Developmental HSC Microenvironments: Lessons from Zebrafish

Abstract

Hematopoietic stem cells (HSCs) posses the ability to maintain the blood system of an organism from birth to adulthood. The behavior of HSCs is modulated by its microenvironment. During development, HSCs acquire the instructions to self-renew and differentiate into all blood cell fates by passing through several developmental microenvironments. In this chapter, we discuss the signals and cell types that inform HSC decisions throughout ontogeny with a focus on HSC specification, mobilization, migration, and engraftment.

Keywords: Blood development; Hematopoietic niche; Hematopoietic stem cell; Zebrafish.

Fig. 4.1

The developmental timing and location of HSC development. (a) Timeline showing when and where primitive and definitive hematopoietic induction occurs in zebrafish. (b) Schema showing the location of the AGM/DA (left) and CHT (right) within zebrafish. Larger diagrams of the boxed regions are shown on the bottom. ICM, inner cell mass, AGM aorta-gonad-mesonephros, DA dorsal aorta, CHT caudal hematopoietic tissue, CA caudal artery, CV caudal vein, CVP caudal vein plexus

Fig. 4.2

The HSC specification niche. (a) Diagram showing the position within the zebrafish shown in the panel (b) cross-section. (b) Diagram of a cross-section within the dorsal aorta HSC specification niche in a zebrafish embryo. The legend is shown to the right. (c) The bottom panel highlights the most recent findings on the signaling pathways involved in the HSC specification niche. HSC hematopoietic stem cell, NC notochord, DA dorsal aorta, CV caudal vein, vegfa vascular endothelial growth factor a, FGF fibroblast growth factor, TGFβ1 a/b-transforming growth factor β 1 a/b, Tnfα tumor necrosis factor α, IFN interferon, Cxcl8-CXC chemokine ligand 8, Gcsf granulocyte-colony stimulating factor

Fig. 4.3

Signals and cell types regulating developmental HSC mobilization and engraftment. (a) The left diagram shows the position within the zebrafish shown in the cross-section (right). The right panel highlights the most recent findings on the niche cells and signaling pathways involved in HSC mobilization/migration from the DA. Expression of the transcription factors c-Myb and Cbfβ in emerging HSCs is important to mediate egress from the DA. Appropriate levels of Cxcl12 are required for this process, and are regulated by endotomal-derived endothelial cells and HSC expression of c-Myb. Macrophages serve as escorts that facilitate HSC migration into the CV. (b) The left diagram shows the position within the zebrafish shown in the cross-section (right). The right panel highlights the most recent findings on the niche cells and signaling pathways involved in HSC engraftment in the CHT niche. Within the CHT, HSCs are surrounded by endothelial cells and contact a stromal cell, which provides cues on the orientation of the division plane. The stromal cells are derived from the somite and are critical for HSC maintenance in the CHT niche. Secreted factors, such as Cxcl8 and G-csf modify HSC interactions and proliferation within the niche. HSC hematopoietic stem cell, NC notochord, DA dorsal aorta, CV caudal vein, Cxcl12-CXC chemokine ligand 12, Cbfβ core binding protein beta, CA caudal artery, CVP caudal vein plexus, CHT caudal hematopoietic tissue, Cxcl8-CXC chemokine ligand 8, Gcsf granulocyte-colony stimulating factor