Blood, as a river of life, continuously provides nutrients and immune protection for the body. Hematopoietic stem cells, as the source of blood, have the ability to self-renew and multidirectional differentiation, which not only maintain the body's lifelong hematopoiesis, but also serve as an important cell source for the transplantation treatment of malignant blood diseases [1, 2]. However, the insufficient source of hematopoietic stem cells is a bottleneck that limits their promotion. How to expand a sufficient number of functional hematopoietic stem cells has always been one of the difficulties and hotspots in basic scientific research. During vertebrate embryonic development, the fetal liver is a natural place for the expansion of hematopoietic stem cells. Here hematopoietic stem cells undergo rapid expansion and maintain a strong dryness [3, 4]. A comprehensive, systematic, and three-dimensional analysis of this amplified hematopoietic organ will provide theoretical guidance for the expansion of hematopoietic stem cells in vitro.
Cell Research
● On August 2, 2021, Li Cheng's team from the School of Life Sciences of Peking University and The Liu Feng team from the Institute of Zoology of the Chinese Academy of Sciences collaborated to publish a research paper entitled Identity of HSC/MPP expansion units in fetal liver by single-cell spatiotemporal transcriptomics in Cell Research Journal. Using the combined analysis of single-cell transcriptome and spatial transcriptome, the paper plotted a single-cell spatiotemporal transcriptome map of fetal liver development in mice, analyzed the transcriptome and functional heterogeneity of hematopoietic stem/progenitor cells, identified the functional units of hematopoietic stem cell expansion (HSC 'pocket-like' units, HSC PLUS) and revealed their molecular mechanisms.
First, the researchers used single-cell transcriptome sequencing techniques to map the transcriptomes of fetal hepatocytes and microenvironmental cell development, and analyzed the transcriptome dynamics of hematopoietic stem/progenitor cells and microenvironment cells. Through bioinformatics analysis and transplantation experiments, the researchers found that CD93 not only enriched hematopoietic stems/progenitor cells with strong stems, but also regulators of hematopoietic stem/progenitor cell development. Subsequently, the researchers used the CellPhoneDB method to construct an interplay regulatory network of microenvironmental cells and hematopoietic stem/progenitor cells, identifying potential pro-hematopoietic stem cell expansion molecules such as growth factorSMDK and PTN.
To verify the spatial relationship between interacting cells and paired signaling molecules, the researchers mapped the spatial transcriptome of fetal liver. Using spatial transcriptome data characterized by spatial coordinates, the researchers divided microenvironment cells and spatial relationships with hematopoietic stem/progenitor cells into three categories: Intra-spot (most closely related), Inter-spot (closely related), and Others (estranged). Through qualitative and quantitative analysis, the researchers found that macrophages are highly enriched around hematopoietic stems/progenitor cells, and that macrophages and hematopoietic stems/progenitors with adjacent relationships express ligands and receptors in interacting molecular pairs, respectively. At the same time, immunofluorescence experimental data show that macrophages can form a "pocket-like" structure around hematopoietic stems/progenitor cells, and functional data show the pro-amplification effect of macrophages and their secreted growth factors. i.e., expanded hematopoietic stem/progenitor cells are in macrophage and growth factor-enriched HSC PLUS. It is well known that cells are the smallest functional units of the body, followed by tissues/organs, and this study found that there are specific functional units of cell behavior between cells and tissues/organs, the basic functional units of hematopoietic stem cell expansion (HSC PLUS).
Finally, by comparing mouse fetal liver and published human fetal liver single-cell transcriptome data, the researchers found that conserved expansion structures and molecular mechanisms are also present in human fetal liver. Based on the above high-throughput omics data, the researchers set up a data interaction website http://liulab.ioz.ac.cn/fetal_liver/ that can retrieve the spatiotemporal expression profile of genes, including cell type and spatial location.
In summary, the study for the first time mapped a single-cell spatiotemporal transcriptome map of fetal liver development in mice, and identified the hematopoietic tissue functional unit (HSC PLUS), which not only deepened our understanding of the expansion mode of hematopoietic stem cells in vivo, expanded our understanding of tissue functional units, and also provided more clues for the in vitro expansion of hematopoietic stem cells.
Schematic diagram of the expansion functional unit of fetal hematopoietic stem cells
●
Researcher Liu Feng of the Institute of Zoology, Chinese Academy of Sciences, and Cheng Li, professor of the School of Life Sciences of Peking University, are the co-corresponding authors of this article. Gao Suwei, ph.D. candidate at the Institute of Zoology, Chinese Academy of Sciences, and Dr. Shi Qiang, School of Life Sciences, Peking University, are co-authors of this paper. The research has been funded by the National Natural Science Foundation of China, the National Key Research and Development Program, and strongly supported by the "Polaris" high-performance computing platform of Peking University.
bibliography
1. Laurenti, E. and B. Gottgens, From haematopoietic stem cells to complex differentiation landscapes. Nature, 2018. 553(7689): p. 418-426.
2. Zhang, Y., et al., Hematopoietic Hierarchy - An Updated Roadmap. Trends Cell Biol, 2018. 28(12): p. 976-986.
3. Ema, H. and H. Nakauchi, Expansion of hematopoietic stem cells in the developing liver of a mouse embryo. Blood, 2000. 95(7): p. 2284-8.
4. Swain, A., et al., Intrinsic and extrinsic regulation of mammalian hematopoiesis in the fetal liver. Histol Histopathol, 2014. 29(9): p. 1077-82.
Thesis Link:
https://www.nature.com/articles/s41422-021-00540-7
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