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Amutaigwe, Ekpereka Uzodinma

University of British Columbia

The liver is the principal site of fetal hematopoiesis. At different developmental stages, hematopoietic progenitors, generated mainly in the yolk sac and the aorta-gonad-mesonephros region (AGM), migrate through the circulation to the fetal liver where they rapidly proliferate and differentiate into lineage-specific cell types. Hematopoietic stem cells/Erythromyeloid progenitors (HSCs/EMPs) and megakaryocyte-erythroid progenitors (MEPs) generate erythroid progenitors (EPs) and megakaryocytes (Mks). EPs differentiate into proerythroblasts. Using single-cell transcriptomics, I identified cell types in mouse embryonic day (E) 10.5, E12.5, and E14.5 livers, computationally investigated the differentiation trajectories and gene expression dynamics of hematopoietic subpopulations within and across the developmental time points and identified putative transcription factors (TFs) driving these changes. As expected, I observed that HSCs/EMPs and MEPs differentiated into EPs and Mks. However, unexpectedly, lineage-committed EPs at E10.5 showed plasticity and a high probability of differentiating into Mks and expressed erythroid and Mk genes. Of interest, the EPs at E12.5 and E14.5 separated into two differentiation pathways; one containing male EPs, and the other female EPs, and the pattern persisted after regressing out sex-specific genes. Genes upregulated in female EPs were significantly enriched in pathways such as heme biosynthesis, cellular response to hypoxia and stress, and cytoprotection by HMOX1. These enriched terms suggest that female EPs are ahead of their male counterparts in development. Genes upregulated only in E10.5 EPs were associated with mainly Mk terms, including platelet activation, signaling and aggregation, predicted to be regulated by myeloid lineage TFs, SPI1 (PU.1), ETS2, and PBX1. Conversely, genes upregulated only in E12.5 and E14.5 EPs were enriched in cell cycle pathways, putatively regulated by NFIA, TFDP2, E2F2, E2F8, POLE3, RB1 and E2F8 TFs, and biological functions related to more mature erythroid cells, including erythrocyte homeostasis and development, and porphyrin-containing compound metabolic process, putatively controlled mainly by KLF1, SOX6 and GATA1 TFs. These outcomes provide information for more in-depth studies on sex-dependent erythropoiesis. Overall, findings from this study will advance knowledge of fetal liver hematopoiesis.

Text

2024-06-20

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/88492

Genome Science and Technology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/