造血干祖细胞 z-bio 2025-01-09 406

　　In the National Natural Science Foundation of China project (Approval No. 81920108005) U23A20417、 With funding from organizations such as 81730007, 31872842, and 91442106, Professor Hong Dengli's research team at Shanghai Jiao Tong University School of Medicine has made progress in revealing the mechanisms by which embryonic tissues maintain stem cell genome stability and the origin of diseases. The research results, titled "Fetal hepatocytes protect the HSPC genome via fetuin-A through fetal globulin A", were published in the journal Nature on December 4, 2024. Paper link: https://doi.org/10.1038/s41586-024-08307-x .

　　During embryonic development, the extensive proliferation and differentiation of the three germ layer cells is a key process in the formation of diverse functional cell types and tissue organs. Maintaining the stability of the tissue stem cell genome during this process is a crucial challenge. It is currently unclear how developing organ tissues form a microenvironment and transmit signals, thereby activating the endogenous genomic stability mechanism of stem cells. In addition, it is urgent to study how the loss of this protective mechanism can lead to the occurrence of developmental related diseases, such as childhood tumors.

　　The research team established a liver cell tracking and knockout mouse model and found that during the early development of fetal liver (the main hematopoietic tissue of the fetus), a large number of hematopoietic stem and progenitor cells (HSPCs) migrate from the placenta to the fetal liver. Due to the small number of liver cells, the newly migrated HSPCs do not receive effective microenvironment protection, resulting in genomic instability; When stimulated by genotoxic substances, DNA breakage and mutation are prone to occur, initiating the development of leukemia. As the fetal liver develops, the number of liver cells increases and the genomic stability of HSPCs is enhanced.

　　Further research has found that fetuin-A secreted by liver cells binds to Toll like receptor 4 (TLR4) receptors on the surface of HSPCs, activating the TLR4-MYD88-bZIP pathway and upregulating the expression of nucleic acid helicase BLM, thereby releasing the R-loops structure generated by DNA replication transcription in HSPCs and maintaining their genomic stability. If the Fetua gene is knocked out in mice, the level of R-loops produced by the replication and transcription of related genes is significantly increased, and the mice are significantly susceptible to leukemia. The above protective mechanism has also been validated in human fetal liver, and low concentrations of fetuin-A are closely related to the occurrence of childhood leukemia.

　　The study revealed the key mechanism by which fetal liver cells maintain the genomic stability of hematopoietic stem and progenitor cells. The research results not only provide theoretical support and experimental evidence for further studying the pathogenesis and prevention strategies of developmental diseases, but also provide a scientific basis for the development of diagnostic tools and therapeutic drugs for predicting and preventing childhood leukemia.