Embryonic origin of the adult hematopoietic system: advances and questions

Abstract

Definitive hematopoietic stem cells (HSCs) lie at the foundation of the adult hematopoietic system and provide an organism throughout its life with all blood cell types. Several tissues demonstrate hematopoietic activity at early stages of embryonic development, but which tissue is the primary source of these important cells and what are the early embryonic ancestors of definitive HSCs? Here, we review recent advances in the field of HSC research that have shed light on such questions, while setting them into a historical context, and discuss key issues currently circulating in this field.

Pdgfrb‐Cre targets lymphatic endothelial cells of both venous and non‐venous origins

“…1A) (Gomez Perdiguero E et al, 2015; Hoeffel et al, 2015; Medvinsky et al, 2011). The R26‐mTmG reporter allows detection of Cre activity by the recombination‐induced expression of membrane‐bound green fluorescent protein (GFP) and inactivation of the red fluorescent protein Tomato expression (Muzumdar et al, 2007).…”

“…This conclusion was based on positive lineage tracing using the endothelial specific Pdgfb‐CreER T2 line induced at embryonic day (E)8‐E9, together with positive tracing of E10‐E11 induced cKit‐CreER T2 (Stanczuk et al ., 2015). cKit is a marker associated with HemECs and HemEC‐derived hematopoietic progenitors from all known hemogenic sites of the embryo and the yolk sac (YS) (Antas et al ., 2013; Medvinsky et al, 2011). In the heart, Pdgfrb‐Cre induced labeling, together with positive labeling with Vav‐Cre , a pan‐hematopoietic lineage marker, and E7 induced Csf1r1‐MeriCreMer , which traces YS‐derived myeloid cells (Gomez Perdiguero et al, 2015; Hoeffel et al, 2015), was proposed to indicate YS HemEC as the source of cardiac LECs (Klotz et al, 2015).…”

Notch1 regulates progenitor cell proliferation and differentiation during mouse yolk sac hematopoiesis

“…47 The Tie2 promoter is active in endothelial and hematopoietic lineages from E7.5 onwards, 48 and almost all primitive hematopoietic cells can be traced to Tie2 þ cells. N1ICD and Tie2 have a similar expression pattern in YS blood islands.…”

A short history of hemogenic endothelium

“…Primitive erythrocytes are thought to derive directly from a mesodermal precursor, and not from a bona fide HSC as the latter are not detectable in the conceptus at this early stage [4,5]. Shortly after the formation of primitive erythrocytes, multi-potent and lineage-restricted hematopoietic progenitor cells that display adult-type morphology are generated asynchronously in different hematopoietic sites of the embryo (reviewed in [6,7]), including the yolk sac, para-aortic splanchnopleura (PAS)/ aorta-gonad-mesonephros (AGM) region, vitelline and umbilical arteries, placenta, and most recently recognized, the heart [8]. These progenitors are generally considered transient in nature as also they emerge in the absence of adult HSC activity, though some specific lymphoid and myeloid cells may persist into adulthood [9][10][11].…”

“…Finally, definitive HSCs capable of founding the adult hematopoietic system and responsible for the life-long production of all blood cells are first and autonomously generated in the wall of the dorsal aorta in the AGM region, starting from E10.5 [4,5,[14][15][16][17][18]. The transient progenitors and long-term HSCs have long been proposed to originate from a specialized subset of endothelium, so-called hemogenic endothelium (reviewed in [7,[19][20][21]). However, it was not until recently, through the application of live single cell imaging, that the endothelial origin of blood gained wider support.…”