Abstract
Human pluripotent stem cells (hPSCs) provide a powerful platform for studying the dynamic molecular network towards hematopoiesis. To date, a comprehensive roadmap at single-cell level for hPSC-derived hematopoietic differentiation has not been established. Here, we performed single-cell transcriptomic analyses to map gene expression programs during hematopoietic differentiation of hPSCs, from which new strategies to improve in vitro hematopoietic differentiation may be thus developed. We firstly established a serum-free, stroma-free and chemically defined monolayer system for hematopoietic differentiation of hPSCs, which enabled single-cell transcriptomic analysis. Through identifying sequential molecular events, we generated a time-course gene expression profile revealing the temporally restricted expression dynamics of stage-specific genes associated with hematopoietic cell fate choices. To better understand the lineage trajectories and gene regulatory networks governing diversification of cell fates, we established transcription factor regulatory networks predicting developmental fate choices during hematopoietic differentiation. By pseudotime analysis, we constructed the endothelial-hematopoietic trajectory revealing a novel hematopoietic development model that hemogenic endothelium initiated first and then differentiated into arteries and veins, whereas arteries had the ability to promote endothelial-to-hematopoietic transition. Moreover, we found that the genes related to aerobic metabolism were significantly decreased in hematopoietic cells and hypoxia-primed hematopoietic differentiation showed higher potency for generating more hematopoietic lineages. Further studies showed that hypoxia enhanced hematopoietic differentiation by promoting the development of arterial endothelium, rather than directly acting on hemogenic endothelium.
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