Temporal specification of blood progenitors from mouse embryonic stem cells and induced pluripotent stem cells

Irion, Stefan; Clarke, Raedun; Luche, Hervé; Kim, Injune; Morrison, Sean J.; Fehling, Hans Jöerg; Keller, Gordon

doi:10.1242/dev.042119

Cited by 73 publications

(66 citation statements)

References 69 publications

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“…45 These results have major implications for understanding hematopoietic cell origins from murine and potentially human ES and iPS cells, because the T-lineage cells derived from these pluripotent cells may emerge independent of a HSC precursor. 46,47 …”

Section: Discussionmentioning

confidence: 99%

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

Yoshimoto¹,

Porayette²,

Glosson³

et al. 2012

Blood

150

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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...

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Section: Discussionmentioning

confidence: 99%

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

Yoshimoto¹,

Porayette²,

Glosson³

et al. 2012

Blood

150

View full text Add to dashboard Cite

show abstract

“…In mouse ESCs, both AF have been described as key players in the development of the hematopoietic mesoderm [54][55][56][57][58]. However, aside from BMP4, whose contribution to the formation of hematopoietic mesoderm has been demonstrated [37][38][39], the role of Activin A in early hESC fate decisions has been considerably less explored, apart from The linear regression analysis of the previous 2 parameters post-transfection with Brachyury (F) and scramble (G) siRNAs.…”

Section: Discussionmentioning

confidence: 99%

Activin A Promotes Hematopoietic Fated Mesoderm Development Through Upregulation of Brachyury in Human Embryonic Stem Cells

Cerdan

McIntyre

Mechael

et al. 2012

Stem Cells and Development

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The development of the hematopoietic system involves multiple cellular steps beginning with the formation of the mesoderm from the primitive streak, followed by emergence of precursor populations that become committed to either the endothelial or hematopoietic lineages. A number of growth factors such as activins and fibroblast growth factors (FGFs) are known to regulate the early specification of hematopoietic fated mesoderm, notably in amphibians. However, the potential roles of these factors in the development of mesoderm and subsequent hematopoiesis in the human have yet to be delineated. Defining the cellular and molecular mechanisms by which combinations of mesoderm-inducing factors regulate this stepwise process in human cells in vitro is central to effectively directing human embryonic stem cell (hESC) hematopoietic differentiation. Herein, using hESCderived embryoid bodies (EBs), we show that Activin A, but not basic FGF/FGF2 (bFGF), promotes hematopoietic fated mesodermal specification from pluripotent human cells. The effect of Activin A treatment relies on the presence of bone morphogenetic protein 4 (BMP4) and both of the hematopoietic cytokines stem cell factor and fms-like tyrosine kinase receptor-3 ligand, and is the consequence of 2 separate mechanisms occurring at 2 different stages of human EB development from mesoderm to blood. While Activin A promotes the induction of mesoderm, as indicated by the upregulation of Brachyury expression, which represents the mesodermal precursor required for hematopoietic development, it also contributes to the expansion of cells already committed to a hematopoietic fate. As hematopoietic development requires the transition through a Brachyury + intermediate, we demonstrate that hematopoiesis in hESCs is impaired by the downregulation of Brachyury, but is unaffected by its overexpression. These results demonstrate, for the first time, the functional significance of Brachyury in the developmental program of hematopoietic differentiation from hESCs and provide an in-depth understanding of the molecular cues that orchestrate stepwise development of hematopoiesis in a human system.

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“…VEGF plays a key role in hematopoietic specification from embryonic and pluripotent induced stem cells. 49 A potential role of VEGF in the retention of progenitor cells in the bone marrow of adult mice has also been described in references 50 and 51. Exogenous administration of VEGF to mice inhibited progenitor mobilization induced by a CXCR4-antagonist and stimulated hematopoietic progenitor entry into cell cycle.…”

Section: Discussionmentioning

confidence: 99%

Identification of in vitro HSC fate regulators by differential lipid raft clustering

et al. 2012

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Temporal specification of blood progenitors from mouse embryonic stem cells and induced pluripotent stem cells

Cited by 73 publications

References 69 publications

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

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

Activin A Promotes Hematopoietic Fated Mesoderm Development Through Upregulation of Brachyury in Human Embryonic Stem Cells

Identification of in vitro HSC fate regulators by differential lipid raft clustering

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