The blood system stores an adult stem cell with the potential of self-renewal and differentiation into various blood cells, called hematopoietic stem cells, which can maintain the body's long-term hematopoiesis and tissue homeostasis. Hematopoietic stem cell transplantation is an effective treatment for malignant hematological cancer, but the insufficient source of stem cells has become a bottleneck restricting the widespread application of this treatment. Therefore, the development of hematopoietic stem cells, especially the expansion of hematopoietic stem cells, has attracted much attention. However, current research mainly focuses on the "linearization" or "planarization" analysis of specific cell populations or key factors, and lacks a comprehensive "stereoscopic" analysis. The analysis of the expanded hematopoietic organs from the perspective of system biology will provide more inspiration for the mechanism research of hematopoietic stem cell expansion. In view of the high degree of conservatism in the hematopoietic development process, the Liu Feng research team and collaborators of the Institute of Zoology, Chinese Academy of Sciences used the zebrafish tail hematopoietic tissue (which is functionally similar to the fetal liver of mammals) and provided specific Microenvironment) as the research object, using the method of multiple transcriptome sequencing, the 3D transcriptome map of the expanded hematopoietic organ was drawn, and the molecular regulatory network between hematopoietic stem cells and microenvironment cells was explained.
First, in order to systematically study how the zebrafish tail hematopoietic tissue supports the mechanism of hematopoietic stem cell expansion and differentiation, the researchers used three transcriptome sequencing methods, specific types of population cell transcriptome, spatial transcriptome and single-cell transcriptome, detailed The spatiotemporal characteristics of hematopoietic tissue in the tail of zebrafish are analyzed. Transcriptome sequencing analysis of specific cell populations at different developmental stages shows that hematopoietic stem cells and corresponding microenvironmental cells have the characteristics of coordinated development and shared gene expression. Spatial transcriptome sequencing reflects cell location information, reveals different microenvironmental factors that regulate different ways of hematopoietic stem cells, and enables three-dimensional transcriptome reconstruction of zebrafish hematopoietic organs. The single-cell transcriptome data elaborately interpreted the tail hematopoietic tissue cell groups, cell characteristics and intercellular molecular regulation, and found that there is a certain correlation between hematopoietic stem and progenitor cell differentiation and cell cycle. Comprehensive analysis of multiple transcriptome sequencing revealed that the expansion of hematopoietic stem cells in the tail hematopoietic tissue was jointly regulated by endogenous and exogenous signals, new marker genes for hematopoietic stem cells were identified, and signal pathways affecting hematopoietic stem cell expansion were discovered , Perfected the molecular regulatory network between hematopoietic stem cells and microenvironment cells. For example, the chromatin structure maintenance protein smchd1 promotes its expansion by regulating the proliferation of hematopoietic stem cells; the Integrin signaling pathway derived from microenvironmental cells negatively regulates hematopoietic stem cell expansion. At the same time, this work also constructed a multi-transcriptome database of zebrafish tail hematopoietic tissue (http://www.picb.ac.cn/hanlab/ichtatlas/Home), which can retrieve the expression profile of any gene in hematopoietic tissue, including gene expression Time, cell type and relative spatial location.
This work not only found the relationship between hematopoietic stem cell characteristic genes, cell status and cell differentiation, explained the regulatory network of the interaction between the microenvironment and hematopoietic stem cells, but also provided a wealth of data resources for blood system research; meanwhile, it will also provide hematopoietic stem cells The in vitro expansion and in vitro assembly of hematopoietic organoids provide theoretical guidance.
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