scholarly journals Identification of Cdca7 as a novel Notch transcriptional target involved in hematopoietic stem cell emergence

2014 ◽  
Vol 211 (12) ◽  
pp. 2411-2423 ◽  
Author(s):  
Jordi Guiu ◽  
Dylan J.M. Bergen ◽  
Emma De Pater ◽  
Abul B.M.M.K. Islam ◽  
Verónica Ayllón ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
De Novo ◽  
Embryonic Stem ◽  
Dependent Manner ◽  
Hematopoietic Differentiation ◽  
Loss Of Function ◽  
Promoter Regions ◽  
Hematopoietic Stem

Hematopoietic stem cell (HSC) specification occurs in the embryonic aorta and requires Notch activation; however, most of the Notch-regulated elements controlling de novo HSC generation are still unknown. Here, we identify putative direct Notch targets in the aorta-gonad-mesonephros (AGM) embryonic tissue by chromatin precipitation using antibodies against the Notch partner RBPj. By ChIP-on-chip analysis of the precipitated DNA, we identified 701 promoter regions that were candidates to be regulated by Notch in the AGM. One of the most enriched regions corresponded to the Cdca7 gene, which was subsequently confirmed to recruit the RBPj factor but also Notch1 in AGM cells. We found that during embryonic hematopoietic development, expression of Cdca7 is restricted to the hematopoietic clusters of the aorta, and it is strongly up-regulated in the hemogenic population during human embryonic stem cell hematopoietic differentiation in a Notch-dependent manner. Down-regulation of Cdca7 mRNA in cultured AGM cells significantly induces hematopoietic differentiation and loss of the progenitor population. Finally, using loss-of-function experiments in zebrafish, we demonstrate that CDCA7 contributes to HSC emergence in vivo during embryonic development. Thus, our study identifies Cdca7 as an evolutionary conserved Notch target involved in HSC emergence.

The Ski oncoprotein regulates Hematopoietic Stem Cell Fitness and Functions as a Corepressor for Gfi1.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1403-1403
Author(s):  
Chinavenmeni S. Velu ◽  
Michael Berk ◽  
Haiming Xu ◽  
Tristan Bourdeau ◽  
Avedis Kazanjian ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Target Genes ◽  
Fetal Liver ◽  
Embryonic Stem ◽  
Loss Of Function ◽  
Hematopoietic Stem ◽  
Myeloid Progenitor ◽  
Multipotent Progenitors

Abstract Ski is a corepressor protein originally identified as a retrovirally transduced oncoprotein. Genetic deletion of Ski has revealed essential roles in multiple developmental processes. Suggestion that Ski may play a role in hematopoiesis first came from expression of v-Ski and c-Kit, which induced the continuous in vitro growth of primary avian multipotent progenitors. However, the hematopoietic phenotype of Ski−/− mice has not been described. Here, we show that Ski loss of function results in loss of hematopoietic stem cell (HSC) fitness and abnormal regulation of myeloid progenitor numbers. Fetal liver Ski−/− HSC engraft well in ablated recipients, but are not competitive in engraftment. Moreover, Ski null embryonic stem cells generate many tissues in chimeras, but infrequently participate in hematopoiesis. Thus, Ski null HSC are not competitive in both transplant and chimera settings, indicating a defect in stem cell fitness. Engrafted Ski−/− fetal liver cells generate fewer myeloid lineage cells than wild type littermates, and accumulate granulocytemonocyte progenitors. Growth factor independent -1 (Gfi1) is a transcriptional repressor that controls HSC maintenance and myeloid progenitor differentiation. Gfi1−/− and Ski−/− hematopoietic stem and myeloid progenitor phenotypes are strikingly similar. We find that Ski functions as a corepressor for Gfi1. Both endogenous and synthetic Gfi1 and Ski physically interact in vitro and upon Gfi1 target genes. Knockdown of Gfi1 or Ski results in derepression of these targets. Thus, our results provide a molecular link between the similar HSC and myeloid progenitor phenotypes engendered by Gfi1 or Ski deletion.

scholarly journals EGFR confers exquisite specificity of Wnt9a-Fzd9b signaling in hematopoietic stem cell development

2018 ◽  
Author(s):  
Stephanie Grainger ◽  
Nicole Nguyen ◽  
Jenna Richter ◽  
Jordan Setayesh ◽  
Brianna Lonquich ◽  
...  
Keyword(s):  
Stem Cell ◽  
Wnt Signaling ◽  
Hematopoietic Stem Cell ◽  
Cell Biology ◽  
Embryonic Stem ◽  
Cell Development ◽  
List Type ◽  
Hematopoietic Stem

SummaryThe mechanisms of Wnt-Frizzled (Fzd) signaling selectivity and their biological implications remain unclear. We demonstrate for the first time that the epidermal growth factor receptor (EGFR) is required as a co-factor for Wnt signaling. Using genetic studies in zebrafish, paired within vitrocell biology and biochemistry, we have determined that Fzd9b signals specifically with Wnt9ain vivoandin vitroto elicit β-catenin dependent Wnt signals that regulate hematopoietic stem and progenitor cell (HSPC) development in the dorsal aorta. This requirement is conserved in the derivation of HSPCs from human embryonic stem cells. Wnt9a-Fzd9b specificity requires two intracellular domains in Fzd9b, which interact with EGFR as a required co-factor to promote signal transduction. EGFR phosphorylates one tyrosine residue on Fzd9b, a requirement for the Wnt signal. These findings indicate that Wnt signaling interactions can be exquisitely specific and inform protocols for derivation of HSPCsin vitro.HighlightsAnin vitrosignaling screen identifies Fzd9b as a Wnt9a-specific receptor.Fzd9b and Wnt9a regulate hematopoietic stem cell development as a cognate pair.WNT9A and FZD9 are required for HSPC derivation from human pluripotent cellsin vitro.EGFR confers specificity to Wnt9a-Fzd9b signaling in zebrafish and human cells.

Identification and Isolation of the Hematopoietic Stem Cell Niche Initiating Cell Population

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3574-3574
Author(s):  
Charles Chan ◽  
Ching-Cheng Chen ◽  
Daniel L. Kraft ◽  
Cynthia Luppen ◽  
Jae-Beom Kim ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Endochondral Ossification ◽  
Dependent Manner ◽  
Renal Capsule ◽  
Hematopoietic Stem ◽  
Marrow Cavity ◽  
Hsc Niche

Abstract Introduction: Identification and understanding of the cells and processes that can generate, sustain and influence the HSC niche and hematopoiesis are critical for the development of a more comprehensive knowledge of normal hematopoiesis, stem cell homing, trafficking, differentiation and hematopoietic pathology. Growth and renewal in many tissues are initiated by stem cells, supported by the microenvironment (niche) in which they reside. While recent work has begun to describe functional interactions between stem cells and their niches, little is known about the formation of stem cell niches. Methods & Results: We established a functional, in vivo assay (via implantation of cells under the renal capsule) to isolate the determinants of hematopoietic stem cell (HSC) niche formation and activity. Using this novel assay, we show that a population of progenitor cells (CD45−Tie2-aV+CD105+Thy1.1−; CD105+Thy1−) sorted from 15.5 dpc fetal limbs and transplanted under the adult mouse renal capsule recruit host-derived vasculatures in a VEGF dependent manner, produce donor-derived ectopic bones through endochondral ossification, and generate a marrow cavity populated by host-derived long term reconstituting HSC (LT-HSC). In contrast, CD45−Tie2-aV+CD105+Thy1a+ (CD105+Thy1+) progenitors form bone that does not contain a marrow cavity. While analyzing these and other sorted populations, we did not observe any instances where niche was present without bone, suggesting that skeletal progenitors are necessary for initiating an HSC niche but osteoblasts alone cannot initiate and support niche activity. Suppression of factors important for HSC maintenance, such as steel factor (SLF), in progenitor populations prior to transplant did not alter their ability to initiate and support an HSC niche. On the other hand, suppression of factors involved in endochondral ossification, such as osterix and VEGF, inhibited niche generation. Furthermore, CD105+Thy1− progenitor populations derived from regions of the fetal mandible or calvaria that do not undergo endochondral ossification form only bone without marrow in our assay. Conclusions: In addition to identifying the limb-derived skeletal progenitor capable of endochondral ossification involved and the basic mechanisms of HSC niche initiation, our study provides a functional framework by which future studies on HSC-niche interactions at the cellular level can be carried out.

scholarly journals The NF-κB pathway regulates heterochromatin at intronic young LINE-1 elements and hematopoietic stem cell gene expression during irradiation stress

2021 ◽  
Author(s):  
Yanis Pelinski ◽  
Donia Hidaoui ◽  
Francois Hermetet ◽  
Anne Stolz ◽  
M'boyba Khadija Diop ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Regulatory Networks ◽  
Loss Of Function ◽  
Hematopoietic Stem ◽  
Tnf Α ◽  
Cell Gene Expression ◽  
And Function

Understanding how ionizing radiations (IR) alter hematopoietic stem cell (HSC) function on the long-term is crucial. We recently showed a link between derepression of L1Md, the mouse young subfamilies of LINE-1/L1 retroelements, and IR-induced HSC injury. L1 contribute to gene regulatory networks. However, the mechanisms involved in IR-induced L1Md derepression, and their impact on HSC transcriptome remain to be addressed. Here we show that IR triggers genome-wide H3K9me3 decreased and transcriptomic changes in HSCs, characterized by a loss of the TNF-α/NF-κB and HSC signatures. HSC gene repression is associated to H3K9me3 loss at specific intronic L1Md displaying NF-κB binding sites. This is correlated with reduced NFKB1 repressor expression. TNF-α treatment before IR rescued all these effects and prevented IR-induced HSC loss of function in vivo. This reveals the importance of the TNF-α/NF-κB pathway to control H3K9me3 levels at selected intronic L1Md and thereby preserve HSC gene expression and function during IR stress.

scholarly journals Hematopoietic Stem Cell Transplantation Resolves the Immune Deficit Associated with STAT3-Dominant-Negative Hyper-IgE Syndrome

2021 ◽  
Author(s):  
Stephanie C. Harrison ◽  
Christo Tsilifis ◽  
Mary A. Slatter ◽  
Zohreh Nademi ◽  
Austen Worth ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Early Report ◽  
Dominant Negative ◽  
Loss Of Function ◽  
Hematopoietic Stem ◽  
Hyper Ige Syndrome

AbstractAutosomal dominant hyper-IgE syndrome caused by dominant-negative loss-of-function mutations in signal transducer and activator of transcription factor 3 (STAT3) (STAT3-HIES) is a rare primary immunodeficiency with multisystem pathology. The quality of life in patients with STAT3-HIES is determined by not only the progressive, life-limiting pulmonary disease, but also significant skin disease including recurrent infections and abscesses requiring surgery. Our early report indicated that hematopoietic stem cell transplantation might not be effective in patients with STAT3-HIES, although a few subsequent reports have reported successful outcomes. We update on progress of our patient now with over 18 years of follow-up and report on an additional seven cases, all of whom have survived despite demonstrating significant disease-related pathology prior to transplant. We conclude that effective cure of the immunological aspects of the disease and stabilization of even severe lung involvement may be achieved by allogeneic hematopoietic stem cell transplantation. Recurrent skin infections and abscesses may be abolished. Donor TH17 cells may produce comparable levels of IL17A to healthy controls. The future challenge will be to determine which patients should best be offered this treatment and at what point in their disease history.

scholarly journals Synthesis and Two-Dimensional 1Η and 13C NMR Investigations of an Inhibitor of Hematopoietic Stem Cell Proliferation Ac–Ser–Asp–Lys–Pro–OH

1992 ◽  
Vol 47 (9) ◽  
pp. 1324-1332 ◽  
Author(s):  
Jens Freund ◽  
Afroditi Kapurniotu ◽  
Tadeusz A. Holak ◽  
Maryse Lenfant ◽  
Wolfgang Voelter
Keyword(s):  
Cell Proliferation ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Solid Phase ◽  
Water Solution ◽  
Random Coil ◽  
Hematopoietic Stem ◽  
Stem Cell Proliferation ◽  
Equilibrium Ratio

The solid phase synthesis of the inhibitor of hematopoietic stem cell proliferation, Ac–Ser–Asp–Lys–Pro–OH, and its derivative Ac–Ala–Asp–Lys–Pro–OH is described. 1H and 13C NMR investigations demonstrate that both peptides show no prefered conformation in water solution. Both peptides exist in a Pro-cis-trans equilibrium ratio of 9 (trans) : 1 (cis). Thymosin β4 is believed to be the precursor molecule of the tetrapeptide Ac–SDKP. The attachement of the random coil tetrapeptide to a rigid helical fragment could facilitate its in vivo enzymatic cleavage.

Loss of FancC Function Results in Decreased Hematopoietic Stem Cell Repopulating Ability

Blood ◽  
1999 ◽  
Vol 94 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Laura S. Haneline ◽  
Troy A. Gobbett ◽  
Rema Ramani ◽  
Madeleine Carreau ◽  
Manuel Buchwald ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Cell Function ◽  
Genetic Disorder ◽  
Test Cell ◽  
Hematopoietic Stem ◽  
Murine Homologue ◽  
Complex Genetic Disorder

Fanconi anemia (FA) is a complex genetic disorder characterized by progressive bone marrow (BM) aplasia, chromosomal instability, and acquisition of malignancies, particularly myeloid leukemia. We used a murine model containing a disruption of the murine homologue ofFANCC (FancC) to evaluate short- and long-term multilineage repopulating ability of FancC −/− cells in vivo. Competitive repopulation assays were conducted where “test”FancC −/− or FancC +/+ BM cells (expressing CD45.2) were cotransplanted with congenic competitor cells (expressing CD45.1) into irradiated mice. In two independent experiments, we determined that FancC −/− BM cells have a profound decrease in short-term, as well as long-term, multilineage repopulating ability. To determine quantitatively the relative production of progeny cells by each test cell population, we calculated test cell contribution to chimerism as compared with 1 × 105 competitor cells. We determined that FancC −/− cells have a 7-fold to 12-fold decrease in repopulating ability compared with FancC +/+cells. These data indicate that loss of FancC function results in reduced in vivo repopulating ability of pluripotential hematopoietic stem cells, which may play a role in the development of the BM failure in FA patients. This model system provides a powerful tool for evaluation of experimental therapeutics on hematopoietic stem cell function.

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