The puzzling origin of lymphocytes

Sanford-Burnham Medical Research Institute.
Blood (Impact Factor: 10.45). 06/2012; 119(24):5609-10. DOI: 10.1182/blood-2012-04-420737
Source: PubMed


In this issue of Blood, Yoshimoto et al show that yolk sac (YS) and para-aortic splanchnopleura (P-Sp) cells, early in development, can generate both adult and fetal type T lymphocytes. The most remarkable conclusion is that T lymphocytes are derived directly from the hemogenic endothelium, before the appearance of hematopoietic stem cells.

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    ABSTRACT: Differentiation of embryonic stem cells can be a useful tool for modeling ontogeny and all the mechanisms involved in its regulation. This is especially true for hematopoiesis where they can recapitulate the two waves observed in embryonic/fetal life: the primitive transient hematopoiesis and the definitive hematopoiesis; both giving rise to distinct morphological and functional cells. This model might be extremely valuable, especially in human to study the ontogeny of the hematopoietic system. My work was focused on the monocyte and macrophage lineages. We have shown that monocyte/macrophage derived from ESC are cells extremely specialized in tissue remodeling, proangiogenesis and immune suppression, but have very low inflammatory potential as demonstrated for embryonic monocyte/macrophage. I have investigated the characteristics of iPSC derived monocyte/macrophage compared to the ESC derived monocyte/macrophage. Results indicate that the monocytes/macrophage obtained from iPSC differentiation were quite similar to those obtained from ESC but exhibited more inflammatory potential, suggesting some incomplete reprogrammation during iPSC generation. We hypothesized that the decrease or absence of inflammatory potential of the monocyte/macrophage cells could be related to a decrease activation of the JAK2/STAT pathway induced by IFN-γ and GM-CSF, two cytokines implicated in M1 polarization. In this purpose we derived iPSC from patient haboring a gain of function mutation, JAK2V617F, associated with myeloproloferative neoplasm. In preliminary results, no significant polarisation differences were observed in JAK2V617F or JAK2WT iPSC derived monocyte/macrophage. Furthermore, we found that IFN-γ was capable to normaly induce STAT1 activation in these cells suggesting that the blockage in inflammatory response is downstream of STAT1 and may be related to epigenetic regulation of inflammatory genes. Finally, I have obtained preliminary results showing tha JAK2V617F may induce an independence to bFGF in the the pluripotent iPSC, a result very similar to those reported by 13 Griffiths et al in JAK2V617F mESC, which could maintain their pluripotent phenotype without addition of LIF. This was not related to the induction of the canonical STAT pathway but to an effect of nuclear JAK2 on the epigenetic regulation of Nanog. These results have to be confirmed and extended but could open a new avenue of research on the role of nuclear JAK2 in MNPs.
    06/2013, Degree: PhD, Supervisor: Norol Francoise, Vainchenker William
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    ABSTRACT: Erythro-myeloid progenitors (EMP) serve as a major source of hematopoiesis in the developing conceptus prior to the formation of a permanent blood system. In this review, we summarize the current knowledge regarding the emergence, fate, and potential of this hematopoietic stem cell (HSC)-independent wave of hematopoietic progenitors, focusing on the murine embryo as a model system. A better understanding of the temporal and spatial control of hematopoietic emergence in the embryo will ultimately improve our ability to derive hematopoietic stem and progenitor cells from embryonic stem cells and induced pluripotent stem cells to serve therapeutic purposes.
    Blood Cells Molecules and Diseases 10/2013; 51(4). DOI:10.1016/j.bcmd.2013.09.006 · 2.65 Impact Factor


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