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Hématopoïèse

Résumé

alt=|vignette|400x400px|Modèle simplifié de l'hématopoïèse. Une CSH multipotente se différencie en progéniteur lymphoïde ou myéloïde. La différenciation du progéniteur lymphoïde aboutit aux différents types de lymphocytes. La différenciation du progéniteur myéloïde fournit après plusieurs étapes les érythrocytes, les autres leucocytes (granulocytes, monocytes et macrophages) ainsi que les plaquettes. L' (du Grec αἷμα, αίματος : « le sang » et ποιεῖν : faire, fabriquer) est le processus physiologique de production des cellules sanguines (érythrocytes et leucocytes qui, avec les plaquettes, forment ce que l'on nomme les éléments figurés du sang). Chez l'adulte sain, la production quotidienne représente cent à mille milliards de cellules sanguines, qui remplacent autant de cellules sénescentes détruites au terme de leur durée de vie. Ainsi, l'hématopoïèse est un renouvellement cellulaire régulé qui permet de maintenir constant le nombre de cellules sanguines. Tous les éléments figurés d

Source officielle

https://fr.wikipedia.org/wiki/H%C3%A9matopo%C3%AF%C3%A8se

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Ce cours décrit le fonctionnement du système immunitaire humain et les bases immunologiques de la vaccination, de la transplantation, de l'immunothérapie, et de l'allergie. Il présente aussi le rôle des cellules souches dans la formation des tissus, notamment la lignée hématopoïétique.

This course introduces the fundamentals of stem cell biology, with a particular focus on the role of stem cells during development, tissue homeostasis/regeneration and disease, and the generation of organoids from stem cells

Self renewing organs. Flow Cytometry as tools for the analysis of the hematopoietic system.

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Publications associées (47)

The chromatin remodeller Chd7 and the calcium ATPase Serca2 - adding new facets to the role of Notch in Hematopoiesis and T-ALL

Monique Coersmeyer

Project I: Chd7 Deficiency does not affect N1-driven T-ALL Induction and Maintenance nor impair Hematopoiesis Notch1 has been shown to be a key driver in pediatric T-cell acute lymphobastic leukemia (T-ALL). Previous work in the lab identified the chromatin-remodeling enzyme Chd7 to be highly over-expressed in aggressive versus pre-malignant disease. The aim of this project was to study if Chd7 is required during T-ALL initiation and disease maintenance as well as to characterize its role in the hematopoietic system under physiological and stress conditions. Therefore, Chd7 cKO animals were crossed with the MxCre deleter to ablate Chd7 specifically in BM progenitors. Chd7 deficiency did not induce any overt phenotype in the hematopoietic system, when studied under âsteadyâ state or stress conditions. In addition, Chd7 proved to be dispensable in the initiation and maintenance of murine and human Notch1-driven T-ALL. Therefore, we can rule out a role of Chd7 during late-stage leukemogenesis in Notch1-induced murine and human T-ALL. Project II: Serca2, a putative drug target to fight Notch1-driven T cell acute lymphoblastic leukemia, and its role in Hematopoiesis The Notch signalling pathway represents a bona fide drug target. We and Roti et al. performed a chemical compound screen and identified Cyclopiazonic acid (CPA) as potent Notch inhibitor. Biological target of this compound is the Sarco/Endoplasmic Reticulum ATPase2 (Serca2) that is involved in calcium homeostasis within the cell. Recently, it was shown that Serca2 regulates Notch1 (N1) receptor maturation and inhibition of Serca ATPases, using thapsigargin, blocks T-ALL progression in xenografts (Roti et al., 2013). The putative global effects of Serca2 inhibition on hematopoiesis have, however, not been addressed in this study. Aim of this study was to characterize the function of Serca2 in the hematopoietic system. Therefore, we crossed Serca2 cKO with MxCre to ablate Serca2 function in BM progenitors. Serca2 haploinsufficiency did not lead to any overt phenotype under physiological or competitive conditions. In contrast, Serca2ÎMxCre chimeras showed (i) impaired long-term reconstitution capacity upon transplantation, (ii) a severe reduction of total BM, splenic and thymic cellularity and (iii) an enrichment of KLS cells, the cell pool that contains HSCs. Mature lineages were highly apoptotic, while KLS were not majorly affected by apoptosis, resided predominantly in G0 phase of the cell cycle, exhibited slower cycling kinetics and were functionally impaired as they formed less and smaller colony forming units in vitro. Deregulated calcium levels can lead to an accumulation of unfolded proteins in the ER. In order to resolve ER stress, the cell activates the unfolded protein response (UPR). In case of unresolved ER stress, however, the cell undergoes apoptosis. We demonstrate that mature hematopoietic lineages up-regulate UPR-associated and pro-apoptotic genes, while KLS cells, in contrast, show unperturbed expression of these genes. In addition, we performed in vitro experiments, inhibiting Serca function in Lin- BM cells via thapsigargin (TH) treatment. TH induced severe apoptosis in the overall cell population, while KLS accumulated and were blocked in the G0 phase, closely mimicking Serca2 LOF in vivo. We therefore question the therapeutic approach of targeting Serca2 in N1-driven T-ALL due to severe side effects induced by Serca2 inactivation in the BM.

EPFL2015

Chargement

Expansion of a VE-Cadherin+CD45+ population in the yolk sac upon Etv2 overexpression in the mouse embryo - Effects of BMP and Wnt signaling inhibition on the differentiation of a Flk1+ extraembryonic mesoderm in vitro model

Matteo Pluchinotta

The difficulty to find compatible donors for bone marrow transplantation makes the need for an alternative source of HSCs urgent. HSC derived from patient-specific iPS cells are ideal candidates for this purpose. Nevertheless, although HSCs are the best characterized adult stem cells, the in vitro generation and expansion of bone fide HSCs still has not been achieved without transgene insertion. Successful derivation of HSCs from ES cells or iPS cells will require a comprehensive understanding of inductive signals and downstream effectors involved in the normal arising of HSCs during embryonic development. BMP and Wnt signaling pathways play a very important role in this differentiation process. Here, we report how BMP and Wnt signaling inhibition cooperatively alter the differentiation of Flk1+PDGFRα- cells after reculture in serum-free, feeder layer-free conditions. This data will be useful in determining the factors that have to be added to a chemically defined culture medium aimed at derivation of bone fide HSC in vitro. In the second part of this master’s project, we studied the spatial and temporal localization requirements of Etv2 expression, a key regulator of the earliest events in the development of the hematopoietic and vascular systems. To gain more insight on this matter, we conditionally knocked-in Etv2 in the early endothelial compartment, using a Tie2Cre system. This leaded to an embryonically lethal phenotype by E11.5, and most interestingly, to the expansion of a VE-Cadherin+CD45+ population in the E10.5 yolk sac. We believe that these cells represent a increased pool of immature pre-definitive hematopoietic stem cells, thus underlining further the importance of Etv2 in the differentiation process towards hematopoietic, and endothelial lineages in the mouse embryo.

2011

Chargement

Adult stem cells represent only a minor proportion of a given tissue and are difficult to amplify in vitro without affecting their biological properties. To circumvent this problem, we used a transgenic/lentiviral based approach to isolate and characterize these cells by driving a fluorescent reporter protein under the control of Spi2a, H2Kb or MELK promoter/enhancer elements, which were previously shown to be active in various stem cells. The first chapter focuses on Spi2a, a serine protease inhibitor (Serpin), which is known to be preferentially expressed in hematopoietic stem cells (HSCs). Taking advantage of the previously characterized minimal Spi2a promoter, we were able to determine its activity profile in the hematopoietic system. For this purpose, we infected HSCs with a lentivirus driving d2eGFP expression under the control of the minimal Spi2a promoter. These cells were then injected into lethally irradiated recipient mice that were analyzed at different time points (≥2 months) after transplantation. Despite variable d2eGFP expression in the hematopoietic compartment, we found a population of bright d2eGFP-expressing bone marrow cells (Spi2a0.1%) that were mostly restricted to HSCs and early myeloid progenitors. Spi2a0.1% cells displayed multilineage colony forming potential in vitro and exhibited long-term multilineage repopulating capacity in vivo, when a restricted numbers of these cells (≥ 300 cells) were transplanted into secondary recipient mice. Furthermore, we generated transgenic mice using a similar construct as used for the lentiviral approach. These mice indicated that the Spi2a promoter may be activated in non-hematopoietic adult stem cells, such as in the brain, the testis or the pancreas. In the second chapter, we describe a transgenic mouse line that expresses a green fluorescent protein variant (zFP) under the control of H2Kb promoter/enhancer element. Despite the broad zFP expression, transgenic HSCs expressed exceptionally high levels of zFP, allowing prospective isolation of a population highly enriched in HSCs by sorting the 0.2% of the brightest green cells from the enriched bone marrow of H2Kb-zFP mice. Up to 90% of zFPbright cells were also c-kithigh, Sca-1high, Linneg, Flk-2neg, which is a bona fide phenotype for long-term HSCs. Double-sorted zFPbright HSCs were capable of long-term multilineage reconstitution at a limiting dilution dose of approximately 12 cells, which is comparable to that of highly purified HSCs obtained by conventional multicolor flow cytometry. Thus, the H2Kb-zFP transgenic mice provide a straightforward and easy setup for the simple and highly efficient enrichment for genetically labeled HSCs. The last chapter is dedicated to MELK. This kinase of the snf1/AMPK family was recently identified to regulate the proliferation of multipotent neural progenitor cells and was also found to be expressed in hematopoietic stem cells and in spermatogonia. Using a transgenic mouse approach by expressing eGFP under a 3.5kb MELK promoter/enhancer element, we demonstrated that eGFP-expressing cells were localized in the subventricular zone (SVZ) of the lateral ventricle and in the subgranular zone of the dentate gyrus, the two major regions of adult neurogenesis. Moreover, the eGFP expression level in SVZ-derived cells positively correlated with their ability to form neurospheres. We also observed strong and restricted expression of eGFP in spermatogonia cells, indicating that MELK may play an important role in early spermatogenesis. Additionally, activation of the MELK promoter in hematopoietic stem/progenitor cells suggested a widespread implication of MELK in various adult stem cells. To conclude, we have generated three different reporter strains and one lentiviral based approach that allow for in vivo identification of stem/progenitor cells in different compartment such as the brain, the bone marrow or the testis. With the raising interest of stem-cell-based therapies in the neurodegenerative or the cancer field, these mice should provide novel and alternative tools to study these phenomena in vivo.

EPFL2008

Chargement

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The chromatin remodeller Chd7 and the calcium ATPase Serca2 - adding new facets to the role of Notch in Hematopoiesis and T-ALL

Monique Coersmeyer

EPFL2015

EPFL2008

Expansion of a VE-Cadherin+CD45+ population in the yolk sac upon Etv2 overexpression in the mouse embryo - Effects of BMP and Wnt signaling inhibition on the differentiation of a Flk1+ extraembryonic mesoderm in vitro model

Matteo Pluchinotta

2011