Concise Review: Hematopoietic Stem Cell Origins: Lessons from Embryogenesis for Improving Regenerative Medicine

Abstract

Hematopoietic stem cells (HSCs) have extensive regenerative capacity to replace all blood cell types, an ability that is harnessed in the clinic for bone marrow transplantation. Finding appropriate donors remains a major limitation to more extensive usage of HSC-based therapies. Derivation of patient-specific HSCs from pluripotent stem cells offers great promise to remedy this problem if scientists could crack the code on how to make robust, transplantable HSCs in a dish. Studies delving into the native origins of HSC production during embryonic development should supply the necessary playbook. This review presents recent discoveries from animal models, with a focus on zebrafish, and discusses the implications of these new advances in the context of prior knowledge. The focus is on the latest research exploring the role of epigenetic regulation, signaling pathways, and niche components needed for proper HSC formation. These studies provide new directions that should be explored for de novo generation and expansion of HSCs for regenerative therapies. Stem Cells Translational Medicine 2017;6:60-67.

Keywords: Bone marrow transplant; Developmental biology; Embryo; Hematopoietic stem cells.

Figure 1

Comparison of timing of hematopoietic development across vertebrates. Time lines showing when and where primitive and definitive hematopoietic induction occurs in zebrafish (top), mice (middle), and humans (bottom). Abbreviations: AGM, aorta‐gonad‐mesonephros; BM, bone marrow; CHT, caudal hematopoietic tissue; FL, fetal liver; ICM, intermediate cell mass; YS, yolk sac.

Figure 2

Diverse signals regulate embryonic HSC behaviors in zebrafish. (A): Inflammatory signals from myeloid effector cells promote HSC emergence through activation of Notch and NFκB signaling. Tet2/3 also regulate Notch signaling, leading to gata2b and runx1 expression in hemogenic endothelial cells. Cbfβ is subsequently required to promote the extravasation of emerging HSC out of the dorsal aorta. (B): Nascent HSCs seeding the CHT induce endothelial remodeling to form a “microniche” comprising an HSC surrounded by endothelial cells adjacent to a CXCL12‐expressing supportive stromal cell. The orientation of the division plane of the HSC is dictated by the position of the stromal cell. An open arrow on the HSC (red) and daughter cell (green) shows the angle of the division plane. Arrows within the vessels show the direction of blood flow. Abbreviations: AGM, aorta‐gonad‐mesonephros; CHT, caudal hematopoietic tissue; EC, endothelial cell; hpf, hours postfertilization; HSC, hematopoietic stem cell; Ifnα/γ, interferon α/γ; Tnfα, tumor necrosis factor α.

Figure 3

Somitic signals regulate hematopoietic stem cell (HSC) formation in zebrafish. (A): Cross‐sectional view of a zebrafish embryo at 14 hpf. The posterior lateral mesoderm migrates medially, sliding under the somites, where it receives Wnt16 and Notch3 signals that promote hematopoietic induction. The close proximity of PLM and somite cells is achieved by heterotypic interactions between Jam1a on PLM and Jam2a on somites, which helps to strengthen the Notch signal. (B): Cross‐sectional view of a zebrafish embryo at 24 hpf. Anterior portions of somites give rise to the endotome, which contributes cells to the dorsal aorta that promote HSC formation, in part by Cxcl12 production. Curved arrows denote the movement of cells. Abbreviations: CV, caudal vein; DA, dorsal aorta; hpf, hours postfertilization; J1a, Jam1a; J2a, Jam2a; PLM, posterior lateral mesoderm.