scholarly journals Cell-to-cell variability in JAK2/STAT5 pathway components and cytoplasmic volumes define survival threshold in erythroid progenitor cells

2019 ◽  
Author(s):  
Lorenz Adlung ◽  
Paul Stapor ◽  
Christian Tönsing ◽  
Leonard Schmiester ◽  
Luisa E. Schwarzmüller ◽  
...  
Keyword(s):  
Single Cell ◽  
Progenitor Cells ◽  
Cell Population ◽  
Population Level ◽  
Minimal Amount ◽  
List Type ◽  
Erythroid Progenitor ◽  
Binary Decision ◽  
Erythroid Progenitor Cells ◽  
Cell To Cell Variability

SummarySurvival or apoptosis is a binary decision in individual cells. Yet, at the cell population level, a graded increase in survival of CFU-E cells is observed upon stimulation with Erythropoietin (Epo). To identify components of JAK2/STAT5 signal transduction that contribute to the graded population response, a cell population-level model calibrated with experimental data was extended to study the behavior in single cells. The single-cell model showed that the high cell-to-cell variability in nuclear phosphorylated STAT5 is caused by variability in the amount of EpoR:JAK2 complexes and of SHP1 as well as the extent of nuclear import due to the large variance in the cytoplasmic volume of CFU-E cells. 24 to 118 pSTAT5 molecules in the nucleus for 120 min are sufficient to ensure cell survival. Thus, variability in membrane-associated processes are responsible to convert a switch-like behavior at the single-cell level to a graded population level response.HighlightsMathematical modeling enables integration of heterogeneous dataSingle-cell modeling captures binary decision processMultiple sources of cell-to-cell variability in erythroid progenitor cellsMinimal amount of active STAT5 sufficient for survival of erythroid progenitor cells

scholarly journals Cell-to-cell variability in JAK2/STAT5 pathway components and cytoplasmic volumes defines survival threshold in erythroid progenitor cells

Cell Reports ◽  
2021 ◽  
Vol 36 (6) ◽  
pp. 109507
Author(s):  
Lorenz Adlung ◽  
Paul Stapor ◽  
Christian Tönsing ◽  
Leonard Schmiester ◽  
Luisa E. Schwarzmüller ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells ◽  
Survival Threshold ◽  
Cell To Cell Variability

scholarly journals HDAC6 promotes PMA-induced megakaryocyte differentiation of K562 cells by regulating ROS levels via NOX4 and repressing Glycophorin A

2019 ◽  
Author(s):  
Githavani Kummari ◽  
Ravi K Gutti ◽  
Arunasree M. Kalle
Keyword(s):  
Progenitor Cells ◽  
Marker Gene ◽  
K562 Cells ◽  
Glycophorin A ◽  
List Type ◽  
Down Regulation ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells ◽  
Lineage Marker ◽  
Megakaryocyte Differentiation

AbstractThe human erythroleukemia (K562) cells are considered as bipotent megakaryocyte-erythroid progenitor cells and the differentiation of these cells to megakaryocytes (MK) in the presence of phorbol 12-myristate 13-acetate (PMA) mimics in vivo differentiation of MEP (megakaryocyte-erythroid progenitor) cells in the bone marrow. Histone deacetylases (HDACs) are involved in gene suppression and their roles during the MK differentiation remains largely undefined. In the present study, we have studied the expression levels of class I and class II HDACs during phorbol 12-myristate 13-acetate (PMA)-induced differentiation of K562 cells to MK. Class IIb HDACs (HDAC6 & HDAC10) were significantly up regulated time dependently upto 4 days of PMA-induced MK differentiation along with decreased acetylation levels of H3K9 and H3K56. Pharmacological inhibition and knockdown studies of HDAC6 using tubastatin A (TubA) and shRNA-HDAC6 respectively, during MK differentiation resulted in down regulation of MK lineage marker CD61 and up regulation of erythroid lineage gene glycophorin A (GYPA). HDAC6 over expression in K562 cells showed significant up regulation of CD61, MK transcription factors (FOG1 and GATA2) and down regulation of GYPA. ChIP-PCR studies showed enrichment of HDAC6 protein on GYPA promoter during differentiation indicating GYPA gene repression by HDAC6. Further studies on elucidating the role of HDAC6 in MK differentiation clearly indicated that HDAC6 is required for the production of sustainable levels of reactive oxygen species (ROS), an important regulator of MK differentiation, via NOX4.- ROS-HDAC6 circuit. In this study, we provide the first evidence that during PMA-induced megakaryocyte differentiation of K562 cells, HDAC6 represses erythroid lineage marker gene, GYPA, and promotes the sustainable levels of ROS via NOX4 required for MK differentiation.Key pointsHDAC6 upregulated during MK differentiation is involved in sustainable production of ROS via the circuit - HDAC6-NOX4-ROS-HDAC6.HDAC6 inhibits erythroid lineage gene, GYPA, by forming a repressor complex over the promoter region.

Human thymic epithelial cells maintain long-term survival of clonogenic myeloid and erythroid progenitor cells in vitro

2000 ◽  
Vol 111 (1) ◽  
pp. 363-370 ◽  
Author(s):  
Katsuto Takenaka ◽  
Mine Harada ◽  
Tomoaki Fujisaki ◽  
Koji Nagafuji ◽  
Shinichi Mizuno ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Progenitor Cells ◽  
Thymic Epithelial Cells ◽  
Erythroid Progenitor ◽  
Term Survival ◽  
Long Term Survival ◽  
Erythroid Progenitor Cells

scholarly journals Fetal erythropoiesis in steel mutant mice. III. Defect in differentiation from BFU-E to CFU-E during early development

Blood ◽  
1978 ◽  
Vol 51 (3) ◽  
pp. 539-547 ◽  
Author(s):  
DH Chui ◽  
SK Liao ◽  
K Walker
Keyword(s):  
Progenitor Cells ◽  
Early Development ◽  
The Other ◽  
Mutant Mice ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells ◽  
Other Hand ◽  
Colony Forming Units ◽  
Fetal Erythropoiesis

Abstract Erythroid progenitor cells in +/+ and Sl/Sld fetal livers manifested as burst-forming units-erythroid (BFU-E) and colony-forming units- erythroid (CFU-E) were assayed in vitro during early development. The proportion of BFU-E was higher as mutant than in normal fetal livers. On the other hand, the proportion of CFU-E was less in the mutant than in the normal. These results suggest that the defect in Sl/Sld fetal hepatic erythropoiesis is expressed at the steps of differentiation that effect the transition from BFU-E to CFU-E.

scholarly journals The Raf‐1 Protein Mediates Insulin‐Like Growth Factor‐Induced Proliferation of Erythroid Progenitor Cells

Stem Cells ◽  
1998 ◽  
Vol 16 (3) ◽  
pp. 200-207 ◽  
Author(s):  
Marilyn R. Sanders ◽  
Hsienwie Lu ◽  
Frederick Walker ◽  
Sandra Sorba ◽  
Nicholas Dainiak
Keyword(s):  
Growth Factor ◽  
Progenitor Cells ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells

scholarly journals Tumor Immune Evasion Induced by Dysregulation of Erythroid Progenitor Cells Development

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 870
Author(s):  
Tomasz M. Grzywa ◽  
Magdalena Justyniarska ◽  
Dominika Nowis ◽  
Jakub Golab
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Progenitor Cells ◽  
Cancer Progression ◽  
Immune Evasion ◽  
Transforming Growth Factor ◽  
Early Stage ◽  
Interleukin 10 ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells

Cancer cells harness normal cells to facilitate tumor growth and metastasis. Within this complex network of interactions, the establishment and maintenance of immune evasion mechanisms are crucial for cancer progression. The escape from the immune surveillance results from multiple independent mechanisms. Recent studies revealed that besides well-described myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) or regulatory T-cells (Tregs), erythroid progenitor cells (EPCs) play an important role in the regulation of immune response and tumor progression. EPCs are immature erythroid cells that differentiate into oxygen-transporting red blood cells. They expand in the extramedullary sites, including the spleen, as well as infiltrate tumors. EPCs in cancer produce reactive oxygen species (ROS), transforming growth factor β (TGF-β), interleukin-10 (IL-10) and express programmed death-ligand 1 (PD-L1) and potently suppress T-cells. Thus, EPCs regulate antitumor, antiviral, and antimicrobial immunity, leading to immune suppression. Moreover, EPCs promote tumor growth by the secretion of growth factors, including artemin. The expansion of EPCs in cancer is an effect of the dysregulation of erythropoiesis, leading to the differentiation arrest and enrichment of early-stage EPCs. Therefore, anemia treatment, targeting ineffective erythropoiesis, and the promotion of EPC differentiation are promising strategies to reduce cancer-induced immunosuppression and the tumor-promoting effects of EPCs.

scholarly journals Ligand-dependent repression of the erythroid transcription factor GATA-1 by the estrogen receptor.

1995 ◽  
Vol 15 (6) ◽  
pp. 3147-3153 ◽  
Author(s):  
G A Blobel ◽  
C A Sieff ◽  
S H Orkin
Keyword(s):  
Bone Marrow ◽  
Estrogen Receptor ◽  
Transcription Factor ◽  
Progenitor Cells ◽  
Erythroid Cell ◽  
High Dose ◽  
Dependent Manner ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells

High-dose estrogen administration induces anemia in mammals. In chickens, estrogens stimulate outgrowth of bone marrow-derived erythroid progenitor cells and delay their maturation. This delay is associated with down-regulation of many erythroid cell-specific genes, including alpha- and beta-globin, band 3, band 4.1, and the erythroid cell-specific histone H5. We show here that estrogens also reduce the number of erythroid progenitor cells in primary human bone marrow cultures. To address potential mechanisms by which estrogens suppress erythropoiesis, we have examined their effects on GATA-1, an erythroid transcription factor that participates in the regulation of the majority of erythroid cell-specific genes and is necessary for full maturation of erythrocytes. We demonstrate that the transcriptional activity of GATA-1 is strongly repressed by the estrogen receptor (ER) in a ligand-dependent manner and that this repression is reversible in the presence of 4-hydroxytamoxifen. ER-mediated repression of GATA-1 activity occurs on an artificial promoter containing a single GATA-binding site, as well as in the context of an intact promoter which is normally regulated by GATA-1. GATA-1 and ER bind to each other in vitro in the absence of DNA. In coimmunoprecipitation experiments using transfected COS cells, GATA-1 and ER associate in a ligand-dependent manner. Mapping experiments indicate that GATA-1 and the ER form at least two contacts, which involve the finger region and the N-terminal activation domain of GATA-1. We speculate that estrogens exert effects on erythropoiesis by modulating GATA-1 activity through protein-protein interaction with the ER. Interference with GATA-binding proteins may be one mechanism by which steroid hormones modulate cellular differentiation.

scholarly journals DOT1L methyltransferase regulates the calcium influx in erythroid progenitor cells in response to erythropoietin

2020 ◽  
Author(s):  
Yi Feng ◽  
Shaon Borosha ◽  
Anamika Ratri ◽  
Sami M. Housami ◽  
V. Praveen Chakravarthi ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Receptor Potential ◽  
Proximal Region ◽  
Yolk Sac ◽  
Hematopoietic Progenitor Cells ◽  
Hematopoietic Progenitor ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells

ABSTRACTErythropoietin (EPO) signaling plays a vital role in erythropoiesis by regulating proliferation and lineage-specific differentiation of hematopoietic progenitor cells. An important downstream response of EPO signaling is calcium influx, which is regulated by transient receptor potential channel (TRPC) proteins, particularly TRPC2 and TRPC6. While EPO induces Ca2+influx through TRPC2, TRPC6 inhibits the function of TRPC2. Thus, interactions between TRPC2 and TRPC6 regulate the rate of Ca2+influx in EPO-induced erythropoiesis. In this study, we observed that the expression of TRPC6 in c-KIT positive erythroid progenitor cells is regulated by DOT1L. DOT1L is a methyltransferase that plays an important role in many biological processes during embryonic development, including early erythropoiesis. We previously reported that Dot1L knockout (Dot1L-KO) hematopoietic progenitors in the yolk sac failed to develop properly, which resulted in lethal anemia. In this study, we have detected a marked downregulation of Trpc6 gene expression in Dot1L-KO progenitor cells in the yolk sac compared to wildtype. However, the expression of Trpc2, the positive regulator of Ca2+influx, remained unchanged. The promoter and the proximal region of the Trpc6 gene loci exhibited an enrichment of H3K79 methylation, which is mediated solely by DOT1L. As the loss of DOT1L affects the expression of TRPC6, which inhibits Ca2+influx by TRPC2, Dot1L-KO progenitor cells in the yolk sac exhibit accelerated and sustained high levels of Ca2+influx. Such heightened Ca2+ levels might have detrimental effects on the development of hematopoietic progenitor cells in response to erythropoietin.

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