Efforts to enhance blood stem cell engraftment: Recent insights from zebrafish hematopoiesis

Abstract

Hematopoietic stem cell transplantation (HSCT) is an important therapy for patients with a variety of hematological malignancies. HSCT would be greatly improved if patient-specific hematopoietic stem cells (HSCs) could be generated from induced pluripotent stem cells in vitro. There is an incomplete understanding of the genes and signals involved in HSC induction, migration, maintenance, and niche engraftment. Recent studies in zebrafish have revealed novel genes that are required for HSC induction and niche regulation of HSC homeostasis. Manipulation of these signaling pathways and cell types may improve HSC bioengineering, which could significantly advance critical, lifesaving HSCT therapies.

Figure 1.

HSC specification is regulated by transcriptional signaling throughout development. (A) Zebrafish studies have revealed transcription factors that are important at different stages of definitive hematopoiesis: hemogenic endothelial formation, HSC specification in the AGM, and HSC budding. (B) Recent studies in zebrafish have identified Notch signaling pathways in the somite that influence HSC specification. Wnt16 signaling induces expression of Notch ligands DeltaC and DeltaD, which interact with Notch1 receptors on vascular precursors from the posterior lateral mesoderm (PLM) as they migrate over the somite surface. This interaction is dependent on the junctional adhesion molecules Jam1a and Jam2a. Notch3 is also expressed in the somite and may provide additional inductive cues to HSCs via the sclerotome. Endothelial precursor cells derived from the endotome are specified by the homeobox gene meox1 and migrate to the dorsal aorta, where they contribute to cxcl12-dependent HSC induction. nc, notochord; nt, neural tube.

Figure 2.

Stromal and endothelial cells in the vascular niche modulate Cxcl12 and Kitlg signaling to regulate HSCs. (A) The mammalian bone marrow contains multiple types of perivascular stromal cells and endothelial cells in the vascular niche. Stromal and endothelial cells are both required to express niche factors Cxcl12 and Kitlg to influence HSC localization, maintenance, retention, and quiescence. Stromal cells express these factors at ∼1,000× greater levels. (B) HSPCs colonize the caudal hematopoietic tissue in the 48 hpf zebrafish. Within the niche, multiple factors influence the expression of niche factors Cxcl12 and Kitlg in the CHT. Vascular endothelial cells require expression of transcription factor tfec and chemokine receptor cxcr1 to regulate expression of kitlgb and cxcl12a, respectively, to control HSPC engraftment and expansion. mmp9 expressed by neutrophils in the niche cleaves cxcl12 to promote HSPC egress and colonization of secondary niches.