scholarly journals Signaling Pathways That Regulate Normal and Aberrant Red Blood Cell Development

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1646
Author(s):  
Mark C. Wilkes ◽  
Aya Shibuya ◽  
Kathleen M. Sakamoto
Keyword(s):  
Blood Cell ◽  
Signaling Pathways ◽  
Therapeutic Potential ◽  
Cell Development ◽  
Signaling Cascades ◽  
Hematopoietic Stem ◽  
Multiple Substrates ◽  
Stem And Progenitor Cells ◽  
Multiple Copies ◽  
Phosphoinositide 3 Kinase

Blood cell development is regulated through intrinsic gene regulation and local factors including the microenvironment and cytokines. The differentiation of hematopoietic stem and progenitor cells (HSPCs) into mature erythrocytes is dependent on these cytokines binding to and stimulating their cognate receptors and the signaling cascades they initiate. Many of these pathways include kinases that can diversify signals by phosphorylating multiple substrates and amplify signals by phosphorylating multiple copies of each substrate. Indeed, synthesis of many of these cytokines is regulated by a number of signaling pathways including phosphoinositide 3-kinase (PI3K)-, extracellular signal related kinases (ERK)-, and p38 kinase-dependent pathways. Therefore, kinases act both upstream and downstream of the erythropoiesis-regulating cytokines. While many of the cytokines are well characterized, the nuanced members of the network of kinases responsible for appropriate induction of, and response to, these cytokines remains poorly defined. Here, we will examine the kinase signaling cascades required for erythropoiesis and emphasize the importance, complexity, enormous amount remaining to be characterized, and therapeutic potential that will accompany our comprehensive understanding of the erythroid kinome in both healthy and diseased states.

scholarly journals The Roles of SNF2/SWI2 Nucleosome Remodeling Enzymes in Blood Cell Differentiation and Leukemia

2015 ◽  
Vol 2015 ◽  
pp. 1-17 ◽  
Author(s):  
Punit Prasad ◽  
Andreas Lennartsson ◽  
Karl Ekwall
Keyword(s):  
Blood Cell ◽  
Chromatin Remodeling ◽  
Large Scale ◽  
Cell Development ◽  
Normal Blood ◽  
Aberrant Expression ◽  
Atpase Subunit ◽  
Hematopoietic Stem ◽  
Nucleosome Remodeling ◽  
Genes Encoding

Here, we review the role of sucrose nonfermenting (SNF2) family enzymes in blood cell development. The SNF2 family comprises helicase-like ATPases, originally discovered in yeast, that can remodel chromatin by changing chromatin structure and composition. The human genome encodes 30 different SNF2 enzymes. SNF2 family enzymes are often part of multisubunit chromatin remodeling complexes (CRCs), which consist of noncatalytic/auxiliary subunit along with the ATPase subunit. However, blood cells express a limited set of SNF2 ATPases that are necessary to maintain the pool of hematopoietic stem cells (HSCs) and drive normal blood cell development and differentiation. The composition of CRCs can be altered by the association of specific auxiliary subunits. Several auxiliary CRC subunits have specific functions in hematopoiesis. Aberrant expressions of SNF2 ATPases and/or auxiliary CRC subunit(s) are often observed in hematological malignancies. Using large-scale data from the International Cancer Genome Consortium (ICGC) we observed frequent mutations in genes encoding SNF2 helicase-like enzymes and auxiliary CRC subunits in leukemia. Hence, orderly function of SNF2 family enzymes is crucial for the execution of normal blood cell developmental program, and defects in chromatin remodeling caused by mutations or aberrant expression of these proteins may contribute to leukemogenesis.

scholarly journals Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms

2016 ◽  
Author(s):  
Michael Guo ◽  
Satish K. Nandakumar ◽  
Jacob C. Ulirsch ◽  
Seyedeh Maryam Zekavat ◽  
Jason D. Buenrostro ◽  
...  
Keyword(s):  
Blood Cell ◽  
Genome Sequencing ◽  
Association Studies ◽  
Population Based ◽  
Regulatory Mechanisms ◽  
Data Sets ◽  
Lineage Specification ◽  
High Coverage ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells

ABSTRACTGenetic variants affecting hematopoiesis can influence commonly measured blood cell traits. To identify factors that affect hematopoiesis, we performed association studies for blood cell traits in the population-based Estonian Biobank using high coverage whole genome sequencing (WGS) in 2,284 samples and SNP genotyping in an additional ~17,000 samples. Our analyses identified 17 associations across 14 blood cell traits. Integration of WGS-based fine-mapping and complementary epigenomic data sets provided evidence for causal mechanisms at several loci, including at a novel basophil count-associated locus near the master hematopoietic transcription factor CEBPA. The fine-mapped variant at this basophil count association near CEBPA overlapped an enhancer active in common myeloid progenitors and influenced its activity. In situ perturbation of this enhancer by CRISPR/Cas9 mutagenesis in hematopoietic stem and progenitor cells demonstrated that it is necessary for and specifically regulates CEBPA expression during basophil differentiation. We additionally identified basophil count-associated variation at another more pleiotropic myeloid enhancer near GATA2, highlighting regulatory mechanisms for ordered expression of master hematopoietic regulators during lineage specification. Our study illustrates how population-based genetic studies can provide key insights into poorly understood cell differentiation processes of considerable physiologic relevance.

scholarly journals Physioxia enhances T-cell development ex vivo from human hematopoietic stem and progenitor cells

Stem Cells ◽  
2020 ◽  
Author(s):  
Dong-Yeop Shin ◽  
Xinxin Huang ◽  
Chang-Hyun Gil ◽  
Arafat Aljoufi ◽  
James Ropa ◽  
...  
Keyword(s):  
T Cell ◽  
Progenitor Cells ◽  
Ex Vivo ◽  
T Cell Development ◽  
Cell Development ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells

The splice factor PTBP1 regulates hematopoietic stem cell function and red blood cell development

2016 ◽  
Vol 44 (9) ◽  
pp. S95-S96
Author(s):  
Matilda Rehn ◽  
Anne-Katrine Frank ◽  
Sachin Pundhir ◽  
Nicolas Rapin ◽  
Ying Ge ◽  
...  
Keyword(s):  
Stem Cell ◽  
Blood Cell ◽  
Hematopoietic Stem Cell ◽  
Red Blood Cell ◽  
Cell Function ◽  
Cell Development ◽  
Splice Factor ◽  
Hematopoietic Stem

scholarly journals The vascular niche controls Drosophila hematopoiesis via fibroblast growth factor signaling

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Manon Destalminil-Letourneau ◽  
Ismaël Morin-Poulard ◽  
Yushun Tian ◽  
Nathalie Vanzo ◽  
Michele Crozatier
Keyword(s):  
Blood Cell ◽  
Vascular System ◽  
Lymph Gland ◽  
Growth Factor Signaling ◽  
Hematopoietic Progenitors ◽  
Hematopoietic Progenitor ◽  
Fibroblast Growth Factor Signaling ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
Signaling Center

In adult mammals, hematopoiesis, the production of blood cells from hematopoietic stem and progenitor cells (HSPCs), is tightly regulated by extrinsic signals from the microenvironment called ‘niche’. Bone marrow HSPCs are heterogeneous and controlled by both endosteal and vascular niches. The Drosophila hematopoietic lymph gland is located along the cardiac tube which corresponds to the vascular system. In the lymph gland, the niche called Posterior Signaling Center controls only a subset of the heterogeneous hematopoietic progenitor population indicating that additional signals are necessary. Here we report that the vascular system acts as a second niche to control lymph gland homeostasis. The FGF ligand Branchless produced by vascular cells activates the FGF pathway in hematopoietic progenitors. By regulating intracellular calcium levels, FGF signaling maintains progenitor pools and prevents blood cell differentiation. This study reveals that two niches contribute to the control ofDrosophila blood cell homeostasis through their differential regulation of progenitors.

Clonal Features of Hematopoietic Stem and Progenitor Cells in Aging

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 243-243
Author(s):  
Jianlong Sun ◽  
Fernando D. Camargo
Keyword(s):  
Blood Cell ◽  
Progenitor Cells ◽  
Peripheral Blood ◽  
Cell Populations ◽  
Multilineage Differentiation ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Cell Production ◽  
Stem And Progenitor Cells

Abstract It is traditionally thought that Hematopoietic Stem Cells (HSCs) maintain blood homeostasis through long-term self-renewal and multilineage differentiation. This concept, however, is challenged by two recent studies in which the fundamental features of unperturbed hematopoiesis are evaluated by different approaches of lineage tracing. Both the kinetic analysis of HSC output by the Rodewald group and our clonal analysis with transposon barcoding suggest a dominant role of non-transplantable short-term HSCs and progenitors, but not the long-term HSCs, in driving native blood cell production. In addition, our longitudinal analysis of peripheral blood demonstrates extensive clonal succession in granulocyte production. These findings collectively suggest a distinct mechanism of native hematopoiesis that differs significantly from what has been learned in transplantation experiments. At the same time, they bring to light new questions regarding the ultimate fate of the progenitor population and the exact contribution of HSCs under normal physiological conditions. To address these questions, we examined clonal features of HSCs and progenitors in aged mice. Our results show a progressive reduction in clonal complexity and a concurrent increase in clonal stability when blood granulocytes are analyzed up to a hundred ten weeks after transposon barcoding. As time elapses, clonal overlapping between granulocytes and B cells become much more extensive, suggesting an increased tendency toward multilineage differentiation during aging. Analysis of stem and progenitor cells in bone marrow of aged mice reveals prevalent lineage output by multipotent progenitors (MPPs), whereas a lower fraction of HSC clones are found to produce mature progeny. While this overall pattern of differentiation is reminiscent of what has been observed in young and middle-aged animals, a two-fold increase in HSC clonal output was observed in these old mice, indicating their increased contribution to blood cell production. A comparison of clonal compositions in blood and marrow cell populations demonstrates an MPP origin of stable peripheral blood clones, and a smaller fraction of these clones can even be traced back to HSCs. These observations hence suggest extensive self-renewal and asymmetric cell division of these two cell populations in aging. Taken together, our results indicate that the aged hematopoietic system is characterized by reduced clonal complexity, increased clonal persistence, and HSC activation. The higher propensity to self-renewal during aging may also explain the elevated risk of malignant transformation in the elderly population. Disclosures Camargo: Cell Signaling Technologies: Consultancy; Vital Therapies: Consultancy.

scholarly journals Vasopressin stimulates the proliferation and differentiation of red blood cell precursors and improves recovery from anemia

2017 ◽  
Vol 9 (418) ◽  
pp. eaao1632 ◽  
Author(s):  
Balázs Mayer ◽  
Krisztián Németh ◽  
Miklós Krepuska ◽  
Vamsee D. Myneni ◽  
Dragan Maric ◽  
...  
Keyword(s):  
Blood Cell ◽  
Red Blood Cell ◽  
Peripheral Blood Cell ◽  
Hematopoietic Stem ◽  
Proliferation And Differentiation ◽  
Stem And Progenitor Cells ◽  
Mouse Cells ◽  
Delayed Recovery ◽  
Human And Mouse ◽  
Sublethal Irradiation

Arginine vasopressin (AVP) made by hypothalamic neurons is released into the circulation to stimulate water resorption by the kidneys and restore water balance after blood loss. Patients who lack this antidiuretic hormone suffer from central diabetes insipidus. We observed that many of these patients were anemic and asked whether AVP might play a role in red blood cell (RBC) production. We found that all three AVP receptors are expressed in human and mouse hematopoietic stem and progenitor cells. The AVPR1B appears to play the most important role in regulating erythropoiesis in both human and mouse cells. AVP increases phosphorylation of signal transducer and activator of transcription 5, as erythropoietin (EPO) does. After sublethal irradiation, AVP-deficient Brattleboro rats showed delayed recovery of RBC numbers compared to control rats. In mouse models of anemia (induced by bleeding, irradiation, or increased destruction of circulating RBCs), AVP increased the number of circulating RBCs independently of EPO. In these models, AVP appears to jump-start peripheral blood cell replenishment until EPO can take over. We suggest that specific AVPR1B agonists might be used to induce fast RBC production after bleeding, drug toxicity, or chemotherapy.

Hierarchy of Sca-1positive and Sca-1negative hematopoietic stem and progenitor cells and their contribution to blood cell production

2017 ◽  
Vol 53 ◽  
pp. S72
Author(s):  
Petr Paral ◽  
Katerina Faltusova ◽  
Martin Molik ◽  
Nicol Renesova ◽  
Ludek Sefc ◽  
...  
Keyword(s):  
Blood Cell ◽  
Progenitor Cells ◽  
Hematopoietic Stem ◽  
Cell Production ◽  
Stem And Progenitor Cells
Sign in / Sign up

Export Citation Format

Share Document