Cells are the basic unit of life. In the past several centuries, scientists have been employing such technologies as the microscope and flow cytometry to classify and identify different types of cells on the strength of phenotypic characteristics. However, selecting phenotypic characteristics is, more often than not, a matter of much subjective bias. Single-cell RNA sequencing (scRNA-seq) technologies have brought in their wake a revolutionary change to the current cell-type classification system by providing a higher resolution of cellular differences and a more insightful understanding of the function of an individual cell in the context of its microenvironment.
The research team led by Prof. GUO Guoji from the Center for Stem Cell and Regenerative Medicine at the Zhejiang University School of Medicine has long been committed to research into single-cell sequencing. In 2018, theyused their self-developed Microwell-seq, a high-throughput and low-cost scRNA-seq platform, to construct a basic scheme for a mouse cell atlas (MCA). On this basis, GUO Guoji worked in close cooperation with ZHANG Dan, WANG Weilin, CHEN Jianghua, LIANG Tingbo and HUANG He. Using Microwell-seq, they analyzed the cell-type composition of all major human organs and constructed a scheme for the human cell landscape (HCL).
The study was published online in a research article entitled “Construction of a Human Cell Landscape at Single-cell Level” on the journal of Nature on March 25.
This study analyzed more than 700,000 single cells from over 50 human issues and cultures. In a global view, the complete human tissue dataset was grouped into over 100 major clusters and over 800 subtypes. By integrating different human single-cell datasets, researcherscreatedanHCL website at https://bis.zju.edu.cn/HCL/(with a mirror website for international users at https://db.cngb.org/HCL/)and the associated scHCL pipeline for human cell type identification.
This study revealed a single-cell hierarchy for many tissues that have not been well characterized. Researchers also established a ‘single-cell HCL analysis’ pipeline that helps to define human cell identity.From HCL, they identified MHC class II+ endothelial cells, CXCL+ epithelial cells, and IL+ stromal cells to be major cell-type categories between classical immune cells and non-immune cells.
By comparing different developmental systems in HCL, researchers propose a landscape model that is conserved in mammals: stem and progenitor cells are transcriptionally ‘indistinct’ and ‘stochastic’ while differentiated cells are transcriptionally “distinct” and “stable”. Moreover, the wiring of the regulons in the genome predetermines the terminal steady cellular states.
It is the first time that researchers have studied human organ development by assessing the similarity of cell types between fetal- and adult-stage tissues. Research data will become a treasury of resources for human biology and research methods will produce a far-reaching effect on the identification of cells in different states.
“Despite the limitations of sequencing depth, our study exhibits exceptional assets in comparison of cross-tissue and cross-species data. A perfect human cell atlas calls for integration of spatial information, multi-omics data and population analysis, which requires the concerted efforts of the global scientific community,” said Prof. GUO Guoji.