8 human organ tissues (including heart, skin, lung, prostate, thymus, skeletal muscle, esophageal mucosa, and esophageal muscle), and linked cells with rare and common disease risk genes ( Image source: Reference [2])
Leading the research is renowned scientist Dr. Aviv Regev, one of the founders of the Human Cell Atlas project. She pointed out: “By linking cells directly to human disease biology, disease risk genes across tissues, we can create new research avenues for many diseases. “
The third and fourth papers give usUnderstanding the body’s immune cellsbrought many new insights. These two studies explored the similarities and differences of immune cells in different tissues of the body, and described the characteristics and immune responses of various types of immune cells at different stages of the human body from developmental stages to adulthood, which are important for the development of new vaccines or immunotherapies. significance.
In one of the studies, researchers from the Wellcome Sanger Institute in the UK, the University of Cambridge and other institutions simultaneously analyzed 330,000 immune cells from 16 tissues of 12 adult organ donors.
The research team developed a special set of algorithms CellTypist. This algorithm can help process the huge number of cells in the database, including cells that produce mutations. In total, CellTypist has identified about 100 different types of immune cells, including special macrophages, T cells, B cells, etc., and their distribution in different tissues.
▲The process of building a cross-tissue map of human immune cells (Image source: Reference [3])
Based on this analysis, the researchers mapped immune cells in lymphoid and non-lymphoid organs in detail. In the atlas, we can see the relationship between immune cells in different tissues,It was found that specific immune cells may accompany specific inflammation, and different T cell subtypes play a key role in controlling infection in different parts of the blood, intestine, etc.,and many more.
Dr Sarah Teichmann, who led the research, said: “These data are publicly available,Not only will it help piece together a more complete map of human cells, but it could also provide a framework for vaccine design, or to improve immunotherapies to fight cancer. “
Another study created a cellular atlas of the human immune system that focused on early development before birth, and the specific locations of specific cells in developing tissues.
A cross-organizational analysis found that,B cell precursors are present in all developing organs, unlike the past thought that the development of the hematopoietic system is limited to the liver, bone marrow, and yolk sac tissue.
The new map alsoIdentifies some immune cell types not found in adults, including an entirely new type of B cell, and a very distinct T cell that emerged early in life. These findings will aid research in in vitro cell engineering and regenerative medicine.
▲Four pan-tissue single-cell sequencing studies report 1 million single-cell transcriptomes from more than 30 tissues, covering more than 500 cell types, revealing rare cell types, discovering tissue-conserved cell characteristics, tissue-specific cell states, and Disease-related cell types (Image source: Reference [5])
In the same issue of Science, Peking University BIOPIC and School of Life SciencesProfessor Zhang ZeminPublished a review article with colleagues. They pointed out,The pan-organizational human cell atlas created by these four research papers brings us one step closer to a true “encyclopedia” of human single-cell atlases, is expected to promote the overall progress of sequencing and analysis technology and biological discovery. “Ultimately, we will systematically understand biological processes at the level of individual genes, cells, tissues and phenotypes.”
When looking forward to how to use these data to benefit human health in the future, Professor Zhang Zemin gave an example that when developing new treatments, the data of human cell atlas can be used to predict possible side effects and avoid safety problems caused by drugs “off-target”. It greatly facilitates the toxicity prediction of new drug research and development, and identifies toxic and side effects before human trials.
Source of title map: Reference [7]; Credit: Aviv Regev and Anna Hupalowska on behalf of the Human Cell Atlas
References:
[1] The Tabula Sapiens Consortium, (2022) The Tabula Sapiens: A multiple-organ, single-cell transcriptomic atlas of human. Science Doi: 10.1126/science.abl4896
[2] Gökcen Eraslan et al., (2022) Single-nucleus cross-tissue molecular reference maps toward understanding disease gene function. Science. Doi: 10.1126/science.abl4290
[3] C. Domínguez Conde et al., (2022) Cross-tissue immune cell analysis reveals tissue-specific features in humans. Science Doi: 10.1126/science.abl5197
[4] Chenqu Suo et al., (2022) Doi:
[5] Zedao Liu & Zemin Zhang (2022) Mapping cell types across human tissues. Science Doi: 10.1126/science.abq2116
[6] Multi-tissue cell atlases lead to leap of understanding of immunity and disease. Retrieved May 13, 2022
[7] Presenting the most comprehensive, cross-tissue cell atlases to date: New findings from the Human Cell Atlas consortium. Retrieved May 13, 2022
