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 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

The Role of Akt-Forkhead Signaling in the Hematopoietic Stem-Progenitor Cell Differentiation: Expansion of Hematopoietic and Endothelial Progenitors from Akt-1 Null Marrows and Peripheral Blood Involving FKHRL1-Activation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1704-1704
Author(s):  
Masaki Mogi ◽  
Kenneth Walsh ◽  
Tetsuro Miki
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Cell Differentiation ◽  
Cell Survival ◽  
Progenitor Cell ◽  
Akt Signaling ◽  
Hematopoietic Stem ◽  
Colony Forming Units ◽  
Macrophage Colony

Abstract Akt is an important regulator of cell survival, growth and glucose metabolism in many cell types. In the previous annual meeting, we first reported the role of Akt in the hematopoietic stem cells with Akt-gene knockout mouse models. We described that Akt-signaling modulates the side population (SP) cell by directly regulating the molecular site of Bcrp1, one of the ATP-binding cassette transporters. Akt regulates many downstream targets through phosphorylation of a number of cellular substrates. FKHRL1, one of the FOXO subclass members of the forkhead box transcription factors, has a role in not only regulation of cell-cycle progression and cell survival phosphorylated but also control of cell-differentiation and transformation. FKHRL1 transcription-activities are inhibited by Akt, following induction of a prompt and sustained nuclear exclusion through phosphorylation. In this meeting, we will exhibit how Akt and its downstream signaling, FKHRL1 act during hematopoietic stem-progenitor cell differentiation with Akt1-null mouse studies and endothelial progenitor cell (EPC) assays. In bone marrow cells, a significant increase in formation of macrophage colony-forming units (CFU-M) and granulocyte-macrophage colony-forming units (CFU-GM) was seen in Akt1-null mice. Multiple growth factor responsive progenitor cultures were also more from Akt1-deficient marrows. Moreover, flow cytometry analysis showed the higher ratio of the lineage-negative progenitor cell-population in these marrows. Previously, we reported that bone marrow cellularity and the number of hematopoietic stem cells is normal in Akt1-null mice. These results indicate that lacking of Akt1-signaling leads to the proliferation potential of progenitor cells. Next, we analyzed the number of EPCs in Akt1-deficit mice from peripheral blood mononuclear cells (PBMCs) cultured on mouse fibronectin (FN)-coated dishes. DiI-Ac-LDL/lectin stained EPCs were detected after 10 days. Interestingly, Akt1-defecit mouse-EPCs were quite an increase in number, whereas few EPCs are usually detected from wild-type PBMCs. To address why EPCs were expanded, we used human EPC assay for analyzing signal transduction at detail. After attached on FN, circulating stem cells in PBMCs differentiated into EPCs with four different steps; foci-formation, sprout from the foci, migration for cord-like structure and maturation. Western blot analysis clearly showed that Akt was gradually activated during EPC-differentiation following the inactivation at the first step of differentiation. On the contrary, Akt-downstream targets, FKHRL1 and GSK3-β were inactivated through phosphorylation during differentiation. Immunofluorescent staining showed FKHRL1 was located in nucleus at the foci-formation and translocated into cytosol at the time of sprout from foci formation. Finally, lentivirus-mediated overexpression of Akt and FKHRL1 gene into mouse PBMCs showed FKHRL1-triple mutant, which is not phosphorylatable because of replacing three phosphorylation sites by alanine residues, significantly increased the number of EPCs, while constitutive active-Akt and dominant negative-FKHRL1 failed to. These data suggest that Akt-signaling has an important modulator of the hematopoietic stem-progenitor cell differentiation. FKHRL1 is involved in this mechanism.

scholarly journals Transcriptome-wide Profiling and Posttranscriptional Analysis of Hematopoietic Stem/Progenitor Cell Differentiation toward Myeloid Commitment

2014 ◽  
Vol 3 (5) ◽  
pp. 858-875 ◽  
Author(s):  
Daniel Klimmeck ◽  
Nina Cabezas-Wallscheid ◽  
Alejandro Reyes ◽  
Lisa von Paleske ◽  
Simon Renders ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Progenitor Cell ◽  
Hematopoietic Stem

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 The Spliceosomal Component Sf3b1 Is Essential for Hematopoietic Differentiation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3582-3582
Author(s):  
Adriana De La Garza-Sauceda ◽  
Rosannah C. Cameron ◽  
Sara Nik ◽  
Michelle Gulfo ◽  
Sara G. Payne ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Endothelial Cells ◽  
Cell Differentiation ◽  
Progenitor Cell ◽  
Cell Development ◽  
Hematopoietic Cell ◽  
Lateral Plate Mesoderm ◽  
Lateral Plate ◽  
Hematopoietic Stem ◽  
Primitive Erythropoiesis

Abstract Myelodysplastic syndrome (MDS) is a disorder arising from hematopoietic stem and progenitor cell (HSPC) dysfunction resulting in ineffective hematopoiesis. A multitude of recurrent somatic mutations in spliceosomal components were recently identified in MDS that likely contribute to the pathogenesis of the disease. The lack of in vivo models to study cell-type specific effects of spliceosomal mutations limits our understanding of why such mutations lead to hematopoietic abnormalities. Using a zebrafish with a loss-of-function mutation in sf3b1 (sf3b1hi3394), an essential member of the spliceosome, we demonstrate hematopoietic cell differentiation and hematopoietic stem and progenitor cell (HSPC) specification are processes sensitive to spliceosomal malfunction. Primitive erythropoiesis initiates normally in sf3b1 mutants as evidenced by expression of scl in the posterior lateral plate mesoderm at 14 hours post fertilization (hpf) as well as gata1 and beta-globin at 24 hpf. Flow cytometry quantification of gata1:gfp positive erythrocytes showed sf3b1 mutants have 25% more cells at 24 hpf, but greater than 3-fold fewer cells at 36 and 48 hpf, time points when wild type erythroblasts are expanding and differentiating. At 48 hpf, we also observed decreased levels of o-dianisidine positive erythrocytes, low numbers of morphologically mature erythroblasts, and higher levels of immature erythroblasts in sf3b1 mutants. Similarly, we observed normal initiation of primitive myelopoiesis marked by stem cell leukemia (scl) expression in the anterior lateral plate mesoderm at 14 hpf, but diminished expression of more differentiated markers, l-plastin and myeloperoxidase at 24 and 28 hpf in sf3b1 mutants. Quantification of lysozyme C:dsred positivemyeloid cells using flow cytometry also showed 24-fold fewer mature myeloid cells in sf3b1 mutants at 36 hpf. Our data on primitive erythropoiesis and myelopoiesis indicate sf3b1 is required for hematopoietic cell differentiation. Additionally, sf3b1 mutants have diminished expression of the definitive HSPC marker runx1 within the aorta at 28 hpf. In contrast, we observed normal expression of the pan-endothelial marker kinase insert domain receptor-like (kdrl) and aorta-specific markers notch1b and notch3 at 24 hpf. Flow cytometry quantification of kdrl:gfp endothelial cells at 24 hpf shows no difference in the frequency of endothelial cells in sf3b1 mutants. Moreover, we observed fewer cmyb:gfp; kdrl:dsred double positive HSPCs along the dorsal aorta. The data suggest that decreased HSPC formation in sf3b1 mutants is due to a failure in hemogenic induction. From these studies, we show sf3b1 is required at specific stages of hematopoietic cell development. These results provide novel insight into the role of splicing in blood cell development, and can afford a deeper understanding of the mechanism of splicing regulation on the origins of MDS. Disclosures No relevant conflicts of interest to declare.

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