Frozen tissues and Tabula Sapiens: the latest studies from the Human Cell Atlas

BioTechniques News
Aisha Al-Janabi

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

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

Studying immune cells across tissues

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

“By comparing particular immune cells in multiple tissues from the same donors we identified different flavors of memory T cells in different areas of the body, which could have great implications for managing infections,” says Sarah Teichmann, who is the Head of Cellular Genetics at the Wellcome Sanger Institute (Cambridge, UK) and a co-author on the paper. “Our openly available data will contribute to the HCA and could serve as a framework for designing vaccines, or to improve the design of immune therapies to attack cancers.”

The second study published 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 beneficial to identify and map out the specific cell types in which disease genes act. To create this, all the cell types need to be profiled, including those that are difficult to collect, for example, fat cells, or cells from skeletal muscle or neurons. Additionally, it is essential to profile cells from many different individuals, so freezing tissue before analysis is required.

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Researchers from 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 200,00 cells from a bank of frozen tissues with rare and common disease genes. A novel 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 gene programs in disease. This could lead to novel starting points for health and disease studies in the future.

Aviv Regev (Genentech Research and Early Development; CA, USA), senior author of the paper explains: “Our single-nucleus HCA study demonstrates a powerful large-scale way to analyze cells from frozen tissue samples across the body with deep-learning 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 roadmap for multiple diseases by directly relating cells to human disease biology and disease-risk genes across tissues.”

The Tabula Sapiens Dataset

The fourth and final paper being published in Science from this collection produced a cross-tissue atlas from live cells. [4] The resulting dataset is called ‘Tabula Sapiens’. This was done using single-cell RNA sequencing of live cells to analyze several organs from the same donors. The Tabula Sapiens has been used to characterize more than 400 specific cell types, distribution and variations in gene expression. This will provide researchers with a large resource 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 across 24 organs in the human body,” said Stephen Quake, a senior author of this paper and a Professor at Stanford University (CA, USA). “It represents the efforts of more than 150 authors across several institutions; the scientific community will be discovering 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 could have therapeutic implications like understanding common and rare diseases, vaccine development, and anti-tumor immunology.

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