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Special Issue "Cell Lineage Choice During Haematopoiesis: A Commemorative Issue in Honor of Professor Antonius Rolink"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 May 2018).

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Dr. Geoffrey Brown
E-Mail Website1 Website2
Guest Editor
Institute of Clinical Sciences, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Interests: haematopoiesis; cell decision-making; cell differentiation; myeloid leukaemias; retinoids
Special Issues and Collections in MDPI journals
Prof. Rhodri Ceredig
E-Mail Website
Guest Editor
Bioscience Building, Corrib Village, National University of Ireland, Galway, Ireland
Interests: mouse lymphocyte development; Interleukin-7; cell lineage decisions in hematopoiesis; mesenchymal stromal cells
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue of the International Journal of Molecular Sciences entitled “Cell Lineage Choice during Haematopoiesis” is dedicated to Professor Antonius Rolink (Ton). Ton was the Director of Research of our Marie Sklodowska Curie FP7 ITN “DECIDE” (www.birmingham.ac.uk/decide), one of the aims of which is to investigate cell lineage choice in haematopoiesis.

For more than 30 years, we seemed to have had a very clear picture of how the haematopoietic stem cell (HSC) gives rise to the many different types of blood and immune cells. In the classic lineage tree model, HSC follow a prescribed route to each of the end cell types and gradually restrict their alternative choices via a series of intermediate oligo-potent progenitor cells. Recent findings have challenged these principles leading to a very different viewpoint whereby a continuum of each fate option is open to HSC. Thus, HSC have lineage biases/affiliations and progenitor cells in bone marrow are either pluripotent or uni-potent. Thus, HSCs can make an immediate choice without traversing a series of intermediate progenitors to progressively close down developmental options. Developing cells can move sideways to adopt an alternative fate. This Special Issue will examine the shift towards a new architecture for the blood cell system and how the development of such cells is controlled.

For an appreciation of Ton’s contribution to DECIDE, see: http://www.birmingham.ac.uk/generic/decide/news/ton-rolink.aspx

Dr. Geoffrey Brown
Prof. Dr. Rhodri Ceredig
Guest Editors

Manuscript Submission Information

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Keywords

  • The haematopietic stem cell
  • The nature of haematopoietic progenitors
  • Decision-making during haematopoiesis
  • Modelling haematopoiesis
  • Culture and in vivo model systems for studying haematopoiesis
  • T lymphocyte development
  • B lymphocyte decelopment
  • The diversity of the mature types of blood cells
  • Molecular controls on haematopoiesis
  • Haematopoietic growth factors
  • Differentiating agents
  • Implications of our understanding of haematopoiesis to leukaemia

Published Papers (11 papers)

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Editorial

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Open AccessEditorial
Cell Lineage Choice during Haematopoiesis: In Honour of Professor Antonius Rolink
Int. J. Mol. Sci. 2018, 19(9), 2798; https://doi.org/10.3390/ijms19092798 - 17 Sep 2018
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Research

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Open AccessArticle
Identification of an Essential Cytoplasmic Region of Interleukin-7 Receptor α Subunit in B-Cell Development
Int. J. Mol. Sci. 2018, 19(9), 2522; https://doi.org/10.3390/ijms19092522 - 25 Aug 2018
Cited by 1
Abstract
Interleukin-7 (IL-7) is essential for lymphocyte development. To identify the functional subdomains in the cytoplasmic tail of the IL-7 receptor (IL-7R) α chain, here, we constructed a series of IL-7Rα deletion mutants. We found that IL-7Rα-deficient hematopoietic progenitor cells (HPCs) gave rise to [...] Read more.
Interleukin-7 (IL-7) is essential for lymphocyte development. To identify the functional subdomains in the cytoplasmic tail of the IL-7 receptor (IL-7R) α chain, here, we constructed a series of IL-7Rα deletion mutants. We found that IL-7Rα-deficient hematopoietic progenitor cells (HPCs) gave rise to B cells both in vitro and in vivo when a wild-type (WT) IL-7Rα chain was introduced; however, no B cells were observed under the same conditions from IL-7Rα-deficient HPCs with introduction of the exogenous IL-7Rα subunit, which lacked the amino acid region at positions 414–441 (d414–441 mutant). Signal transducer and activator of transcription 5 (STAT5) was phosphorylated in cells with the d414–441 mutant, similar to that in WT cells, in response to IL-7 stimulation. In contrast, more truncated STAT5 (tSTAT5) was generated in cells with the d414–441 mutant than in WT cells. Additionally, the introduction of exogenous tSTAT5 blocked B lymphopoiesis but not myeloid cell development from WT HPCs in vivo. These results suggested that amino acids 414–441 in the IL-7Rα chain formed a critical subdomain necessary for the supportive roles of IL-7 in B-cell development. Full article
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Open AccessArticle
Mining the Plasma Cell Transcriptome for Novel Cell Surface Proteins
Int. J. Mol. Sci. 2018, 19(8), 2161; https://doi.org/10.3390/ijms19082161 - 24 Jul 2018
Cited by 2
Abstract
Antibody Secreting Cells (ASCs) are a fundamental component of humoral immunity, however, deregulated or excessive antibody production contributes to the pathology of autoimmune diseases, while transformation of ASCs results in the malignancy Multiple Myeloma (MM). Despite substantial recent improvements in treating these conditions, [...] Read more.
Antibody Secreting Cells (ASCs) are a fundamental component of humoral immunity, however, deregulated or excessive antibody production contributes to the pathology of autoimmune diseases, while transformation of ASCs results in the malignancy Multiple Myeloma (MM). Despite substantial recent improvements in treating these conditions, there is as yet no widely used ASC-specific therapeutic approach, highlighting a critical need to identify novel methods of targeting normal and malignant ASCs. Surface molecules specifically expressed by the target cell population represent ideal candidates for a monoclonal antibody-based therapy. By interrogating the ASC gene signature that we previously defined we identified three surface proteins, Plpp5, Clptm1l and Itm2c, which represent potential targets for novel MM treatments. Plpp5, Clptm1l and Itm2c are highly and selectively expressed by mouse and human ASCs as well as MM cells. To investigate the function of these proteins within the humoral immune system we have generated three novel mouse strains, each carrying a loss-of-function mutation in either Plpp5, Clptm1l or Itm2c. Through analysis of these novel strains, we have shown that Plpp5, Clptm1l and Itm2c are dispensable for the development, maturation and differentiation of B-lymphocytes, and for the production of antibodies by ASCs. As adult mice lacking either protein showed no apparent disease phenotypes, it is likely that targeting these molecules on ASCs will have minimal on-target adverse effects. Full article
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Open AccessArticle
Regulation of Expression of CEBP Genes by Variably Expressed Vitamin D Receptor and Retinoic Acid Receptor α in Human Acute Myeloid Leukemia Cell Lines
Int. J. Mol. Sci. 2018, 19(7), 1918; https://doi.org/10.3390/ijms19071918 - 29 Jun 2018
Cited by 5
Abstract
All-trans-retinoic acid (ATRA) and 1α,25-dihydroxyvitamin D (1,25D) are potent inducers of differentiation of myeloid leukemia cells. During myeloid differentiation specific transcription factors are expressed at crucial developmental stages. However, precise mechanism controlling the diversification of myeloid progenitors is largely unknown, CCAAT/enhancer-binding [...] Read more.
All-trans-retinoic acid (ATRA) and 1α,25-dihydroxyvitamin D (1,25D) are potent inducers of differentiation of myeloid leukemia cells. During myeloid differentiation specific transcription factors are expressed at crucial developmental stages. However, precise mechanism controlling the diversification of myeloid progenitors is largely unknown, CCAAT/enhancer-binding protein (C/EBP) transcription factors have been characterized as key regulators of the development and function of the myeloid system. Past data point at functional redundancy among C/EBP family members during myeloid differentiation. In this study, we show that in acute myeloid leukemia (AML) cells, high expression of vitamin D receptor gene (VDR) is needed for strong and sustained upregulation of CEBPB gene, while the moderate expression of VDR is sufficient for upregulation of CEBPD in response to 1,25D. The high expression level of the gene encoding for retinoic acid receptor α (RARA) allows for high and sustained expression of CEBPB, which becomes decreased along with a decrease of RARA expression. Expression of CEBPB induced by ATRA is accompanied by upregulated expression of CEBPE with similar kinetics. Our results suggest that CEBPB is the major VDR and RARA-responsive gene among the CEBP family, necessary for expression of genes connected with myeloid functions. Full article
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Open AccessArticle
Ferritin Heavy Subunit Silencing Blocks the Erythroid Commitment of K562 Cells via miR-150 up-Regulation and GATA-1 Repression
Int. J. Mol. Sci. 2017, 18(10), 2167; https://doi.org/10.3390/ijms18102167 - 17 Oct 2017
Cited by 4
Abstract
Erythroid differentiation is a complex and multistep process during which an adequate supply of iron for hemoglobinization is required. The role of ferritin heavy subunit, in this process, has been mainly attributed to its capacity to maintain iron in a non-toxic form. We [...] Read more.
Erythroid differentiation is a complex and multistep process during which an adequate supply of iron for hemoglobinization is required. The role of ferritin heavy subunit, in this process, has been mainly attributed to its capacity to maintain iron in a non-toxic form. We propose a new role for ferritin heavy subunit (FHC) in controlling the erythroid commitment of K562 erythro-myeloid cells. FHC knockdown induces a change in the balance of GATA transcription factors and significantly reduces the expression of a repertoire of erythroid-specific genes, including α- and γ-globins, as well as CD71 and CD235a surface markers, in the absence of differentiation stimuli. These molecular changes are also reflected at the morphological level. Moreover, the ability of FHC-silenced K562 cells to respond to the erythroid-specific inducer hemin is almost completely abolished. Interestingly, we found that this new role for FHC is largely mediated via regulation of miR-150, one of the main microRNA implicated in the cell-fate choice of common erythroid/megakaryocytic progenitors. These findings shed further insight into the biological properties of FHCand delineate a role in erythroid differentiation where this protein does not act as a mere iron metabolism-related factor but also as a critical regulator of the expression of genes of central relevance for erythropoiesis. Full article
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Review

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Open AccessReview
Murine Bone Marrow Niches from Hematopoietic Stem Cells to B Cells
Int. J. Mol. Sci. 2018, 19(8), 2353; https://doi.org/10.3390/ijms19082353 - 10 Aug 2018
Cited by 8
Abstract
After birth, the development of hematopoietic cells occurs in the bone marrow. Hematopoietic differentiation is finely tuned by cell-intrinsic mechanisms and lineage-specific transcription factors. However, it is now clear that the bone marrow microenvironment plays an essential role in the maintenance of hematopoietic [...] Read more.
After birth, the development of hematopoietic cells occurs in the bone marrow. Hematopoietic differentiation is finely tuned by cell-intrinsic mechanisms and lineage-specific transcription factors. However, it is now clear that the bone marrow microenvironment plays an essential role in the maintenance of hematopoietic stem cells (HSC) and their differentiation into more mature lineages. Mesenchymal and endothelial cells contribute to a protective microenvironment called hematopoietic niches that secrete specific factors and establish a direct contact with developing hematopoietic cells. A number of recent studies have addressed in mouse models the specific molecular events that are involved in the cellular crosstalk between hematopoietic subsets and their niches. This has led to the concept that hematopoietic differentiation and commitment towards a given hematopoietic pathway is a dynamic process controlled at least partially by the bone marrow microenvironment. In this review, we discuss the evolving view of murine hematopoietic–stromal cell crosstalk that is involved in HSC maintenance and commitment towards B cell differentiation. Full article
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Open AccessReview
Regulation of Energy Metabolism during Early B Lymphocyte Development
Int. J. Mol. Sci. 2018, 19(8), 2192; https://doi.org/10.3390/ijms19082192 - 27 Jul 2018
Cited by 3
Abstract
The most important feature of humoral immunity is the adaptation of the diversity of newly generated B cell receptors, that is, the antigen receptor repertoire, to the body’s own and foreign structures. This includes the transient propagation of B progenitor cells and B [...] Read more.
The most important feature of humoral immunity is the adaptation of the diversity of newly generated B cell receptors, that is, the antigen receptor repertoire, to the body’s own and foreign structures. This includes the transient propagation of B progenitor cells and B cells, which possess receptors that are positively selected via anabolic signalling pathways under highly competitive conditions. The metabolic regulation of early B-cell development thus has important consequences for the expansion of normal or malignant pre-B cell clones. In addition, cellular senescence programs based on the expression of B cell identity factors, such as Pax5, act to prevent excessive proliferation and cellular deviation. Here, we review the basic mechanisms underlying the regulation of glycolysis and oxidative phosphorylation during early B cell development in bone marrow. We focus on the regulation of glycolysis and mitochondrial oxidative phosphorylation at the transition from non-transformed pro- to pre-B cells and discuss some ongoing issues. We introduce Swiprosin-2/EFhd1 as a potential regulator of glycolysis in pro-B cells that has also been linked to Ca2+-mediated mitoflashes. Mitoflashes are bioenergetic mitochondrial events that control mitochondrial metabolism and signalling in both healthy and disease states. We discuss how Ca2+ fluctuations in pro- and pre-B cells may translate into mitoflashes in early B cells and speculate about the consequences of these changes. Full article
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Open AccessReview
The Making of Hematopoiesis: Developmental Ancestry and Environmental Nurture
Int. J. Mol. Sci. 2018, 19(7), 2122; https://doi.org/10.3390/ijms19072122 - 21 Jul 2018
Cited by 7
Abstract
Evidence from studies of the behaviour of stem and progenitor cells and of the influence of cytokines on their fate determination, has recently led to a revised view of the process by which hematopoietic stem cells and their progeny give rise to the [...] Read more.
Evidence from studies of the behaviour of stem and progenitor cells and of the influence of cytokines on their fate determination, has recently led to a revised view of the process by which hematopoietic stem cells and their progeny give rise to the many different types of blood and immune cells. The new scenario abandons the classical view of a rigidly demarcated lineage tree and replaces it with a much more continuum-like view of the spectrum of fate options open to hematopoietic stem cells and their progeny. This is in contrast to previous lineage diagrams, which envisaged stem cells progressing stepwise through a series of fairly-precisely described intermediate progenitors in order to close down alternative developmental options. Instead, stem and progenitor cells retain some capacity to step sideways and adopt alternative, closely related, fates, even after they have “made a lineage choice.” The stem and progenitor cells are more inherently versatile than previously thought and perhaps sensitive to lineage guidance by environmental cues. Here we examine the evidence that supports these views and reconsider the meaning of cell lineages in the context of a continuum model of stem cell fate determination and environmental modulation. Full article
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Open AccessReview
Vitamins D: Relationship between Structure and Biological Activity
Int. J. Mol. Sci. 2018, 19(7), 2119; https://doi.org/10.3390/ijms19072119 - 20 Jul 2018
Cited by 6
Abstract
The most active metabolite of vitamin D is 1α,25-dihydroxyvitamin D3, which is a central regulator of mineral homeostasis: excessive administration leads to hypercalcemia. Additionally, 1α,25-dihydroxyvitamin D3 is important to decision-making by cells, driving many cell types to growth arrest, differentiate [...] Read more.
The most active metabolite of vitamin D is 1α,25-dihydroxyvitamin D3, which is a central regulator of mineral homeostasis: excessive administration leads to hypercalcemia. Additionally, 1α,25-dihydroxyvitamin D3 is important to decision-making by cells, driving many cell types to growth arrest, differentiate and undergo apoptosis. 1α,25-Dihydroxyvitamin D3 regulates gene transcription by binding to a single known receptor, the vitamin D receptor. Rapid intracellular signals are also elicited in vitro by 1α,25-dihydroxyvitamin D3 that are independent of transcription. There are many aspects of the multiple actions of 1α,25-dihydroxyvitamin D3 that we do not fully understand. These include how a single receptor and provoked rapid events relate to the different actions of 1α,25-dihydroxyvitamin D3, its calcemic action per se, and whether a large number of genes are activated directly, via the vitamin D receptor, or indirectly. A strategy to resolving these issues has been to generate synthetic analogues of 1α,25-dihydroxyvitamin D3: Some of these separate the anti-proliferative and calcemic actions of the parent hormone. Crystallography is important to understanding how differences between 1α,25-dihydroxyvitamin D3- and analogue-provoked structural changes to the vitamin D receptor may underlie their different activity profiles. Current crystallographic resolution has not revealed such information. Studies of our new analogues have revealed the importance of the A-ring adopting the chair β-conformation upon interaction with the vitamin D receptor to receptor-affinity and biological activity. Vitamin D analogues are useful probes to providing a better understanding of the physiology of vitamin D. Full article
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Open AccessReview
Molecular Regulation of Differentiation in Early B-Lymphocyte Development
Int. J. Mol. Sci. 2018, 19(7), 1928; https://doi.org/10.3390/ijms19071928 - 30 Jun 2018
Cited by 4
Abstract
B-lymphocyte differentiation is one of the best understood developmental pathways in the hematopoietic system. Our understanding of the developmental trajectories linking the multipotent hematopoietic stem cell to the mature functional B-lymphocyte is extensive as a result of efforts to identify and prospectively isolate [...] Read more.
B-lymphocyte differentiation is one of the best understood developmental pathways in the hematopoietic system. Our understanding of the developmental trajectories linking the multipotent hematopoietic stem cell to the mature functional B-lymphocyte is extensive as a result of efforts to identify and prospectively isolate progenitors at defined maturation stages. The identification of defined progenitor compartments has been instrumental for the resolution of the molecular features that defines given developmental stages as well as for our understanding of the mechanisms that drive the progressive maturation process. Over the last years it has become increasingly clear that the regulatory networks that control normal B-cell differentiation are targeted by mutations in human B-lineage malignancies. This generates a most interesting link between development and disease that can be explored to improve diagnosis and treatment protocols in lymphoid malignancies. The aim of this review is to provide an overview of our current understanding of molecular regulation in normal and malignant B-cell development. Full article
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Open AccessReview
The Making of Leukemia
Int. J. Mol. Sci. 2018, 19(5), 1494; https://doi.org/10.3390/ijms19051494 - 17 May 2018
Cited by 4
Abstract
Due to the clonal nature of human leukemia evolution, all leukemic cells carry the same leukemia-initiating genetic lesions, independently of the intrinsic tumoral cellular heterogeneity. However, the latest findings have shown that the mode of action of oncogenes is not homogeneous throughout the [...] Read more.
Due to the clonal nature of human leukemia evolution, all leukemic cells carry the same leukemia-initiating genetic lesions, independently of the intrinsic tumoral cellular heterogeneity. However, the latest findings have shown that the mode of action of oncogenes is not homogeneous throughout the developmental history of leukemia. Studies on different types of hematopoietic tumors have shown that the contribution of oncogenes to leukemia is mainly mediated through the epigenetic reprogramming of the leukemia-initiating target cell. This driving of cancer by a malignant epigenetic stem cell rewiring is, however, not exclusive of the hematopoietic system, but rather represents a common tumoral mechanism that is also at work in epithelial tumors. Tumoral epigenetic reprogramming is therefore a new type of interaction between genes and their target cells, in which the action of the oncogene modifies the epigenome to prime leukemia development by establishing a new pathological tumoral cellular identity. This reprogramming may remain latent until it is triggered by either endogenous or environmental stimuli. This new view on the making of leukemia not only reveals a novel function for oncogenes, but also provides evidence for a previously unconsidered model of leukemogenesis, in which the programming of the leukemia cellular identity has already occurred at the level of stem cells, therefore showing a role for oncogenes in the timing of leukemia initiation. Full article
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