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Hematopoietic System under Physiological Conditions and Following Hematopoietic Reconstitution or Stress

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (15 November 2022) | Viewed by 24425

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Guest Editor
Laboratory of Stem and Progenitor Cell Biology, Engelhardt Institute of Molecular Biology RAS, Vavilov Str. 32, 119991 Moscow, Russia
Interests: clonal hematopoiesis, cardiovascular diseases and hematopoietic stem cells
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Special Issue Information

The seminal work of Till & McCulloch on CFU-Ss in 1961 proved the remarkable conjecture of Maximov some 50 years earlier on the existence of hematopoietic stem cells (HSCs) and laid foundations for their quantitative analysis. Ever since then, in this field, leading labs have dedicated significant effort to the progressive refinement of HSC features and physical isolation of more defined HSC and progenitor cell populations. This was mainly achieved with the use of monoclonal antibodies developed against various blood cell subsets, whereas transplantation into irradiated hosts has been accepted as a gold standard for quantitative functional characterization of purified cell fractions.

These efforts resulted in the appearance of a hierarchical, pyramidal model of blood cell differentiation, which presented a clear-cut scheme of stages that HCSs follow to produce huge amounts of differentiated blood cells to meet the physiological needs of an organism. The hierarchical model provided a very rational and logical explanation of how the hematopoietic system works. Alas, nature rarely follows human reasoning, and this model has not become an exception. The recent introduction of new sophisticated techniques such as single-cell transplantation, specific cell lineage/stage marking using transgenic mouse lines, cell barcoding, next-generation sequencing, single-cell transcriptome analysis, and related bioinformatics tools demonstrated that patterns of HSC differentiation are likely more complex than previously thought. Moreover, recent studies demonstrate that hematopoiesis established in irradiated animals using transplanted cell fractions, and the physiological steady-state hematopoiesis taking place in non-treated animals, not only formally differ from each other, but represent fairly different physiological systems, in which the same cell subsets may demonstrate contrasting behaviors. Given the currently accepted notion that the behavior of HSCs is determined to a large extent by the niches in which they reside, this difference may be partly explained by the irradiation damage sustained by the niche components and, possibly, peculiarities of homing to niches of various cell subsets in different physiological states. As suggested by some recent indirect data, it cannot be taken for granted that HSCs detached from their niches and subjected to significant stress during cell sorting do not substantially change their properties. If such a change occurs, this may warrant a significant revision of the results of previous experiments with transplanted sorted cells.

The true size of the “iceberg” of the complexity of the hematopoietic system is just becoming apparent and, obviously, many more studies using the most advanced techniques are needed to obtain accurate and consistent knowledge of how the hematopoietic system work. In this Special Issue, we invite researchers to submit original research articles on HSC/progenitor cells, hematopoietic microenvironment, and hematopoiesis under different conditions, or reviews on the last developments in these fields.

Dr. Alexander V. Belyavsky
Guest Editor

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Keywords

  • hematopoietic stem/progenitor cells
  • hematopoietic differentiation
  • hematopoietic niches
  • niche-HSC/progenitor cell interactions
  • steady-state hematopoiesis
  • reconstituted hematopoiesis
  • hematopoietic stress response
  • cell fate tracing

Published Papers (7 papers)

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Editorial

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5 pages, 209 KiB  
Editorial
Hematopoietic System under Physiological Conditions and Following Hematopoietic Reconstitution or Stress
by Maria Kalashnikova and Alexander Belyavsky
Int. J. Mol. Sci. 2023, 24(10), 8983; https://doi.org/10.3390/ijms24108983 - 19 May 2023
Cited by 2 | Viewed by 891
Abstract
The hematopoietic system performs the most vital functions in the human body, integrating the work of various organs while producing enormous numbers of mature cells daily [...] Full article

Research

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21 pages, 6510 KiB  
Article
Gamma-Tocotrienol Modulates Total-Body Irradiation-Induced Hematopoietic Injury in a Nonhuman Primate Model
by Tarun K. Garg, Sarita Garg, Isabelle R. Miousse, Stephen Y. Wise, Alana D. Carpenter, Oluseyi O. Fatanmi, Frits van Rhee, Vijay K. Singh and Martin Hauer-Jensen
Int. J. Mol. Sci. 2022, 23(24), 16170; https://doi.org/10.3390/ijms232416170 - 18 Dec 2022
Cited by 8 | Viewed by 1506
Abstract
Radiation exposure causes acute damage to hematopoietic and immune cells. To date, there are no radioprotectors available to mitigate hematopoietic injury after radiation exposure. Gamma-tocotrienol (GT3) has demonstrated promising radioprotective efficacy in the mouse and nonhuman primate (NHP) models. We determined GT3-mediated hematopoietic [...] Read more.
Radiation exposure causes acute damage to hematopoietic and immune cells. To date, there are no radioprotectors available to mitigate hematopoietic injury after radiation exposure. Gamma-tocotrienol (GT3) has demonstrated promising radioprotective efficacy in the mouse and nonhuman primate (NHP) models. We determined GT3-mediated hematopoietic recovery in total-body irradiated (TBI) NHPs. Sixteen rhesus macaques divided into two groups received either vehicle or GT3, 24 h prior to TBI. Four animals in each treatment group were exposed to either 4 or 5.8 Gy TBI. Flow cytometry was used to immunophenotype the bone marrow (BM) lymphoid cell populations, while clonogenic ability of hematopoietic stem cells (HSCs) was assessed by colony forming unit (CFU) assays on day 8 prior to irradiation and days 2, 7, 14, and 30 post-irradiation. Both radiation doses showed significant changes in the frequencies of B and T-cell subsets, including the self-renewable capacity of HSCs. Importantly, GT3 accelerated the recovery in CD34+ cells, increased HSC function as shown by improved recovery of CFU-granulocyte macrophages (CFU-GM) and burst-forming units erythroid (B-FUE), and aided the recovery of circulating neutrophils and platelets. These data elucidate the role of GT3 in hematopoietic recovery, which should be explored as a potential medical countermeasure to mitigate radiation-induced injury to the hematopoietic system. Full article
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18 pages, 2190 KiB  
Article
The Reconstitution Dynamics of Cultivated Hematopoietic Stem Cells and Progenitors Is Independent of Age
by Frauke Gotzhein, Tim Aranyossy, Lars Thielecke, Tanja Sonntag, Vanessa Thaden, Boris Fehse, Ingo Müller, Ingmar Glauche and Kerstin Cornils
Int. J. Mol. Sci. 2022, 23(6), 3160; https://doi.org/10.3390/ijms23063160 - 15 Mar 2022
Cited by 1 | Viewed by 2277
Abstract
Hematopoietic stem cell transplantation (HSCT) represents the only curative treatment option for numerous hematologic malignancies. While the influence of donor age and the composition of the graft have already been examined in clinical and preclinical studies, little information is available on the extent [...] Read more.
Hematopoietic stem cell transplantation (HSCT) represents the only curative treatment option for numerous hematologic malignancies. While the influence of donor age and the composition of the graft have already been examined in clinical and preclinical studies, little information is available on the extent to which different hematological subpopulations contribute to the dynamics of the reconstitution process and on whether and how these contributions are altered with age. In a murine model of HSCT, we therefore simultaneously tracked different cultivated and transduced hematopoietic stem and progenitor cell (HSPC) populations using a multicolor-coded barcode system (BC32). We studied a series of age-matched and age-mismatched transplantations and compared the influence of age on the reconstitution dynamics. We show that reconstitution from these cultured and assembled grafts was substantially driven by hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) independent of age. The reconstitution patterns were polyclonal and stable in all age groups independently of the variability between individual animals, with higher output rates from MPPs than from HSCs. Our experiments suggest that the dynamics of reconstitution and the contribution of cultured and individually transduced HSPC subpopulations are largely independent of age. Our findings support ongoing efforts to expand the application of HSCT in older individuals as a promising strategy to combat hematological diseases, including gene therapy applications. Full article
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Review

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28 pages, 1274 KiB  
Review
Hematopoietic Stem Cells and the Immune System in Development and Aging
by Daniil Shevyrev, Valeriy Tereshchenko, Tatiana N. Berezina and Stanislav Rybtsov
Int. J. Mol. Sci. 2023, 24(6), 5862; https://doi.org/10.3390/ijms24065862 - 20 Mar 2023
Cited by 9 | Viewed by 3332
Abstract
Hematopoietic stem cells (HSCs) support haematopoiesis throughout life and give rise to the whole variety of cells of the immune system. Developing in the early embryo, passing through the precursor stage, and maturing into the first HSCs, they undergo a fairly large number [...] Read more.
Hematopoietic stem cells (HSCs) support haematopoiesis throughout life and give rise to the whole variety of cells of the immune system. Developing in the early embryo, passing through the precursor stage, and maturing into the first HSCs, they undergo a fairly large number of divisions while maintaining a high regenerative potential due to high repair activity. This potential is greatly reduced in adult HSCs. They go into a state of dormancy and anaerobic metabolism to maintain their stemness throughout life. However, with age, changes occur in the pool of HSCs that negatively affect haematopoiesis and the effectiveness of immunity. Niche aging and accumulation of mutations with age reduces the ability of HSCs to self-renew and changes their differentiation potential. This is accompanied by a decrease in clonal diversity and a disturbance of lymphopoiesis (decrease in the formation of naive T- and B-cells) and the predominance of myeloid haematopoiesis. Aging also affects mature cells, regardless of HSC, therefore, phagocytic activity and the intensity of the oxidative burst decrease, and the efficiency of processing and presentation of antigens by myeloid cells is impaired. Aging cells of innate and adaptive immunity produce factors that form a chronic inflammatory background. All these processes have a serious negative impact on the protective properties of the immune system, increasing inflammation, the risk of developing autoimmune, oncological, and cardiovascular diseases with age. Understanding the mechanisms of reducing the regenerative potential in a comparative analysis of embryonic and aging HSCs, the features of inflammatory aging will allow us to get closer to deciphering the programs for the development, aging, regeneration and rejuvenation of HSCs and the immune system. Full article
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30 pages, 1201 KiB  
Review
Bone Marrow Niches of Hematopoietic Stem and Progenitor Cells
by Oleg Kandarakov, Alexander Belyavsky and Ekaterina Semenova
Int. J. Mol. Sci. 2022, 23(8), 4462; https://doi.org/10.3390/ijms23084462 - 18 Apr 2022
Cited by 19 | Viewed by 5943
Abstract
The mammalian hematopoietic system is remarkably efficient in meeting an organism’s vital needs, yet is highly sensitive and exquisitely regulated. Much of the organismal control over hematopoiesis comes from the regulation of hematopoietic stem cells (HSCs) by specific microenvironments called niches in bone [...] Read more.
The mammalian hematopoietic system is remarkably efficient in meeting an organism’s vital needs, yet is highly sensitive and exquisitely regulated. Much of the organismal control over hematopoiesis comes from the regulation of hematopoietic stem cells (HSCs) by specific microenvironments called niches in bone marrow (BM), where HSCs reside. The experimental studies of the last two decades using the most sophisticated and advanced techniques have provided important data on the identity of the niche cells controlling HSCs functions and some mechanisms underlying niche-HSC interactions. In this review we discuss various aspects of organization and functioning of the HSC cell niche in bone marrow. In particular, we review the anatomy of BM niches, various cell types composing the niche, niches for more differentiated cells, metabolism of HSCs in relation to the niche, niche aging, leukemic transformation of the niche, and the current state of HSC niche modeling in vitro. Full article
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21 pages, 838 KiB  
Review
Hematopoietic Progenitors and the Bone Marrow Niche Shape the Inflammatory Response and Contribute to Chronic Disease
by Yangsong Xu, Andrew J. Murphy and Andrew J. Fleetwood
Int. J. Mol. Sci. 2022, 23(4), 2234; https://doi.org/10.3390/ijms23042234 - 17 Feb 2022
Cited by 7 | Viewed by 3397
Abstract
It is now well understood that the bone marrow (BM) compartment can sense systemic inflammatory signals and adapt through increased proliferation and lineage skewing. These coordinated and dynamic alterations in responding hematopoietic stem and progenitor cells (HSPCs), as well as in cells of [...] Read more.
It is now well understood that the bone marrow (BM) compartment can sense systemic inflammatory signals and adapt through increased proliferation and lineage skewing. These coordinated and dynamic alterations in responding hematopoietic stem and progenitor cells (HSPCs), as well as in cells of the bone marrow niche, are increasingly viewed as key contributors to the inflammatory response. Growth factors, cytokines, metabolites, microbial products, and other signals can cause dysregulation across the entire hematopoietic hierarchy, leading to lineage-skewing and even long-term functional adaptations in bone marrow progenitor cells. These alterations may play a central role in the chronicity of disease as well as the links between many common chronic disorders. The possible existence of a form of “memory” in bone marrow progenitor cells is thought to contribute to innate immune responses via the generation of trained immunity (also called innate immune memory). These findings highlight how hematopoietic progenitors dynamically adapt to meet the demand for innate immune cells and how this adaptive response may be beneficial or detrimental depending on the context. In this review, we will discuss the role of bone marrow progenitor cells and their microenvironment in shaping the scope and scale of the immune response in health and disease. Full article
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27 pages, 1422 KiB  
Review
Hematopoiesis during Ontogenesis, Adult Life, and Aging
by Alexander Belyavsky, Nataliya Petinati and Nina Drize
Int. J. Mol. Sci. 2021, 22(17), 9231; https://doi.org/10.3390/ijms22179231 - 26 Aug 2021
Cited by 16 | Viewed by 6120
Abstract
In the bone marrow of vertebrates, two types of stem cells coexist—hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs). Hematopoiesis only occurs when these two stem cell types and their descendants interact. The descendants of HSCs supply the body with all the [...] Read more.
In the bone marrow of vertebrates, two types of stem cells coexist—hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs). Hematopoiesis only occurs when these two stem cell types and their descendants interact. The descendants of HSCs supply the body with all the mature blood cells, while MSCs give rise to stromal cells that form a niche for HSCs and regulate the process of hematopoiesis. The studies of hematopoiesis were initially based on morphological observations, later extended by the use of physiological methods, and were subsequently augmented by massive application of sophisticated molecular techniques. The combination of these methods produced a wealth of new data on the organization and functional features of hematopoiesis in the ontogenesis of mammals and humans. This review summarizes the current views on hematopoiesis in mice and humans, discusses the development of blood elements and hematopoiesis in the embryo, and describes how the hematopoietic system works in the adult organism and how it changes during aging. Full article
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