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Hematopoietic System under Physiological Conditions and Following Hematopoietic Reconstitution or Stress: 2nd Edition

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

Deadline for manuscript submissions: 20 June 2025 | Viewed by 5216

Special Issue Editor

Dr. Alexander V. Belyavsky

E-Mail Website
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
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our previous Special Issue entitled Hematopoietic System under Physiological Conditions and Following Hematopoietic Reconstitution or Stress.

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

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Published Papers (4 papers)

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Research

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22 pages, 4045 KiB  
Article
Differential Response and Recovery Dynamics of HSPC Populations Following Plasmodium chabaudi Infection
by Federica Bruno, Christiana Georgiou, Deirdre Cunningham, Lucy Bett, Marine A. Secchi, Samantha Atkinson, Sara González Antón, Flora Birch, Jean Langhorne and Cristina Lo Celso
Int. J. Mol. Sci. 2025, 26(6), 2816; https://doi.org/10.3390/ijms26062816 - 20 Mar 2025
Viewed by 398
Abstract
Severe infections such as malaria are on the rise worldwide, driven by both climate change and increasing drug resistance. It is therefore paramount that we better understand how the host responds to severe infection. Hematopoiesis is particularly of interest in this context because [...] Read more.
Severe infections such as malaria are on the rise worldwide, driven by both climate change and increasing drug resistance. It is therefore paramount that we better understand how the host responds to severe infection. Hematopoiesis is particularly of interest in this context because hematopoietic stem and progenitor cells (HSPCs) maintain the turnover of all blood cells, including all immune cells. Severe infections have been widely acknowledged to affect HSPCs; however, this disruption has been mainly studied during the acute phase, and the process and level of HSPC recovery remain understudied. Using a self-resolving model of natural rodent malaria, infection by Plasmodium chabaudi, here we systematically assess phenotypically defined HSPCs’ acute response and recovery upon pathogen clearance. We demonstrate that during the acute phase of infection the most quiescent and functional stem cells are depleted, multipotent progenitor compartments are drastically enlarged, and oligopotent progenitors virtually disappear, underpinned by dramatic, population-specific and sometimes unexpected changes in proliferation rates. HSPC populations return to homeostatic size and proliferation rate again through specific patterns of recovery. Overall, our data demonstrate that HSPC populations adopt different responses to cope with severe infection and suggest that the ability to adjust proliferative capacity becomes more restricted as differentiation progresses. Full article
(This article belongs to the Special Issue Hematopoietic System under Physiological Conditions and Following Hematopoietic Reconstitution or Stress: 2nd Edition)
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15 pages, 2276 KiB  
Article
Integrated Local and Systemic Communication Factors Regulate Nascent Hematopoietic Progenitor Escape During Developmental Hematopoiesis
by Carson Shalaby, James Garifallou and Christopher S. Thom
Int. J. Mol. Sci. 2025, 26(1), 301; https://doi.org/10.3390/ijms26010301 - 31 Dec 2024
Viewed by 806
Abstract
Mammalian blood cells originate from specialized ‘hemogenic’ endothelial (HE) cells in major arteries. During the endothelial-to-hematopoietic transition (EHT), nascent hematopoietic stem cells (HSCs) bud from the arterial endothelial wall and enter circulation, destined to colonize the fetal liver before ultimately migrating to the [...] Read more.
Mammalian blood cells originate from specialized ‘hemogenic’ endothelial (HE) cells in major arteries. During the endothelial-to-hematopoietic transition (EHT), nascent hematopoietic stem cells (HSCs) bud from the arterial endothelial wall and enter circulation, destined to colonize the fetal liver before ultimately migrating to the bone marrow. Mechanisms and processes that facilitate EHT and the release of nascent HSCs are incompletely understood, but may involve signaling from neighboring vascular endothelial cells, stromal support cells, circulating pre-formed hematopoietic cells, and/or systemic factors secreted by distal organs. We used single cell RNA sequencing analysis from human embryonic cells to identify relevant signaling pathways that support nascent HSC release. In addition to intercellular and secreted signaling modalities that have been previously functionally validated to support EHT and/or developmental hematopoiesis in model systems, we identify several novel modalities with plausible mechanisms to support EHT and HSC release. Our findings paint a portrait of the complex inter-regulated signals from the local niche, circulating hematopoietic/inflammatory cells, and distal fetal liver that support hematopoiesis. Full article
(This article belongs to the Special Issue Hematopoietic System under Physiological Conditions and Following Hematopoietic Reconstitution or Stress: 2nd Edition)
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13 pages, 2313 KiB  
Article
Lentivirus-Mediated BCL-XL Overexpression Inhibits Stem Cell Apoptosis during Ex Vivo Expansion and Provides Competitive Advantage Following Xenotransplantation
by Patricia M. A. Zehnle, Ying Wu, Naile Koleci, Sheila Bohler and Miriam Erlacher
Int. J. Mol. Sci. 2024, 25(7), 4105; https://doi.org/10.3390/ijms25074105 - 7 Apr 2024
Viewed by 1774
Abstract
Hematopoietic reconstitution after hematopoietic stem cell transplantation (HSCT) is influenced by the number of transplanted cells. However, under certain conditions donor cell counts are limited and impair clinical outcome. Hematopoietic stem and progenitor cell (HSPC) expansion prior to HSCT is a widely used [...] Read more.
Hematopoietic reconstitution after hematopoietic stem cell transplantation (HSCT) is influenced by the number of transplanted cells. However, under certain conditions donor cell counts are limited and impair clinical outcome. Hematopoietic stem and progenitor cell (HSPC) expansion prior to HSCT is a widely used method to achieve higher donor cell counts and minimize transplantation-related risks such as graft failure or delayed engraftment. Still, expansion in a non-physiological environment can trigger cell death mechanisms and hence counteract the desired effect. We have shown earlier that during HSCT a relevant amount of HSPCs were lost due to apoptosis and that cell death inhibition in donor HSPCs improved engraftment in xenotransplantation experiments. Here, we assessed the effect of combined ex vivo expansion and cell death inhibition on HSPC yield and their reconstitution potential in vivo. During expansion with cytokines and the small molecule inhibitor StemRegenin 1, concomitant lentiviral overexpression of antiapoptotic BCL-XL resulted in an increased yield of transduced HSPCs. Importantly, BCL-XL overexpression enhanced the reconstitution potential of HSPCs in xenotransplantation experiments in vivo. In contrast, treatment with caspase and necroptosis inhibitors had no favorable effects on HSPC yields nor on cell viability. We postulate that overexpression of antiapoptotic BCL-XL, both during ex vivo expansion and transplantation, is a promising approach to improve the outcome of HSCT in situations with limited donor cell numbers. However, such apoptosis inhibition needs to be transient to avoid long-term sequelae like leukemia. Full article
(This article belongs to the Special Issue Hematopoietic System under Physiological Conditions and Following Hematopoietic Reconstitution or Stress: 2nd Edition)
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Review

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54 pages, 3352 KiB  
Review
Deciphering the Complexities of Adult Human Steady State and Stress-Induced Hematopoiesis: Progress and Challenges
by Suzanne M. Watt and Maria G. Roubelakis
Int. J. Mol. Sci. 2025, 26(2), 671; https://doi.org/10.3390/ijms26020671 - 14 Jan 2025
Viewed by 1361
Abstract
Human hematopoietic stem cells (HSCs) have traditionally been viewed as self-renewing, multipotent cells with enormous potential in sustaining essential steady state blood and immune cell production throughout life. Indeed, around 86% (1011–1012) of new cells generated daily in a [...] Read more.
Human hematopoietic stem cells (HSCs) have traditionally been viewed as self-renewing, multipotent cells with enormous potential in sustaining essential steady state blood and immune cell production throughout life. Indeed, around 86% (1011–1012) of new cells generated daily in a healthy young human adult are of hematopoietic origin. Therapeutically, human HSCs have contributed to over 1.5 million hematopoietic cell transplants (HCTs) globally, making this the most successful regenerative therapy to date. We will commence this review by briefly highlighting selected key achievements (from 1868 to the end of the 20th century) that have contributed to this accomplishment. Much of our knowledge of hematopoiesis is based on small animal models that, despite their enormous importance, do not always recapitulate human hematopoiesis. Given this, we will critically review the progress and challenges faced in identifying adult human HSCs and tracing their lineage differentiation trajectories, referring to murine studies as needed. Moving forward and given that human hematopoiesis is dynamic and can readily adjust to a variety of stressors, we will then discuss recent research advances contributing to understanding (i) which HSPCs maintain daily steady state human hematopoiesis, (ii) where these are located, and (iii) which mechanisms come into play when homeostatic hematopoiesis switches to stress-induced or emergency hematopoiesis. Full article
(This article belongs to the Special Issue Hematopoietic System under Physiological Conditions and Following Hematopoietic Reconstitution or Stress: 2nd Edition)
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