Autonomous murine T-cell progenitor production in the extra-embryonic yolk sac before HSC emergence

Abstract

The extra-embryonic yolk sac (YS) is the first hematopoietic site in the mouse embryo and is thought to generate only primitive erythroid and myeloerythroid progenitor cells before definitive HSC emergence within the embryo on E10.5. Here, we have shown the existence of T cell-restricted progenitors in the E9.5 YS that directly engraft in recipient immunodeficient mice. T-cell progenitors were also produced in vitro from both YS and para-aortic splanchnopleura hemogenic endothelial cells, and these T-cell progenitors repopulated the thymus and differentiated into mature T-cell subsets in vivo on transplantation. Our data confirm that the YS produces T-lineage-restricted progenitors that are available to colonize the thymus and provide new insight into the YS as a definitive hematopoietic site in the mouse embryo. (Blood. 2012;119(24): 5706-5714) IntroductionEmbryonic stem (ES) or induced pluripotent stem (iPS) cells have been intensively studied to understand the mechanisms regulating stem cell self-renewal and cell lineage specification and differentiation. Because ES-cell differentiation into the hematopoietic lineage mirrors the earliest aspects of normal embryonic development, 1 it is important to understand the process of developmental hematopoiesis to anticipate the products of ES or iPS differentiation. The first blood progenitor cells appear in the extra-embryonic yolk sac (YS) on E7.0. 2 These nucleated red blood cells express embryonic hemoglobin molecules and are called primitive erythroid progenitors. On E8.25, erythroid progenitor cells that express adult-type hemoglobin molecules appear in the YS and are called definitive erythroid progenitors. Likewise, primitive and definitive myeloid cells and megakaryocytes emerge in distinct waves in the YS. 3,4 HSCs, which reconstitute all the blood cell lineages that arise in adult mouse BM emerge at E10.5 in the ventral endothelial lining of the aorta in the aorta-gonad-mesonephros (AGM) region, 5,6 followed soon after on E11 in the YS, fetal liver, and placenta. 7,8 Later in development, HSCs accumulate in the fetal liver before mobilization and emigration into the BM just before birth. In adult mice, medullary HSCs self-renew and provide homeostatic blood cell production throughout life.T lymphocytes are produced and matured in the thymus, but, because there are no self-renewing stem cells in the thymus, T lymphopoiesis depends on circulating progenitor cells to continuously replenish the organ with precursors. Which BM hematopoietic progenitors colonize the adult thymus has long been controversial, but recent reports suggest that early T-lineage progenitors (lin Ϫ CD44 ϩ CD25 Ϫ CD117 ϩ IL-7R␣ loϪneg ) are the most immature T-cell progenitors found in the murine thymus. 9 Fetal T lymphopoiesis is also initiated by the colonization of extrathymic progenitor cells into the thymic anlage at E11. 10 The site and tissue of T-lymphoid progenitor emergence remains obscure. Interestingly, T, B, and myeloid lineage-committed progenitor cells, as well as multipoten...

Human haematopoietic stem cell development: from the embryo to the dish

“…The dependence of AGM-type, but not yolk sac-type haematopoiesis on Notch signals in the mouse embryo (Kumano et al, 2003;Hadland et al, 2004) has been used to further strengthen the case that the hPSC-derived T cells are progeny of an intra-embryonic haematopoietic progenitor. An important caveat, however, is the realisation that, in the mouse, both T-and B-cell potential is present in the pre-AGM stage yolk sac (Yoshimoto et al, 2011(Yoshimoto et al, , 2012McGrath et al, 2015). The dependence of human yolk sac-derived EMP or lymphoid cells on Notch signals is not known.…”

A short history of hemogenic endothelium

“…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]. It is the yolk sac that provides most, if not all, of the hematopoietic progenitor cells that seed the fetal liver at E10.…”

Inflammatory signaling regulates embryonic hematopoietic stem and progenitor cell production

“…Definitive erythrocytes and myeloid lineage cells differentiate in the YS starting at E8.25 from a committed erythro-myeloid progenitor (EMP) (Bertrand et al 2007;Frame et al 2013). Cells with lymphoid potential (B and T) can be found in the YS and para-aortic splanchopleura at E8.5-E9.5 (Liu and Auerbach 1991;Godin et al 1995;Yokota et al 2006;Yoshimoto et al 2012). HSCs first appear at E10.5-E11.5 in the aorta/gonad/mesonephros (AGM) region and umbilical and vitelline arteries (M€ uller et al 1994;de Bruijn et al 2000).…”