Hematopoietic stem and progenitor cells (HSPCs) arise from hemogenic endothelial cells (HECs) via the endothelial-to-hematopoietic transition (EHT). As a signature gene of hematopoietic stem cell-primed HECs, Mycn is highly expressed in these cells alongside its paralog, Myc. However, their roles and underlying mechanisms in EHT remain unclear. Here, we demonstrate that endothelial-specific deletion of Mycn, but not Myc, impairs HSPC formation in mouse embryos. Single-cell transcriptomics and functional assays reveal that Mycn deficiency specifically attenuates the HEC-to-HSPC transition but not thereafter. We also establish a mosaic analysis strategy to distinguish Mycn deletion states in mutant embryos, enabling precise characterization. Unlike control HECs that downregulate adhesion signatures during their specification, Mycn-deficient HECs aberrantly upregulate adhesion pathways. Inhibiting focal adhesion kinase, a critical modulator of cell adhesion, rescues HSPC production in Mycn-deficient explant cultures. These findings uncover a regulatory mechanism whereby Mycn promotes HSPC generation from endothelial cells by suppressing adhesion signaling.
Chi Wang, Zhe Chen, Mei-Lin Jiang et al.· Cell Reports· 0 citations
The relationship between lineage output and transcriptional features of hematopoietic stem cells (HSCs) has been reported in adult bone marrow, yet it remains unclear in fetal liver, given their distinct developmental stage and microenvironment. Here, we systematically characterized the functions of E14.5 mouse fetal liver HSCs by lentiviral barcode labeling followed by transplantation, with subsequent single-cell RNA sequencing (scRNA-seq) and clonal analysis performed on donor-derived HSCs and their progeny in recipient bone marrow. We identified three HSC subtypes based on lineage bias, with myeloid-biased and balanced subtypes predominating. Importantly, within the same subtype, HSCs and their progeny share several transcriptional programs, and these programs show minimal overlap between subtypes. We term the retention of subtype-specific transcriptional features across lineages as "transcriptional persistence". Notably, this phenomenon was not observed in adult bone marrow. Alternatively, classification by progeny output activity revealed the presence of low-output and high-output subtypes within fetal liver HSCs. Although these two subtypes showed no significant difference in stemness features, they exhibited distinct transcriptional features and signaling activation states, which also differed from their counterparts in bone marrow, indicating that the biological characteristics of HSCs with different output activities vary by developmental stage. Of note, in both fetal liver and adult bone marrow, transcriptional persistence showed no obvious correlation with output activity, suggesting a specific coupling relationship between transcriptional persistence and lineage bias. Collectively, our study provides a clonal-resolution view of fetal liver HSC heterogeneity, enhancing our understanding of HSC diversity across different developmental stages.
Man Zhang, Yan-Li Ni, Di Liu et al.· Zoological Research· 0 citations
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