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Hematopoietic Stem Cells, Metabolic Regulations, and Aging
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Hematopoietic Stem Cells, Metabolic Regulations, and Aging

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

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 28698

Special Issue Editors

Prof. Dr. Anthony Dick Ho

E-Mail Website
Guest Editor
Department of Medicine Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany
Interests: blood stem cell transplantation; biology and cell divisions of stem cells – control mechanisms of self-renewal versus differentiation; aging and senescence of HSC
Prof. Dr. Toshio Suda

E-Mail Website
Guest Editor
Senior Principal Investigator, ProfessorCancer Science Institute (CSI)National University of Singapore (NUS)Director, Distinguished Professor, International Research Center for Medical Sciences (IRCM), Kumamoto University, Japan
Interests: Hematopoietic stem cells; Aging; Metabolism; Glucose metabolism; Cellular senescence; Epigenetic dysregulation; Genomics, transcriptomics, and proteomics; Mitochondrial aging; Fatty acid metabolism; Autophagy; Clonal proliferation by aging

Special Issue Information

Dear Colleagues, 

In the 1920s Otto Warburg discovered that cancer cells consumed enormous amount of glucose to fuel their accelerated metabolism. He believed that tumors could be treated by controlling aerobic versus anaerobic glycolysis. In the meantime, changes in metabolism have been shown to regulate cell signaling, gene expression, cellular fate and tissue function. Metabolic perturbations impair cellular differentiation, long-term fate, and play a major role in aging as well as in malignant transformation. The theme of this Special Issue focuses on metabolic regulation of self-renewal and differentiation, and on how disrupted metabolism can result in dysregulation, aging, cellular senescence, and malignant transformation. Topics will include – but need not be confined to – how metabolites impact developmental decisions in hematopoietic stem cells and their niche, how mitochondrial and lysosomal function affect stem cell aging, the epigenetic roles of metabolites, signaling roles of metabolites across stem cells and their niche, and the impact of metabolic interventions in aging and disease. Our aim is to foster collaborations across a range of disciplines and ultimately how interventions in metabolic pathways may modulate the aging process.

Prof. Dr. Anthony Dick Ho
Prof. Dr. Toshio Suda
Guest Editors

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Keywords

  • Hematopoietic stem cells
  • Aging
  • Metabolism
  • Glucose metabolism
  • Fatty acid metabolism
  • Cellular senescence
  • Epigenetic dysregulation
  • Genomics, transcriptomics, and proteomics
  • Mitochondrial aging
  • Autophagy

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Published Papers (6 papers)

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Research

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8 pages, 1592 KiB  
Communication
Epigenetic Clocks Are Not Accelerated in COVID-19 Patients
by Julia Franzen, Selina Nüchtern, Vithurithra Tharmapalan, Margherita Vieri, Miloš Nikolić, Yang Han, Paul Balfanz, Nikolaus Marx, Michael Dreher, Tim H. Brümmendorf, Edgar Dahl, Fabian Beier and Wolfgang Wagner
Int. J. Mol. Sci. 2021, 22(17), 9306; https://doi.org/10.3390/ijms22179306 - 27 Aug 2021
Cited by 22 | Viewed by 5203
Abstract
Age is a major risk factor for severe outcome of the 2019 coronavirus disease (COVID-19). In this study, we followed the hypothesis that particularly patients with accelerated epigenetic age are affected by severe outcomes of COVID-19. We investigated various DNA methylation datasets of [...] Read more.
Age is a major risk factor for severe outcome of the 2019 coronavirus disease (COVID-19). In this study, we followed the hypothesis that particularly patients with accelerated epigenetic age are affected by severe outcomes of COVID-19. We investigated various DNA methylation datasets of blood samples with epigenetic aging signatures and performed targeted bisulfite amplicon sequencing. Overall, epigenetic clocks closely correlated with the chronological age of patients, either with or without acute respiratory distress syndrome. Furthermore, lymphocytes did not reveal significantly accelerated telomere attrition. Thus, these biomarkers cannot reliably predict higher risk for severe COVID-19 infection in elderly patients. Full article
(This article belongs to the Special Issue Hematopoietic Stem Cells, Metabolic Regulations, and Aging)
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Review

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30 pages, 1225 KiB  
Review
Increasing Complexity of Molecular Landscapes in Human Hematopoietic Stem and Progenitor Cells during Development and Aging
by Suzanne M. Watt, Peng Hua and Irene Roberts
Int. J. Mol. Sci. 2022, 23(7), 3675; https://doi.org/10.3390/ijms23073675 - 27 Mar 2022
Cited by 5 | Viewed by 4403
Abstract
The past five decades have seen significant progress in our understanding of human hematopoiesis. This has in part been due to the unprecedented development of advanced technologies, which have allowed the identification and characterization of rare subsets of human hematopoietic stem and progenitor [...] Read more.
The past five decades have seen significant progress in our understanding of human hematopoiesis. This has in part been due to the unprecedented development of advanced technologies, which have allowed the identification and characterization of rare subsets of human hematopoietic stem and progenitor cells and their lineage trajectories from embryonic through to adult life. Additionally, surrogate in vitro and in vivo models, although not fully recapitulating human hematopoiesis, have spurred on these scientific advances. These approaches have heightened our knowledge of hematological disorders and diseases and have led to their improved diagnosis and therapies. Here, we review human hematopoiesis at each end of the age spectrum, during embryonic and fetal development and on aging, providing exemplars of recent progress in deciphering the increasingly complex cellular and molecular hematopoietic landscapes in health and disease. This review concludes by highlighting links between chronic inflammation and metabolic and epigenetic changes associated with aging and in the development of clonal hematopoiesis. Full article
(This article belongs to the Special Issue Hematopoietic Stem Cells, Metabolic Regulations, and Aging)
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16 pages, 1197 KiB  
Review
Glucose Metabolism and Aging of Hematopoietic Stem and Progenitor Cells
by Laura Poisa-Beiro, Jonathan J. M. Landry, Simon Raffel, Motomu Tanaka, Judith Zaugg, Anne-Claude Gavin and Anthony D. Ho
Int. J. Mol. Sci. 2022, 23(6), 3028; https://doi.org/10.3390/ijms23063028 - 11 Mar 2022
Cited by 7 | Viewed by 3265
Abstract
Comprehensive proteomics studies of human hematopoietic stem and progenitor cells (HSPC) have revealed that aging of the HSPC compartment is characterized by elevated glycolysis. This is in addition to deregulations found in murine transcriptomics studies, such as an increased differentiation bias towards the [...] Read more.
Comprehensive proteomics studies of human hematopoietic stem and progenitor cells (HSPC) have revealed that aging of the HSPC compartment is characterized by elevated glycolysis. This is in addition to deregulations found in murine transcriptomics studies, such as an increased differentiation bias towards the myeloid lineage, alterations in DNA repair, and a decrease in lymphoid development. The increase in glycolytic enzyme activity is caused by the expansion of a more glycolytic HSPC subset. We therefore developed a method to isolate HSPC into three distinct categories according to their glucose uptake (GU) levels, namely the GUhigh, GUinter and GUlow subsets. Single-cell transcriptomics studies showed that the GUhigh subset is highly enriched for HSPC with a differentiation bias towards myeloid lineages. Gene set enrichment analysis (GSEA) demonstrated that the gene sets for cell cycle arrest, senescence-associated secretory phenotype, and the anti-apoptosis and P53 pathways are significantly upregulated in the GUhigh population. With this series of studies, we have produced a comprehensive proteomics and single-cell transcriptomics atlas of molecular changes in human HSPC upon aging. Although many of the molecular deregulations are similar to those found in mice, there are significant differences. The most unique finding is the association of elevated central carbon metabolism with senescence. Due to the lack of specific markers, the isolation and collection of senescent cells have yet to be developed, especially for human HSPC. The GUhigh subset from the human HSPC compartment possesses all the transcriptome characteristics of senescence. This property may be exploited to accurately enrich, visualize, and trace senescence development in human bone marrow. Full article
(This article belongs to the Special Issue Hematopoietic Stem Cells, Metabolic Regulations, and Aging)
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21 pages, 3028 KiB  
Review
Aging and Clonal Behavior of Hematopoietic Stem Cells
by Masayuki Yamashita and Atsushi Iwama
Int. J. Mol. Sci. 2022, 23(4), 1948; https://doi.org/10.3390/ijms23041948 - 9 Feb 2022
Cited by 14 | Viewed by 5125
Abstract
Hematopoietic stem cells (HSCs) are the only cell population that possesses both a self-renewing capacity and multipotency, and can give rise to all lineages of blood cells throughout an organism’s life. However, the self-renewal capacity of HSCs is not infinite, and cumulative evidence [...] Read more.
Hematopoietic stem cells (HSCs) are the only cell population that possesses both a self-renewing capacity and multipotency, and can give rise to all lineages of blood cells throughout an organism’s life. However, the self-renewal capacity of HSCs is not infinite, and cumulative evidence suggests that HSCs alter their function and become less active during organismal aging, leading ultimately to the disruption of hematopoietic homeostasis, such as anemia, perturbed immunity and increased propensity to hematological malignancies. Thus, understanding how HSCs alter their function during aging is a matter of critical importance to prevent or overcome these age-related changes in the blood system. Recent advances in clonal analysis have revealed the functional heterogeneity of murine HSC pools that is established upon development and skewed toward the clonal expansion of functionally poised HSCs during aging. In humans, next-generation sequencing has revealed age-related clonal hematopoiesis that originates from HSC subsets with acquired somatic mutations, and has highlighted it as a significant risk factor for hematological malignancies and cardiovascular diseases. In this review, we summarize the current fate-mapping strategies that are used to track and visualize HSC clonal behavior during development or after stress. We then review the age-related changes in HSCs that can be inherited by daughter cells and act as a cellular memory to form functionally distinct clones. Altogether, we link aging of the hematopoietic system to HSC clonal evolution and discuss how HSC clones with myeloid skewing and low regenerative potential can be expanded during aging. Full article
(This article belongs to the Special Issue Hematopoietic Stem Cells, Metabolic Regulations, and Aging)
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16 pages, 3329 KiB  
Review
Inflammation Regulates Haematopoietic Stem Cells and Their Niche
by Nicole Pui-Yu Ho and Hitoshi Takizawa
Int. J. Mol. Sci. 2022, 23(3), 1125; https://doi.org/10.3390/ijms23031125 - 20 Jan 2022
Cited by 17 | Viewed by 4946
Abstract
Haematopoietic stem cells (HSCs) reside in the bone marrow and are supported by the specialised microenvironment, a niche to maintain HSC quiescence. To deal with haematopoietic equilibrium disrupted during inflammation, HSCs are activated from quiescence directly and indirectly to generate more mature immune [...] Read more.
Haematopoietic stem cells (HSCs) reside in the bone marrow and are supported by the specialised microenvironment, a niche to maintain HSC quiescence. To deal with haematopoietic equilibrium disrupted during inflammation, HSCs are activated from quiescence directly and indirectly to generate more mature immune cells, especially the myeloid lineage cells. In the process of proliferation and differentiation, HSCs gradually lose their self-renewal potential. The extensive inflammation might cause HSC exhaustion/senescence and malignant transformation. Here, we summarise the current understanding of how HSC functions are maintained, damaged, or exhausted during acute, prolonged, and pathological inflammatory conditions. We also highlight the inflammation-altered HSC niche and its impact on escalating the insults on HSCs. Full article
(This article belongs to the Special Issue Hematopoietic Stem Cells, Metabolic Regulations, and Aging)
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16 pages, 1407 KiB  
Review
Mitochondrial Contributions to Hematopoietic Stem Cell Aging
by Claudia Morganti and Keisuke Ito
Int. J. Mol. Sci. 2021, 22(20), 11117; https://doi.org/10.3390/ijms222011117 - 15 Oct 2021
Cited by 22 | Viewed by 4931
Abstract
Mitochondrial dysfunction and stem cell exhaustion are two hallmarks of aging. In the hematopoietic system, aging is linked to imbalanced immune response and reduced regenerative capacity in hematopoietic stem cells (HSCs), as well as an increased predisposition to a spectrum of diseases, including [...] Read more.
Mitochondrial dysfunction and stem cell exhaustion are two hallmarks of aging. In the hematopoietic system, aging is linked to imbalanced immune response and reduced regenerative capacity in hematopoietic stem cells (HSCs), as well as an increased predisposition to a spectrum of diseases, including myelodysplastic syndrome and acute myeloid leukemia. Myeloid-biased differentiation and loss of polarity are distinct features of aged HSCs, which generally exhibit enhanced mitochondrial oxidative phosphorylation and increased production of reactive oxygen species (ROS), suggesting a direct role for mitochondria in the degenerative process. Here, we provide an overview of current knowledge of the mitochondrial mechanisms that contribute to age-related phenotypes in HSCs. These include mitochondrial ROS production, alteration/activation of mitochondrial metabolism, the quality control pathway of mitochondria, and inflammation. Greater understanding of the key machineries of HSC aging will allow us to identify new therapeutic targets for preventing, delaying, or even reversing aspects of this process. Full article
(This article belongs to the Special Issue Hematopoietic Stem Cells, Metabolic Regulations, and Aging)
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