The molecular and cellular hematopoietic stem cell specification niche

Abstract

Hematopoietic stem cells (HSCs) are a population of tissue-specific stem cells that reside in the bone marrow of adult mammals, where they self-renew and continuously regenerate the adult hematopoietic lineages over the life of the individual. Prominence as a stem cell model and clinical usefulness have driven interest in understanding the physiologic processes that lead to the specification of HSCs during embryonic development. High-efficiency directed differentiation of HSCs by the instruction of defined progenitor cells using sequentially defined instructive molecules and conditions remains impossible, indicating that comprehensive knowledge of the complete set of precursor intermediate identities and required inductive inputs remains incompletely understood. Recently, interest in the molecular and cellular microenvironment where HSCs are specified from endothelial precursors-the "specification niche"-has increased. Here we review recent progress in understanding these niche spaces across vertebrate phyla, as well as how a better characterization of the origin and molecular phenotypes of the niche cell populations has helped inform and complicate previous understanding of signaling required for HSC emergence and maturation.

Figure 1.. Geography of the hematopoietic stem cell specification niche.

Whole embryo depictions of E10.5 mouse (A) or 23 hpf zebrafish (B) to show the regions (dashed blue boxes) of the transverse trunk sections schematized in (C) and (D). Inset in (B) shows whole mount in situ hybridization for runx1 transcript in the floor of the dorsal aorta (blue arrowhead), which marks emerging HSC precursors in vertebrates. (C, D) Geography of the AGM with neural tube, notochord, somite, dorsal aorta (green), and emerging HSPCs (red) indicated. Note that zebrafish HSPCs predominantly bud into the posterior cardinal vein (PCV). The location of mouse paired veins and urogenital ridges are indicated in (C). The location of intersegmental vessels budding from the dorsal aorta are indicated in (D).

Figure 2.. Cellular tissue origins and movements of the AGM regions leading up to formation of hematopoietic clusters in the dorsal aorta.

Schematized transverse trunk sections from mouse E7.5 / chick E1.0 (A) to E11.0 / E3.5 (E). In the early gastrula embryo (A) the mesoderm can be divided from most axial chordamesoderm (dark orange) fated to form notochord (no), progressively more lateral to paraxial mesoderm (lighter orange) fated to form somites, intermediate mesoderm (gray), and lateral plate mesoderm (light blue), which can be further subdivided into somatopleural (dorsal) and splanchnopleural (ventral) mesoderm. The endothelium of the dorsal aorta (DA; green) and immediate subaortic mesenchyme (light blue) derive from the splanchnopleural mesoderm [57]. By E8.25/1.5 (B), lumenized, paired DA have formed with some ventral endothelium contributed from paraxial mesoderm, which is now forming somites (so; orange) [50, 56, 57]. By E9.5/2.0 (C) the neural folds have developed into the neural plate (np) and neural crest (nc; yellow) begin to be specified, the paired DA are proximal to the gut, and the somites are compartmentalizing into dorsal and ventral compartments (graded orange shading). The urogenital ridges (UGR) are forming at the dorsal crest of the coelom (coe) [50, 51, 54, 56, 58, 59]. At E10.0/2.5 (D), nc (yellow) migration (yellow arrow) is underway. The somite has compartmentalized into dermomyotome (dm; darker orange) and sclerotome (sc; lighter orange), which begins associating with the roof of the DA, likely as VSMC precursors. Subaortic splanchnopleural-derived mesenchyme also expresses VSMC markers, including smooth muscle actin [51, 53, 54, 56, 58, 59] [Wiegreffe 2007; Pouget, 2008; Wasteson, 2008; Wiegreffe 2009; Jaffredo 2010; Sato, 2013]. By E11.0/3.5 (E), intra-aortic hematopoietic clusters (IAHC) containing HSC precursors (red cells) in the ventral DA are budding into the lumen. The migration of nc has reached the ventrolateral DA and sc has enveloped the DA [44, 53, 54, 56, 58, 59].