Our tissues – cell by cell

As part of the large-scale Human Cell Atlas research project, an international research consortium is working on detailed mapping of all cells in the human body. While previous publications focused on individual organs, the consortium published for the first time four large tissue-wide cell atlases that collectively contain over one million individual cells from 33 tissue types. The results show how different cell types transform their genetic material differently, shed light on the properties of immune cells during fetal-to-adult development, and provide a better understanding of many diseases.

Since its inception in 2016, the Human Cell Atlas (HCA) consortium has been working on mapping all types of cells in the human body. More than 2,300 scientists from 83 countries around the world are involved. All data is published as publicly available, making the results available as a source for further research. Earlier publications have focused on specific tissues and organs. They have already provided important information about the structure and functioning of the relevant organs. However, inter-tissue analysis has been lacking so far.

Single cells mapped in tissues

Now consortium members have mapped cells from 33 different tissues in detail. They present their results in four studies published in the journal Science. The first study by the Tabula Sapiens Consortium, a group of over 150 researchers, provides the most comprehensive inter-tissue atlas yet. For the Tabula Sapiens cell atlas, the authors sequenced transcripts, or RNAs selected for protein production, from nearly 500,000 living cells from 24 different tissues. It provides information about the activity of genes in cells and tissues.

Special feature: “In order to enable inter-tissue comparisons, we developed an approach in which we examined a large number of organs of the same person,” explain the authors. The donors came from a variety of ethnicities, ages, and medical backgrounds. “Tabula Sapiens is the reference atlas that will provide the scientific community with a new perspective on human biology for many years to come,” said Stanford University’s Stephen Quake, one of the consortium leaders.

Same genes used differently

Among other things, the authors used the data to show how differently different types of cells carry out the genetic program with which they are equipped. “While the genome is often referred to as the blueprint of an organism, it is perhaps more accurately described as a list of building blocks made up of different genes that may or may not be used in different cell types in a multicellular organism,” the authors explain. “While almost every cell in the body has essentially the same genome, each cell type uses that genome in different ways and expresses a subset of all possible genes.”

The findings of how the same gene can become active differently in different cell types could also help in the future when it comes to better understanding the causes and effects of genetic diseases – an important area of ​​application for cell atlases. In addition, a team led by Gökcen Eraslan of the Broad Institute in Cambridge presents a new method in a second Science study that can also be used to map frozen tissue samples at the single cell level. “Our study paves the way for the study of tissue from entire patient cohorts at the single cell level,” says Aviv Regev, one of the two chairmen of the HCA consortium. “We have succeeded in mapping the pathways for many diseases by directly linking cells to human disease biology and disease-prone genes in various tissues.”

Atlas of immune cells

The third and fourth studies look closely at immune cells in different tissue types. ‘Most of the research on human immunity focuses on blood-derived cells,’ explain the researchers. “But the immune cells that colonize peripheral tissue also play an important role in health and disease.” A team led by Cecilia Domínguez Conde of the Wellcome Sanger Institute in Cambridge therefore sequenced the RNA of approximately 330,000 immune cells from different parts of the body.

“By comparing certain immune cells in different tissues from the same donors, we identified different types of memory T cells in different areas of the body, which could have serious implications for treating infections,” says Conde’s colleague Sarah Teichmann, author of the HCA consortium leaders. Scientists have also developed a program that can automatically recognize different types of immune cells using machine learning.

Development from fetus to adult

In addition, a team led by Conde’s colleague Chenqu Suo mapped the cells of a developing fetal immune system at different stages of pregnancy. “This comprehensive human immune development atlas reveals the tissues involved in the formation of blood and immune cells, which improves our understanding of immune system and blood diseases,” says Suo’s colleague Muzlifah Hannifa. “In collaboration with other studies, it enables the mapping of the immune system from development to adulthood and reveals the types of cells that are lost during adolescence. It also helps to support research in cellular engineering and regenerative medicine. ‘

In a comment accompanying the study, also published in Science, Zedao Liu and Zemin Zhang of Peking University write that atlases of tissue-encompassing cells are important reference datasets that can also be used in medical research, for example to predict possible side effects of new drugs before the first clinical trials. “Together, this inter-tissue research brings us closer to building a comprehensive atlas of individual human cells,” they write.

Sources: Tabula Sapiens Consortium, Science, doi: 10.1126 / science.abl4896; Gokcen Eraslan (Broad Institute of MIT and Harvard, Cambridge) et al., Science, doi: 10.1126 / science.abl4290; Cecilia Domínguez Conde (Wellcome Sanger Institute, Cambridge) et al., Science, doi: 10.1126 / science.abl5197; Chenqu Suo (Wellcome Sanger Institute, Cambridge) et al., Science, doi: 10.1126 / science.abo0510

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