Activation of lineage competence in hemogenic endothelium precedes the formation of hematopoietic stem cell heterogeneity.
Jun XiaMengyao LiuCaiying ZhuShicheng LiuLanlan AiDongyuan MaCaiying ZhuLu WangFeng LiuPublished in: Cell research (2023)
Hematopoietic stem and progenitor cells (HSPCs) are considered as a heterogeneous population, but precisely when, where and how HSPC heterogeneity arises remain largely unclear. Here, using a combination of single-cell multi-omics, lineage tracing and functional assays, we show that embryonic HSPCs originate from heterogeneous hemogenic endothelial cells (HECs) during zebrafish embryogenesis. Integrated single-cell transcriptome and chromatin accessibility analysis demonstrates transcriptional heterogeneity and regulatory programs that prime lymphoid/myeloid fates at the HEC level. Importantly, spi2 + HECs give rise to lymphoid/myeloid-primed HSPCs (L/M-HSPCs) and display a stress-responsive function under acute inflammation. Moreover, we uncover that Spi2 is required for the formation of L/M-HSPCs through tightly controlling the endothelial-to-hematopoietic transition program. Finally, single-cell transcriptional comparison of zebrafish and human HECs and human induced pluripotent stem cell-based hematopoietic differentiation results support the evolutionary conservation of L/M-HECs and a conserved role of SPI1 (spi2 homolog in mammals) in humans. These results unveil the lineage origin, biological function and molecular determinant of HSPC heterogeneity and lay the foundation for new strategies for induction of transplantable lineage-primed HSPCs in vitro.
Keyphrases
- single cell
- endothelial cells
- rna seq
- high glucose
- transcription factor
- high throughput
- bone marrow
- stem cells
- gene expression
- hematopoietic stem cell
- dendritic cells
- vascular endothelial growth factor
- acute myeloid leukemia
- oxidative stress
- induced pluripotent stem cells
- nitric oxide
- liver failure
- dna damage
- genome wide
- respiratory failure
- drug induced
- immune response
- diabetic rats
- aortic dissection
- hepatitis b virus
- acute respiratory distress syndrome
- mechanical ventilation