Frozen Tissues and Tabula Sapiens: The Latest Studies from the Human Cell Atlas

The latest studies published by The Human Cell Atlas are making further progress toward their goal of mapping every human cell type, and these four papers focus on multi-tissue cell analysis.

Founded in 2016, the Human Cell Atlas (HCA) is an international consortium of 2,300 members from 83 countries working to map every cell type in healthy human bodies. The HCA has made detailed maps of more than a million cells collected from 33 organs and systems and has focused primarily on individual organs and tissues, or smaller subsets of tissues. Now they have developed methods to collect data needed for multi-tissue atlases. The resulting cell atlases are openly available, meaning researchers can compare specific cell types and their functions across the body.

Studying immune cells in tissues

Until now, the HCA has targeted immune cells that are transported in the blood; however, immune cells in tissues also play an important role in the immune system. Researchers at the HCA have created a catalog of immune cells after sequencing RNA from 330,000 individual immune cells to understand their function in different tissues. [1] Based on this catalog, they developed a machine learning tool called cell typist automate cell identification. Using this tool, they identified about 100 different types of immune cells and their distribution across tissues, for example T cells, B cells and macrophages.

“By comparing certain immune cells in multiple tissues from the same donors, we identified different flavors of memory T cells in different parts of the body, which could have major implications for controlling infections,” said Sarah Teichmann, head of Cellular Genetics at the Welcome Sanger Institute (Cambridge, UK) and a co-author of the paper. “Our freely available data will contribute to the HCA and could serve as a framework for vaccine design, or to improve the design of immune therapies to target cancers.”

The second published study looks at the tissues involved in the formation of blood and immune cells and reveals the cell types lost from childhood to adulthood. This could inform in vitro cell engineering and research into regenerative medicine. [2]

Freezing tissues for analysis

A single-cell atlas would be useful to identify and map the specific cell types in which disease genes work. To do this, all cell types have to be profiled, including those that are difficult to collect, for example fat cells or cells from skeletal muscle or neurons. In addition, it is essential to profile cells from many different individuals, so freezing tissue before analysis is required.

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Researchers at the HCA have developed a single-nucleus RNA sequencing method using frozen cells. [3] They then used this method to create a cross-tissue atlas and analyze 200,000 cells from a bank of frozen tissues containing rare and common disease genes. A new machine learning algorithm was used to associate cells in the atlas with 6,000 single gene diseases and 2,000 complex genetic diseases and traits to identify cell types and disease gene programs. This could lead to new starting points for health and disease studies in the future.

Aviv Regev (Genentech Research and early development; CA, USA), explains senior author of the article: “Our single-nucleus HCA study demonstrates a powerful large-scale way to analyze cells from frozen tissue samples all over the body with deep computational advances and opens the way to studies of tissues from entire patient cohorts at the single-cell level. We were able to create a new multi-disease roadmap by directly relating cells to human disease biology and disease risk genes in tissues.”

The Tabula Sapiens dataset

The fourth and final article to be published in Science from this collection produced a cross-tissue atlas of living cells. [4] The resulting dataset is called ‘Tabula Sapiens’. This was done using single-cell RNA sequencing of living cells to analyze different organs from the same donors. The Tabula Sapiens has been used to characterize over 400 specific cell types, distribution and variations in gene expression. This will provide researchers with a large source of annotated cell types, and the Tabula Sapiens enabled the first large-scale analysis of alternative gene splicing in a single-cell atlas.

“The Tabular Sapiens is a reference atlas that provides a molecular definition of hundreds of cell types in 24 organs in the human body,” said Stephen Quake, a senior author of this paper and a professor at Stanford University (CA, USA). β€œIt represents the efforts of more than 150 authors in various settings; the scientific community will discover new insights into human biology from this resource for many years to come.”

Together, these four studies contribute to the single human cell atlas being created by the consortium and may have therapeutic implications such as understanding common and rare diseases, vaccine development and anti-tumor immunology.

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