This article, published in the journal Blood Science, elucidates groundbreaking advancements in understanding the endothelial origins of the hematopoietic system. As a leading platform in clinical and experimental hematology, Blood Science continues to publish high-impact research that transforms molecular biology and physiology. Authored by Professor Yu Lan from the Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University and Professor Bing Liu from the Fifth Medical Center, Chinese PLA General Hospital, this study delves into the complex cellular evolution of hemogenic endothelial cells (HECs), the molecular mechanisms driving endothelial-to-hematopoietic transition (EHT), and the striking parallels between human and mouse systems. These insights mark a significant leap toward regenerative medicine and innovative treatments for hematological disorders.

Hematopoietic stem progenitor cells (HSPCs) arise from hemogenic endothelial cells, a specialized subset of embryonic endothelial cells. Through the tightly regulated process of EHT, these cells transition into hematopoietic cells. Advances in research have unveiled the heterogeneity of HECs, with some subsets exhibiting dual potential for endothelial or hematopoietic fates. Marker combinations like PK44 have enriched our understanding of HSC-competent HECs, while pre-HECs, an earlier stage with arterial features and low Runx1 expression, highlight the nuanced progression toward fully hemogenic endothelium.

The differentiation of HECs unfolds in a two-step process. First, primitive endothelial cells adopt an arterial identity, marked by the expression of Dll4 and Unc5b. Subsequently, a subset of these arterial endothelial cells transitions into HECs, guided by the activation of Runx1 and other regulatory factors. These arterial endothelial cells either mature into vascular structures or transiently assume HEC characteristics. Similarly, arterial vascular plexus cells, derived from venous endothelium via fate conversion, contribute to HEC populations, albeit through mechanisms still under investigation. Extra-embryonic sources like the yolk sac also produce HECs with considerable hematopoietic potential, despite their weaker arterial features.

Regulating the EHT process involves a sophisticated interplay of transcriptional, epigenetic, and post-transcriptional controls. Among these, Runx1 plays a critical role, essential for pre-HECs to progress into fully functional HSCs. Epigenetic mechanisms, such as DNA methylation and histone modification, prime endothelial cells for hematopoietic transitions while preserving their original identity. Additionally, alternative splicing, driven by regulators like Srsf2, fine-tunes the expression of hematopoietic genes, ensuring the accuracy and efficiency of the transition.

（Blood Science 6(4):p e00199, October 2024. | DOI: 10.1097/BS9.0000000000000199）

In human embryonic development, research mirrors findings from mouse models, confirming the endothelial origin of HSCs. Single-cell transcriptomic studies and functional assays have identified intra-aortic hematopoietic clusters (IAHCs) in the dorsal aorta’s ventral region as the birthplace of HSCs. These cells express markers such as RUNX1, HOXA9, and MECOM, which distinguish them from lineage-restricted progenitors. Identifying human HECs with markers like CD44 provides critical insights into their molecular and functional properties, advancing the field significantly.

Conclusion

Recent innovations in single-cell omics and lineage tracing have revolutionized our understanding of hemogenic endothelium and its pivotal role in hematopoietic development. Key regulators like Runx1 and Kit have been instrumental in refining the isolation and characterization of functional HECs. Comparative studies between human and mouse systems have highlighted the evolutionary conservation of these mechanisms, underscoring their importance in biology and medicine. Future research must focus on integrating multi-omics data to decode the regulatory networks governing EHT and translate these findings into therapeutic innovations, including in vitro HSC generation for hematological treatments.

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https://journals.lww.com/bls/fulltext/2024/10000/new_insights_into_the_endothelial_origin_of.1.aspx