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Cells
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Hematopoiesis and Stem Cells
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Hematopoiesis and Stem Cells

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Stem Cells".

Deadline for manuscript submissions: closed (31 January 2020) | Viewed by 39213

Special Issue Editors

Prof. Giovanni Morrone

E-Mail Website
Guest Editor
Laboratory of Molecular Haematopoiesis and Stem Cell Biology, Universita degli studi Magna Graecia di Catanzaro, Catanzaro, Italy
Interests: stem cell biology; hematopoiesis; myeloid leukemia; gene expression; gene transfer; signal transduction
Dr. Heather M. Bond

E-Mail Website
Guest Editor
Laboratory of Molecular Haematopoiesis and Stem Cell Biology, Universita degli studi Magna Graecia di Catanzaro, Catanzaro, Italy
Interests: stem cell biology; hematopoiesis; myeloid leukemia; gene expression; gene transfer; signal transduction

Special Issue Information

Dear Colleagues,

Since the pioneering studies of McCulloch and Till that marked the beginning of modern experimental hematology, over five decades of extensive research have yielded a tremendous wealth of information about the biology of the hematopoietic stem cell (HSC) compartment and the molecular mechanisms that govern its development and homeostasis, and have led to clinical applications of HSCs in the treatment of a variety of congenital and acquired disorders of the hematopoietic system. However, several aspects of HSC biology remain only partially understood, or controversial. This Special Issue of Cells aims to collect qualified contributions to shed additional light on our understanding of these cells. Therefore, we invite you to submit original research articles or reviews in all areas of HSC research, in particular focused on topics including, but not limited to:

  • HSC heterogeneity
  • Interactions between HSCs and the microenvironment in development, adult life and malignancies
  • Influence of metabolism on HSC fate choice
  • Epigenetic regulation of normal and malignant HSCs
  • Stem cells in hematopoietic malignancies: biologic features and targeting strategies

Prof. Giovanni Morrone
Dr. Heather M. Bond
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. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

  • hematopoietic ontogeny
  • microenvironment
  • HSC self-renewal
  • lineage specification
  • signalling mechanisms, transcription factors and epigenetic modifiers
  • non-coding RNAs
  • genetic and epigenetic aberrations
  • HSC transformation
  • leukemia stem cells

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Published Papers (6 papers)

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Research

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15 pages, 2872 KiB  
Article
Perturbation of Methionine/S-adenosylmethionine Metabolism as a Novel Vulnerability in MLL Rearranged Leukemia
by Aditya Barve, Alexis Vega, Parag P. Shah, Smita Ghare, Lavona Casson, Mark Wunderlich, Leah J. Siskind and Levi J. Beverly
Cells 2019, 8(11), 1322; https://doi.org/10.3390/cells8111322 - 25 Oct 2019
Cited by 23 | Viewed by 4800
Abstract
Leukemias bearing mixed lineage leukemia (MLL) rearrangement (MLL-R) resulting in expression of oncogenic MLL fusion proteins (MLL-FPs) represent an especially aggressive disease subtype with the worst overall prognoses and chemotherapeutic response. MLL-R leukemias are uniquely dependent on the epigenetic function of the H3K79 [...] Read more.
Leukemias bearing mixed lineage leukemia (MLL) rearrangement (MLL-R) resulting in expression of oncogenic MLL fusion proteins (MLL-FPs) represent an especially aggressive disease subtype with the worst overall prognoses and chemotherapeutic response. MLL-R leukemias are uniquely dependent on the epigenetic function of the H3K79 methyltransferase DOT1L, which is misdirected by MLL-FPs activating gene expression, driving transformation and leukemogenesis. Given the functional necessity of these leukemias to maintain adequate methylation potential allowing aberrant activating histone methylation to proceed, driving leukemic gene expression, we investigated perturbation of methionine (Met)/S-adenosylmethionine (SAM) metabolism as a novel therapeutic paradigm for MLL-R leukemia. Disruption of Met/SAM metabolism, by either methionine deprivation or pharmacologic inhibition of downstream metabolism, reduced overall cellular methylation potential, reduced relative cell numbers, and induced apoptosis selectively in established MLL-AF4 cell lines or MLL-AF6-expressing patient blasts but not in BCR-ABL-driven K562 cells. Global histone methylation dynamics were altered, with a profound loss of requisite H3K79 methylation, indicating inhibition of DOT1L function. Relative occupancy of the repressive H3K27me3 modification was increased at the DOT1L promoter in MLL-R cells, and DOT1L mRNA and protein expression was reduced. Finally, pharmacologic inhibition of Met/SAM metabolism significantly prolonged survival in an advanced, clinically relevant patient–derived MLL-R leukemia xenograft model, in combination with cytotoxic induction chemotherapy. Our findings provide support for further investigation into the development of highly specific allosteric inhibitors of enzymatic mediators of Met/SAM metabolism or dietary manipulation of methionine levels. Such inhibitors may lead to enhanced treatment outcomes for MLL-R leukemia, along with cytotoxic chemotherapy or DOT1L inhibitors. Full article
(This article belongs to the Special Issue Hematopoiesis and Stem Cells)
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17 pages, 3133 KiB  
Article
Synergy of NUP98-HOXA10 Fusion Gene and NrasG12D Mutation Preserves the Stemness of Hematopoietic Stem Cells on Culture Condition
by Yong Dong, Chengxiang Xia, Qitong Weng, Tongjie Wang, Fangxiao Hu, Kaitao Wang, Xiaofei Liu, Yang Geng, Lijuan Liu, Hongling Wu and Juan Du
Cells 2019, 8(9), 951; https://doi.org/10.3390/cells8090951 - 22 Aug 2019
Cited by 5 | Viewed by 4349
Abstract
Natural hematopoietic stem cells (HSC) are susceptible and tend to lose stemness, differentiate, or die on culture condition in vitro, which adds technical challenge for maintaining bona fide HSC-like cells, if ever generated, in protocol screening from pluripotent stem cells. It remains largely [...] Read more.
Natural hematopoietic stem cells (HSC) are susceptible and tend to lose stemness, differentiate, or die on culture condition in vitro, which adds technical challenge for maintaining bona fide HSC-like cells, if ever generated, in protocol screening from pluripotent stem cells. It remains largely unknown whether gene-editing of endogenous genes can genetically empower HSC to endure the culture stress and preserve stemness. In this study, we revealed that both NUP98-HOXA10HD fusion and endogenous Nras mutation modifications (NrasG12D) promoted the engraftment competitiveness of HSC. Furthermore, the synergy of these two genetic modifications endowed HSC with super competitiveness in vivo. Strikingly, single NAV-HSC successfully maintained its stemness and showed robust multi-lineage engraftments after undergoing the in vitro culture. Mechanistically, NUP98-HOXA10HD fusion and NrasG12D mutation distinctly altered multiple pathways involving the cell cycle, cell division, and DNA replication, and distinctly regulated stemness-related genes including Hoxa9, Prdm16, Hoxb4, Trim27, and Smarcc1 in the context of HSC. Thus, we develop a super-sensitive transgenic model reporting the existence of HSC at the single cell level on culture condition, which could be beneficial for protocol screening of bona fide HSC regeneration from pluripotent stem cells in vitro. Full article
(This article belongs to the Special Issue Hematopoiesis and Stem Cells)
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Review

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12 pages, 248 KiB  
Review
Matrix Mechanosensation in the Erythroid and Megakaryocytic Lineages
by Christina M. Ward and Katya Ravid
Cells 2020, 9(4), 894; https://doi.org/10.3390/cells9040894 - 6 Apr 2020
Cited by 8 | Viewed by 3803
Abstract
The biomechanical properties of the bone marrow microenvironment emerge from a combination of interactions between various extracellular matrix (ECM) structural proteins and soluble factors. Matrix stiffness directs stem cell fate, and both bone marrow stromal and hematopoietic cells respond to biophysical cues. Within [...] Read more.
The biomechanical properties of the bone marrow microenvironment emerge from a combination of interactions between various extracellular matrix (ECM) structural proteins and soluble factors. Matrix stiffness directs stem cell fate, and both bone marrow stromal and hematopoietic cells respond to biophysical cues. Within the bone marrow, the megakaryoblasts and erythroblasts are thought to originate from a common progenitor, giving rise to fully mature magakaryocytes (the platelet precursors) and erythrocytes. Erythroid and megakaryocytic progenitors sense and respond to the ECM through cell surface adhesion receptors such as integrins and mechanosensitive ion channels. While hematopoietic stem progenitor cells remain quiescent on stiffer ECM substrates, the maturation of the erythroid and megakaryocytic lineages occurs on softer ECM substrates. This review surveys the major matrix structural proteins that contribute to the overall biomechanical tone of the bone marrow, as well as key integrins and mechanosensitive ion channels identified as ECM sensors in context of megakaryocytosis or erythropoiesis. Full article
(This article belongs to the Special Issue Hematopoiesis and Stem Cells)
8 pages, 242 KiB  
Review
Nuclear-cytoplasmic Shuttling in Chronic Myeloid Leukemia: Implications in Leukemia Maintenance and Therapy
by Giovanna Carrà, Isabella Russo, Angelo Guerrasio and Alessandro Morotti
Cells 2019, 8(10), 1248; https://doi.org/10.3390/cells8101248 - 14 Oct 2019
Cited by 5 | Viewed by 2837
Abstract
Nuclear-cytoplasmic shuttling is a highly regulated and complex process, which involves both proteins and nucleic acids. Changes in cellular compartmentalization of various proteins, including oncogenes and tumor suppressors, affect cellular behavior, promoting or inhibiting proliferation, apoptosis and sensitivity to therapies. In this review, [...] Read more.
Nuclear-cytoplasmic shuttling is a highly regulated and complex process, which involves both proteins and nucleic acids. Changes in cellular compartmentalization of various proteins, including oncogenes and tumor suppressors, affect cellular behavior, promoting or inhibiting proliferation, apoptosis and sensitivity to therapies. In this review, we will recapitulate the role of various shuttling components in Chronic Myeloid Leukemia and we will provide insights on the potential role of shuttling proteins as therapeutic targets. Full article
(This article belongs to the Special Issue Hematopoiesis and Stem Cells)
10 pages, 1359 KiB  
Review
“Hierarchy” and “Holacracy”; A Paradigm of the Hematopoietic System
by Takafumi Yokota
Cells 2019, 8(10), 1138; https://doi.org/10.3390/cells8101138 - 24 Sep 2019
Cited by 11 | Viewed by 8930
Abstract
The mammalian hematopoietic system has long been viewed as a hierarchical paradigm in which a small number of hematopoietic stem cells (HSCs) are located at the apex. HSCs were traditionally thought to be homogeneous and quiescent in a homeostatic state. However, recent observations, [...] Read more.
The mammalian hematopoietic system has long been viewed as a hierarchical paradigm in which a small number of hematopoietic stem cells (HSCs) are located at the apex. HSCs were traditionally thought to be homogeneous and quiescent in a homeostatic state. However, recent observations, through extramedullary hematopoiesis and clonal assays, have cast doubt on the validity of the conventional interpretation. A key issue is understanding the characteristics of HSCs from different viewpoints, including dynamic physics and social network theory. The aim of this literature review is to propose a new paradigm of our hematopoietic system, in which individual HSCs are actively involved. Full article
(This article belongs to the Special Issue Hematopoiesis and Stem Cells)
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11 pages, 1120 KiB  
Review
Role of Lipid Rafts in Hematopoietic Stem Cells Homing, Mobilization, Hibernation, and Differentiation
by Munther Alomari, Dana Almohazey, Sarah Ameen Almofty, Firdos Alam Khan, Mohammad Al hamad and Deena Ababneh
Cells 2019, 8(6), 630; https://doi.org/10.3390/cells8060630 - 22 Jun 2019
Cited by 13 | Viewed by 12991
Abstract
Hematopoietic stem cells (HSCs) are multipotent, self-renewing cells that can differentiate into myeloid or lymphoid cells. The mobilization and differentiation processes are affected by the external environment, such as extracellular matrix and soluble molecules in the niche, where the lipid rafts (LRs) of [...] Read more.
Hematopoietic stem cells (HSCs) are multipotent, self-renewing cells that can differentiate into myeloid or lymphoid cells. The mobilization and differentiation processes are affected by the external environment, such as extracellular matrix and soluble molecules in the niche, where the lipid rafts (LRs) of the HSCs act as the receptors and control platforms for these effectors. LRs are membrane microdomains that are enriched in cholesterol, sphingolipid, and proteins. They are involved in diverse cellular processes including morphogenesis, cytokinesis, signaling, endocytic events, and response to the environment. They are also involved in different types of diseases, such as cancer, Alzheimer’s, and prion disease. LR clustering and disruption contribute directly to the differentiation, homing, hibernation, or mobilization of HSCs. Thus, characterization of LR integrity may provide a promising approach to controlling the fate of stem cells for clinical applications. In this review, we show the critical role of LR modification (clustering, disruption, protein incorporation, and signal responding) in deciding the fate of HSCs, under the effect of soluble cytokines such as stem cell factor (SCF), transforming growth factor- β (TGF-β), hematopoietic-specific phospholipase Cβ2 (PLC-β2), and granulocyte colony-stimulating factor (G-CSF). Full article
(This article belongs to the Special Issue Hematopoiesis and Stem Cells)
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