Bloodhounds chasing the origin of blood cells

Abstract

The generation of blood cells during embryonic development involves a process resembling lineage reprogramming, where specialized cells within the vasculature become blood forming, or hemogenic. These hemogenic cells undergo rapid transcriptional and morphological changes as they appear to switch from an endothelial to blood identity. What controls this process and the exact nature of the hemogenic cells remains debated, with evidence supporting several hypotheses. In this opinion, we synthesize current knowledge and propose a model reconciling conflicting observations, integrating evolutionary and mechanistic insights into blood cell emergence.

Keywords: endothelial cells; hemangioblast; hematopoietic development; hematopoietic stem cells; hemogenesis.

Figure 1:. Models of intra-embryonic hematopoietic cells emergence.

(a) The hemangioblast-based model: hemangioblasts migrating through the sub-aortic mesenchyme surrounding the ventral side of the dorsal aorta (DA) generate both endothelial and hemogenic cells. Hemogenic cells will then differentiate into blood cells. (b) The arterial-derived model: a hemogenic- competent progenitor gives rise to arterial endothelial cells that localize in the ventral side of the DA. These arterial cells undergo an endothelial to hematopoietic transition (EHT) resulting in hematopoietic cell formation. (c) Distinct lineages model: two separate precursors, the hemogenic-restricted progenitor and the endothelial-restricted progenitor, give rise to hemogenic cells and endothelial cells, respectively. This figure was created using BioRender (https://biorender.com/).

Figure 2:. Proposed model of cell contributions to the DA during and after hemogenic events.

There are distinct routes by which endothelial cells and hemogenic cells (HemCs) contribute to the dorsal aorta (DA). The first route consists of cells derived from the endotome (ET) that initially colonize only the dorsal side of the DA (Stage 1, left panel). The second route involves a separate lineage referred to as HemC precursors. All these HemC precursors harbor the potential of generating hematopoietic cells, but the final outcome is influenced by the levels of NOTCH signaling they detect during their migration. When they sense high levels of NOTCH, HemC precursors colonize the ventral layer of the DA, while low levels direct them to the ventral layer of the cardinal vein (CV)[99]. HemC precursors that detect intermediate levels of NOTCH signaling will colonize the DA and differentiate into hematopoietic cells. Later, (Stage 2, right panel) cells generated from HemC precursors are replaced in both the CV and DA by endothelial cells originating from the ET. The fate of these ET-derived endothelial cells is guided by the levels of NOTCH signaling: low levels support the venous fate in the CV, whereas high levels drive the arterial one in the DA [99]. This figure was created using BioRender (https://biorender.com/).

Figure 3:. Proposed model for mammalian hematopoietic development.

The schematic illustrates the proposed model for the induction and specification stages in hemogenic cell (HemC) emergence. The induction stage occurs over gastrulation and includes patterning of the different hemogenic mesoderms by varying exposure to Wnt signaling. HemCs contributing to YS-hematopoiesis are specified directly in the YS from two separate hemogenic mesoderms: one giving rise to HemCs harboring primitive hematopoietic potential via a hemangioblast intermediate, the other contributing to the erythro-myeloid progenitor (EMP)-restricted HemCs for which the presence of a hemangioblast has not been formally proven yet (dashed line). On the other hand, the specification of intra-embryonic HemCs occurs notably at the vessel of confluence (VOC) and may or may not include a hemangioblast stage, as indicated by dashed lines. Different levels of exposure to NOTCH signaling during migration from and remodeling of the VOC results in the varied hematopoietic differentiation potential of HemCs in the embryo.

Timeline of emergence and hematopoietic potential associated with the precursors belonging to the different hematopoietic developmental programs described herein. This figure was created using BioRender (https://biorender.com/).

Anatomy and signaling of the hematopoietic (HSC) specification niche in the aorta-gonad-mesonephros (AGM) region. This figure was created using BioRender (https://biorender.com/).