[Show abstract][Hide abstract] 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
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
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
[Show abstract][Hide abstract] 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.
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