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Cellular and Molecular Mechanisms of Hematopoiesis

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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 July 2020) | Viewed by 31246

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Special Issue Editors

Prof. Dr. Geoffrey Brown

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Guest Editor

School of Biomedical Sciences, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Interests: the use of synthetic retinoids and vitamins D as drug substances; cancer and normal stem cells; anticancer therapies; blood cell development; abnormalities in cancer stem cells
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Ken Mills

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Guest Editor

Patrick G. Johnson Centre for Cancer Research, Queen’s University Belfast, Lisburn Road, Belfast BT9 7AE, UK
Interests: acute myeloid leukaemia (AML); myelodysplastic syndrome (MDS)
Special Issues, Collections and Topics in MDPI journals

Dr. Maarten Hoogenkamp

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Guest Editor

Insitute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Interests: cell differentiation; chromatin organisation; transcription factor interplay; carcinogenesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The way that we view the development of the many different types of blood and immune cells from a hematopoietic stem cell has changed dramatically over the past few years to accommodate many new findings. Those changes have particularly changed our understanding of the inherent nature of hematopoietic stem cells. For example, we now know that some of these cells affiliate to a single cell lineage as opposed to being pluripotent in nature. There are also new views of how environment factors influence hematopoiesis. For example, we have for years viewed the hematopoietic cytokines as merely survival and growth factors, but now we know that some of them instruct cell lineage. An ongoing rewriting of hematopoiesis has also changed how we view the malignant transformation of hematopoietic stem cells and the various hematological malignancies. The aims of this Special Issue are to examine the molecular aspects of the nature of hematopoietic stem cells and their progeny, how the environment nurtures cells to change their behavior, and the importance of all of this to understanding leukemia.

From new findings, investigators are continuing to rewrite the nature of hematopoiesis. This includes views on the inherent nature of the hematopoietic stem cell, whether pluripotent or whether some of them are in fact lineage affiliated, and the extent to which cytokines are survival/growth factors and instruct cell lineage choice. Changes to our view of hematopoiesis are also changing the way we view leukemia. The Special Issue welcomes articles on all these areas.

Dr. Geoffrey Brown
Dr. Ken Mills
Dr. Maarten Hoogenkamp
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Hematopoiesis
hematopoietic stem cells
hematopoietic progenitor cells
mature blood cells
lineage decision-making
cell differentiation
hematopoietic cytokines
environmental influences
regulation of cell numbers
control of transcription
control of survival
leukemia

Published Papers (6 papers)

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Research

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10 pages, 2166 KiB

Open AccessArticle

Gemfibrozil Induces Anemia, Leukopenia and Reduces Hematopoietic Stem Cells via PPAR-α in Mice

by Gabriel Rufino Estrela, Adriano Cleis Arruda, Heron Fernandes Vieira Torquato, Leandro Ceotto Freitas-Lima, Mauro Sérgio Perilhão, Frederick Wasinski, Alexandre Budu, Ricardo Ambrósio Fock, Edgar Julian Paredes-Gamero and Ronaldo Carvalho Araujo

Int. J. Mol. Sci. 2020, 21(14), 5050; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21145050 - 17 Jul 2020

Cited by 7 | Viewed by 2897

Abstract

Hypercholesterolemia, also called high cholesterol, is a form of hyperlipidemia, which may be a consequence of diet, obesity or diabetes. In addition, increased levels of low-density lipoprotein (LDL) and reduced levels of high-density lipoprotein (HDL) cholesterol are associated with a higher risk of atherosclerosis and coronary heart disease. Thus, controlling cholesterol levels is commonly necessary, and fibrates have been used as lipid-lowering drugs. Gemfibrozil is a fibrate that acts via peroxisome proliferator-activated receptor alpha to promote changes in lipid metabolism and decrease serum triglyceride levels. However, anemia and leukopenia are known side effects of gemfibrozil. Considering that gemfibrozil may lead to anemia and that gemfibrozil acts via peroxisome proliferator-activated receptor alpha, we treated wild-type and peroxisome proliferator-activated receptor alpha-knockout mice with gemfibrozil for four consecutive days. Gemfibrozil treatment led to anemia seven days after the first administration of the drug; we found reduced levels of hemoglobin, as well as red blood cells, white blood cells and a reduced percentage of hematocrits. PPAR-alpha-knockout mice were capable of reversing all of those reduced parameters induced by gemfibrozil treatment. Erythropoietin levels were increased in the serum of gemfibrozil-treated animals, and we also observed an increased expression of hypoxia-inducible factor-2 alpha (HIF-2α) and erythropoietin in renal tissue, while PPAR-alpha knockout mice treated with gemfibrozil did not present increased levels of serum erythropoietin or tissue HIF-2α and erythropoietin mRNA levels in the kidneys. We analyzed bone marrow and found that gemfibrozil reduced erythrocytes and hematopoietic stem cells in wild-type mice but not in PPAR-alpha-knockout mice, while increased colony-forming units were observed only in wild-type mice treated with gemfibrozil. Here, we show for the first time that gemfibrozil treatment leads to anemia and leukopenia via peroxisome proliferator-activated receptor alpha in mice. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Hematopoiesis)

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15 pages, 3058 KiB

Open AccessArticle

CRISPR Gene Editing of Murine Blood Stem and Progenitor Cells Induces MLL-AF9 Chromosomal Translocation and MLL-AF9 Leukaemogenesis

by Evgenia Sarrou, Laura Richmond, Ruaidhrí J. Carmody, Brenda Gibson and Karen Keeshan

Int. J. Mol. Sci. 2020, 21(12), 4266; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124266 - 15 Jun 2020

Cited by 8 | Viewed by 4146

Abstract

Chromosomal rearrangements of the mixed lineage leukaemia (MLL, also known as KMT2A) gene on chromosome 11q23 are amongst the most common genetic abnormalities observed in human acute leukaemias. MLL rearrangements (MLLr) are the most common cytogenetic abnormalities in infant and childhood acute myeloid leukaemia (AML) and acute lymphocytic leukaemia (ALL) and do not normally acquire secondary mutations compared to other leukaemias. To model these leukaemias, we have used clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing to induce MLL-AF9 (MA9) chromosomal rearrangements in murine hematopoietic stem and progenitor cell lines and primary cells. By utilizing a dual-single guide RNA (sgRNA) approach targeting the breakpoint cluster region of murine Mll and Af9 equivalent to that in human MA9 rearrangements, we show efficient de novo generation of MA9 fusion product at the DNA and RNA levels in the bulk population. The leukaemic features of MA9-induced disease were observed including increased clonogenicity, enrichment of c-Kit-positive leukaemic stem cells and increased MA9 target gene expression. This approach provided a rapid and reliable means of de novo generation of Mll-Af9 genetic rearrangements in murine haematopoietic stem and progenitor cells (HSPCs), using CRISPR/Cas9 technology to produce a cellular model of MA9 leukaemias which faithfully reproduces many features of the human disease in vitro. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Hematopoiesis)

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Review

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30 pages, 1474 KiB

Open AccessReview

Cellular and Molecular Mechanisms of Environmental Pollutants on Hematopoiesis

by Pablo Scharf, Milena Fronza Broering, Gustavo Henrique Oliveira da Rocha and Sandra Helena Poliselli Farsky

Int. J. Mol. Sci. 2020, 21(19), 6996; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21196996 - 23 Sep 2020

Cited by 23 | Viewed by 9624

Abstract

Hematopoiesis is a complex and intricate process that aims to replenish blood components in a constant fashion. It is orchestrated mostly by hematopoietic progenitor cells (hematopoietic stem cells (HSCs)) that are capable of self-renewal and differentiation. These cells can originate other cell subtypes that are responsible for maintaining vital functions, mediate innate and adaptive immune responses, provide tissues with oxygen, and control coagulation. Hematopoiesis in adults takes place in the bone marrow, which is endowed with an extensive vasculature conferring an intense flow of cells. A myriad of cell subtypes can be found in the bone marrow at different levels of activation, being also under constant action of an extensive amount of diverse chemical mediators and enzymatic systems. Bone marrow platelets, mature erythrocytes and leukocytes are delivered into the bloodstream readily available to meet body demands. Leukocytes circulate and reach different tissues, returning or not returning to the bloodstream. Senescent leukocytes, specially granulocytes, return to the bone marrow to be phagocytized by macrophages, restarting granulopoiesis. The constant high production and delivery of cells into the bloodstream, alongside the fact that blood cells can also circulate between tissues, makes the hematopoietic system a prime target for toxic agents to act upon, making the understanding of the bone marrow microenvironment vital for both toxicological sciences and risk assessment. Environmental and occupational pollutants, therapeutic molecules, drugs of abuse, and even nutritional status can directly affect progenitor cells at their differentiation and maturation stages, altering behavior and function of blood compounds and resulting in impaired immune responses, anemias, leukemias, and blood coagulation disturbances. This review aims to describe the most recently investigated molecular and cellular toxicity mechanisms of current major environmental pollutants on hematopoiesis in the bone marrow. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Hematopoiesis)

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13 pages, 555 KiB

Open AccessReview

Epitranscriptomics in Normal and Malignant Hematopoiesis

by Crescenzio Francesco Minervini, Elisa Parciante, Luciana Impera, Luisa Anelli, Antonella Zagaria, Giorgina Specchia, Pellegrino Musto and Francesco Albano

Int. J. Mol. Sci. 2020, 21(18), 6578; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186578 - 09 Sep 2020

Cited by 3 | Viewed by 3061

Abstract

Epitranscriptomics analyze the biochemical modifications borne by RNA and their downstream influence. From this point of view, epitranscriptomics represent a new layer for the control of genetic information and can affect a variety of molecular processes including the cell cycle and the differentiation. In physiological conditions, hematopoiesis is a tightly regulated process that produces differentiated blood cells starting from hematopoietic stem cells. Alteration of this process can occur at different levels in the pathway that leads from the genetic information to the phenotypic manifestation producing malignant hematopoiesis. This review focuses on the role of epitranscriptomic events that are known to be implicated in normal and malignant hematopoiesis, opening a new pathophysiological and therapeutic scenario. Moreover, an evolutionary vision of this mechanism will be provided. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Hematopoiesis)

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30 pages, 1131 KiB

Open AccessReview

Philadelphia Chromosome-Positive Leukemia in the Lymphoid Lineage—Similarities and Differences with the Myeloid Lineage and Specific Vulnerabilities

by Lukasz Komorowski, Klaudyna Fidyt, Elżbieta Patkowska and Malgorzata Firczuk

Int. J. Mol. Sci. 2020, 21(16), 5776; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165776 - 12 Aug 2020

Cited by 15 | Viewed by 7154

Abstract

Philadelphia chromosome (Ph) results from a translocation between the breakpoint cluster region (BCR) gene on chromosome 9 and ABL proto-oncogene 1 (ABL1) gene on chromosome 22. The fusion gene, BCR-ABL1, is a constitutively active tyrosine kinase which promotes development of leukemia. Depending on the breakpoint site within the BCR gene, different isoforms of BCR-ABL1 exist, with p210 and p190 being the most prevalent. P210 isoform is the hallmark of chronic myeloid leukemia (CML), while p190 isoform is expressed in majority of Ph-positive B cell acute lymphoblastic leukemia (Ph+ B-ALL) cases. The crucial component of treatment protocols of CML and Ph+ B-ALL patients are tyrosine kinase inhibitors (TKIs), drugs which target both BCR-ABL1 isoforms. While TKIs therapy is successful in great majority of CML patients, Ph+ B-ALL often relapses as a drug-resistant disease. Recently, the high-throughput genomic and proteomic analyses revealed significant differences between CML and Ph+ B-ALL. In this review we summarize recent discoveries related to differential signaling pathways mediated by different BCR-ABL1 isoforms, lineage-specific genetic lesions, and metabolic reprogramming. In particular, we emphasize the features distinguishing Ph+ B-ALL from CML and focus on potential therapeutic approaches exploiting those characteristics, which could improve the treatment of Ph+ B-ALL. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Hematopoiesis)

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15 pages, 1550 KiB

Open AccessReview

Lineage Decision-Making within Normal Haematopoietic and Leukemic Stem Cells

by Geoffrey Brown, Lucía Sánchez and Isidro Sánchez-García

Int. J. Mol. Sci. 2020, 21(6), 2247; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21062247 - 24 Mar 2020

Viewed by 3616

Abstract

To produce the wide range of blood and immune cell types, haematopoietic stem cells can “choose” directly from the entire spectrum of blood cell fate-options. Affiliation to a single cell lineage can occur at the level of the haematopoietic stem cell and these cells are therefore a mixture of some pluripotent cells and many cells with lineage signatures. Even so, haematopoietic stem cells and their progeny that have chosen a particular fate can still “change their mind” and adopt a different developmental pathway. Many of the leukaemias arise in haematopoietic stem cells with the bulk of the often partially differentiated leukaemia cells belonging to just one cell type. We argue that the reason for this is that an oncogenic insult to the genome “hard wires” leukaemia stem cells, either through development or at some stage, to one cell lineage. Unlike normal haematopoietic stem cells, oncogene-transformed leukaemia stem cells and their progeny are unable to adopt an alternative pathway. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Hematopoiesis)

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