scholarly journals Interplay between the EMT transcription factors ZEB1 and ZEB2 regulates hematopoietic stem and progenitor cell differentiation and hematopoietic lineage fidelity

PLoS Biology ◽  
2021 ◽  
Vol 19 (9) ◽  
pp. e3001394
Author(s):  
Jueqiong Wang ◽  
Carlos Farkas ◽  
Aissa Benyoucef ◽  
Catherine Carmichael ◽  
Katharina Haigh ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Family Member ◽  
Progenitor Cell ◽  
Transition Point ◽  
Rna Seq ◽  
Short Term ◽  
Hematopoietic Stem ◽  
Close Family Member ◽  
Lineage Differentiation ◽  
Hematopoietic Lineage

The ZEB2 transcription factor has been demonstrated to play important roles in hematopoiesis and leukemic transformation. ZEB1 is a close family member of ZEB2 but has remained more enigmatic concerning its roles in hematopoiesis. Here, we show using conditional loss-of-function approaches and bone marrow (BM) reconstitution experiments that ZEB1 plays a cell-autonomous role in hematopoietic lineage differentiation, particularly as a positive regulator of monocyte development in addition to its previously reported important role in T-cell differentiation. Analysis of existing single-cell (sc) RNA sequencing (RNA-seq) data of early hematopoiesis has revealed distinctive expression differences between Zeb1 and Zeb2 in hematopoietic stem and progenitor cell (HSPC) differentiation, with Zeb2 being more highly and broadly expressed than Zeb1 except at a key transition point (short-term HSC [ST-HSC]➔MPP1), whereby Zeb1 appears to be the dominantly expressed family member. Inducible genetic inactivation of both Zeb1 and Zeb2 using a tamoxifen-inducible Cre-mediated approach leads to acute BM failure at this transition point with increased long-term and short-term hematopoietic stem cell numbers and an accompanying decrease in all hematopoietic lineage differentiation. Bioinformatics analysis of RNA-seq data has revealed that ZEB2 acts predominantly as a transcriptional repressor involved in restraining mature hematopoietic lineage gene expression programs from being expressed too early in HSPCs. ZEB1 appears to fine-tune this repressive role during hematopoiesis to ensure hematopoietic lineage fidelity. Analysis of Rosa26 locus–based transgenic models has revealed that Zeb1 as well as Zeb2 cDNA-based overexpression within the hematopoietic system can drive extramedullary hematopoiesis/splenomegaly and enhance monocyte development. Finally, inactivation of Zeb2 alone or Zeb1/2 together was found to enhance survival in secondary MLL-AF9 acute myeloid leukemia (AML) models attesting to the oncogenic role of ZEB1/2 in AML.

scholarly journals Single cell transcriptome analysis reveals an essential role for Gata2b in hematopoietic lineage decisions in zebrafish

2019 ◽  
Author(s):  
Emanuele Gioacchino ◽  
Cansu Koyunlar ◽  
Hans de Looper ◽  
Madelon de Jong ◽  
Tomasz Dobrzycki ◽  
...  
Keyword(s):  
Single Cell ◽  
Transcriptome Analysis ◽  
Progenitor Cell ◽  
Adult Zebrafish ◽  
Hematopoietic Stem ◽  
Lineage Differentiation ◽  
Hematopoietic Lineage ◽  
Cell Transcriptome ◽  
Single Cell Transcriptome ◽  
Monocytic Lineage

AbstractHematopoietic stem cells (HSCs) are tightly controlled to keep a balance between myeloid and lymphoid cell differentiation. Gata2 is a pivotal hematopoietic transcription factor required for HSC generation and maintenance. We generated a zebrafish mutant for the mammalianGata2orthologue,gata2b. We found that in adult zebrafish,gata2bis required for both neutrophilic- and monocytic lineage differentiation. Single cell transcriptome analysis revealed that the myeloid defect present in Gata2b deficient zebrafish arise in the most immature hematopoietic stem and progenitor cell (HSPC) compartment and that this population is instead committed towards the lymphoid and erythroid lineage. Taken together, we find that Gata2b is vital for the fate choice between the myeloid and lymphoid lineages.

scholarly journals CHD7 and Runx1 interaction provides a braking mechanism for hematopoietic differentiation

2020 ◽  
Vol 117 (38) ◽  
pp. 23626-23635
Author(s):  
Jingmei Hsu ◽  
Hsuan-Ting Huang ◽  
Chung-Tsai Lee ◽  
Avik Choudhuri ◽  
Nicola K. Wilson ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Progenitor Cell ◽  
Hematopoietic Differentiation ◽  
Hematopoietic Stem ◽  
Binding Motifs ◽  
Hematopoietic Development ◽  
Lineage Differentiation ◽  
Hematopoietic Lineage ◽  
Evolutionarily Conserved ◽  
And Function

Hematopoietic stem and progenitor cell (HSPC) formation and lineage differentiation involve gene expression programs orchestrated by transcription factors and epigenetic regulators. Genetic disruption of the chromatin remodeler chromodomain-helicase-DNA-binding protein 7 (CHD7) expanded phenotypic HSPCs, erythroid, and myeloid lineages in zebrafish and mouse embryos. CHD7 acts to suppress hematopoietic differentiation. Binding motifs for RUNX and other hematopoietic transcription factors are enriched at sites occupied by CHD7, and decreased RUNX1 occupancy correlated with loss of CHD7 localization. CHD7 physically interacts with RUNX1 and suppresses RUNX1-induced expansion of HSPCs during development through modulation of RUNX1 activity. Consequently, the RUNX1:CHD7 axis provides proper timing and function of HSPCs as they emerge during hematopoietic development or mature in adults, representing a distinct and evolutionarily conserved control mechanism to ensure accurate hematopoietic lineage differentiation.

Hematopoietic stem/progenitor cell differentiation towards myeloid lineage is modulated by LIGHT/LIGHT receptor signaling

2017 ◽  
Vol 233 (2) ◽  
pp. 1095-1103 ◽  
Author(s):  
Weikai Chen ◽  
Xin Lv ◽  
Changlong Liu ◽  
Ruoping Chen ◽  
Jianhe Liu ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Progenitor Cell ◽  
Receptor Signaling ◽  
Myeloid Lineage ◽  
Hematopoietic Stem ◽  
Light Receptor

scholarly journals Jagged2 acts as a Delta-like Notch ligand during early hematopoietic cell fate decisions

Blood ◽  
2011 ◽  
Vol 117 (17) ◽  
pp. 4449-4459 ◽  
Author(s):  
Inge Van de Walle ◽  
Greet De Smet ◽  
Martina Gärtner ◽  
Magda De Smedt ◽  
Els Waegemans ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Promoter Activation ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions ◽  
Lineage Differentiation ◽  
Hematopoietic Lineage ◽  
Myeloid Development ◽  
Dose Dependent ◽  
Notch Ligands

Abstract Notch signaling critically mediates various hematopoietic lineage decisions and is induced in mammals by Notch ligands that are classified into 2 families, Delta-like (Delta-like-1, -3 and -4) and Jagged (Jagged1 and Jagged2), based on structural homology with both Drosophila ligands Delta and Serrate, respectively. Because the functional differences between mammalian Notch ligands were still unclear, we have investigated their influence on early human hematopoiesis and show that Jagged2 affects hematopoietic lineage decisions very similarly as Delta-like-1 and -4, but very different from Jagged1. OP9 coculture experiments revealed that Jagged2, like Delta-like ligands, induces T-lineage differentiation and inhibits B-cell and myeloid development. However, dose-dependent Notch activation studies, gene expression analysis, and promoter activation assays indicated that Jagged2 is a weaker Notch1-activator compared with the Delta-like ligands, revealing a Notch1 specific signal strength hierarchy for mammalian Notch ligands. Strikingly, Lunatic-Fringe– mediated glycosylation of Notch1 potentiated Notch signaling through Delta-like ligands and also Jagged2, in contrast to Jagged1. Thus, our results reveal a unique role for Jagged1 in preventing the induction of T-lineage differentiation in hematopoietic stem cells and show an unexpected functional similarity between Jagged2 and the Delta-like ligands.

scholarly journals Short-term ex-vivo exposure to hydrogen sulfide enhances murine hematopoietic stem and progenitor cell migration, homing, and proliferation

2020 ◽  
Vol 14 (1) ◽  
pp. 214-226
Author(s):  
Anoushka Khanna ◽  
Namita Indracanti ◽  
Rina Chakrabarti ◽  
Prem Kumar Indraganti
Keyword(s):  
Cell Migration ◽  
Hydrogen Sulfide ◽  
Progenitor Cell ◽  
Ex Vivo ◽  
Short Term ◽  
Hematopoietic Stem

scholarly journals A 3D Atlas of Hematopoietic Stem and Progenitor Cell Expansion by Multi-dimensional RNA-Seq Analysis

Cell Reports ◽  
2019 ◽  
Vol 27 (5) ◽  
pp. 1567-1578.e5 ◽  
Author(s):  
Yuanyuan Xue ◽  
Denghui Liu ◽  
Guizhong Cui ◽  
Yanyan Ding ◽  
Daosheng Ai ◽  
...  
Keyword(s):  
Cell Expansion ◽  
Progenitor Cell ◽  
Rna Seq ◽  
Hematopoietic Stem

scholarly journals IFN-γ causes aplastic anemia by altering hematopoietic stem/progenitor cell composition and disrupting lineage differentiation

Blood ◽  
2014 ◽  
Vol 124 (25) ◽  
pp. 3699-3708 ◽  
Author(s):  
Fan-ching Lin ◽  
Megan Karwan ◽  
Bahara Saleh ◽  
Deborah L. Hodge ◽  
Tim Chan ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Progenitor Cells ◽  
Progenitor Cell ◽  
Inhibitory Effect ◽  
Hematopoietic Stem ◽  
Cell Composition ◽  
Lineage Differentiation ◽  
Key Points ◽  
Ifn Γ ◽  
Myeloid Progenitors

Key Points IFN-γ alone leads to aplastic anemia by disrupting the generation of common myeloid progenitors and lineage differentiation. The inhibitory effect of IFN-γ on hematopoiesis is intrinsic to hematopoietic stem/progenitor cells.

scholarly journals Hhexis Required at Multiple Stages of Adult Hematopoietic Stem and Progenitor Cell Differentiation

Stem Cells ◽  
2015 ◽  
Vol 33 (8) ◽  
pp. 2628-2641 ◽  
Author(s):  
Charnise Goodings ◽  
Elizabeth Smith ◽  
Elizabeth Mathias ◽  
Natalina Elliott ◽  
Susan M. Cleveland ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Progenitor Cell ◽  
Hematopoietic Stem ◽  
Multiple Stages

scholarly journals Metabolic Programming of the Fetal Liver Hematopoietic Stem and Progenitor Cell Pool

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4315-4315
Author(s):  
Ashley N. Kamimae-Lanning ◽  
Natalya A. Goloviznina ◽  
Stephanie M. Krasnow ◽  
Daniel L. Marks ◽  
Peter Kurre
Keyword(s):  
Progenitor Cell ◽  
Maternal Obesity ◽  
Fetal Liver ◽  
Control Diet ◽  
Liver Cells ◽  
Rna Seq ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Qrt Pcr ◽  
Fetal Liver Cells

Abstract Evidence in several organ systems demonstrates that pregnancy presents a window of vulnerability for establishing a foundation for health or chronic disease. Overnutrition and the complex metabolic changes that can accompany it can result in permanent phenotypic changes and a predisposition to metabolic syndrome, inflammatory or immune-mediated diseases. We previously reported that prenatal overnutrition stunted fetal liver size. Herein, we hypothesize that this might perturb hematopoietic stem and progenitor cell (HSPC) expansion. To test the effects of a high-fat diet (HFD) and maternal obesity on offspring hematopoiesis, we used a mouse model of diet-induced obesity, feeding female mice a HFD or control diet starting at 5-7 weeks of age and keeping them on the respective diet during subsequent breeding and pregnancy. We then studied offspring at gestational day 14.5 by immunophenotyping, gene expression analysis, qRT-PCR, and transplantation. Fetal livers from HFD offspring had 51% fewer c-Kit+ Sca-1+ Linlo/- and 27% fewer AA4.1+ Sca-1+ Linlo/- (ASL) hematopoietic stem and progenitor cells (HSPC) than controls. This restriction in HSPC numbers was not due to apoptosis or increased reactive oxygen species, as tested by flow cytometry. To determine whether there might be an increase in hematopoietic differentiation to account for relative HSPC deficiencies in HFD livers, we examined hematopoietic lineage subsets. HFD fetal livers had a relative increase in myeloid (Gr-1+/Ter119+) and B220+ lymphoid cells, with comparable proportion of CD3+ cells to controls. Taken together, these results suggest that chronic HFD fetal programming skews fetal liver HSPCs toward differentiation. When we examined global gene expression of male HFD fetal livers versus controls by RNA-seq, we found differential expression of 125 genes. Among the upregulated transcripts, several were involved in hematopoietic regulation, stress response, and HSPC migration. We then used qRT-PCR to test for expression of several of these genes, along with genes critically involved in fetal HSPC self-renewal, within an HSPC-enriched (Sca-1+) population of chronic HFD fetal liver cells. As in RNA-seq, Matrixmetalloproteinase-8 and 9 (Mmp8, Mmp9), which are involved in cell mobilization, were upregulated in HFD-programmed cells. Early growth response-1 (Egr-1) was downregulated as well, further suggesting premature migration of HSPCs from HFD fetal liver. Hmga2, which is implicated in fetal stem cell self-renewal, and its direct target, Igf2bp2, were significantly downregulated in chronic HFD Sca-1+ cells. Along with the immunophenotyping data, these findings suggest that maternal obesity and HFD bias HSPCs toward differentiation, at the expense of self-renewal. To dissect the direct metabolic impact, we studied fetal livers from timed pregnancy cohorts after acute HFD exposure or diet reversal in obese dams, which partially ameliorated several molecular and immunophenotypic endpoints. Finally, we performed a functional test of chronic HFD fetal liver cells by transplantation. A non-competitive transplant into irradiated male recipients yielded no difference in chimerism between HFD or control fetal liver-engrafted animals. Next, we preconditioned a cohort of female and male animals on HFD (or control diet) for 11 weeks, irradiated them, and then competitively transplanted them with a 1:1 ratio of HFD and control fetal liver cells. HFD-programmed fetal liver HSPCs engrafted HFD-conditioned male recipients at significantly lower rates than in HFD-conditioned female or control recipients of either sex. HFD-programmed donor cells retained the significant bias toward the myeloid (Gr-1+/Mac-1+) lineage, noted in the primary graft cells, and away from the B220+ B cell lineage in HFD-conditioned males. In aggregate, prenatal HFD and maternal obesity suppress self-renewal in favor of HSPC differentiation during a time of critical developmental expansion. This suggests an HSPC defect that appears at least partly specified by the stem cell microenvironment. Our work is the first to demonstrate metabolic vulnerability of the hematopoietic stem and progenitor cell compartment and establishes the hematopoietic system as a target for in utero developmental programming. Disclosures No relevant conflicts of interest to declare.

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