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1
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Bhartiya D, Sharma N, Tripathi A, Tripathi A. Do PGCCs in Solid Tumors Appear Due to Treatment-related Stress or Clonal Expansion of CSCs that Survive Oncotherapy? Stem Cell Rev Rep 2025:10.1007/s12015-025-10891-y. [PMID: 40338514 DOI: 10.1007/s12015-025-10891-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/24/2025] [Indexed: 05/09/2025]
Abstract
Dedifferentiation of epithelial cells during epithelial-mesenchymal transition (EMT) results in circulating tumor cells (CTCs) that are mobilized singly or in clusters in association with blood cells and results in metastasis. However, lineage tracing studies have failed to delineate any role of EMT during metastasis. Research is also focused on polyploid giant cancer cells (PGCCs) in solid tumors which appear in response to oncotherapy-related stress for their role in metastasis. But how to explain PGCCs role in metastatic tumors in treatment-naïve patients? Studies done using mouse models and clinical samples suggest that cancer initiates due to dysfunctions of tissue-resident, pluripotent very small embryonic-like stem cells (VSELs). VSELs are the most primitive and pluripotent stem cells that exist at top of cellular hierarchy in multiple tissues. They are normally quiescent and undergo asymmetrical cell divisions to give rise to two cells of different sizes and fates including smaller cells to self-renew and bigger tissue-specific progenitors. Progenitors undergo symmetrical cell divisions and clonal expansion (rapid proliferation, endoduplication with incomplete cytokinesis) to form giant cells that further breakdown and differentiate into tissue-specific cell types. Oncotherapy destroys actively dividing cells, but CSCs survive. We hypothesize that excessive self-renewal and clonal expansion of cancer stem cells (CSCs, dysfunctional VSELs) result in multinucleated giant cells (PGCCs) that accumulate as further differentiation into tissue-specific cell types is blocked in cancerous conditions. PGCCS are being reported by multiple groups whereas CSCs remain elusive due to small size and low abundance and actually contribute to both cancer initiation and metastasis.
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Affiliation(s)
- Deepa Bhartiya
- Epigeneres Biotech Pvt Ltd, Todi Mill Compound, Senapati Bapat Marg, Lower Parel, Mumbai, 400013, India.
| | - Nripen Sharma
- Epigeneres Biotech Pvt Ltd, Todi Mill Compound, Senapati Bapat Marg, Lower Parel, Mumbai, 400013, India
| | - Anish Tripathi
- Epigeneres Biotech Pvt Ltd, Todi Mill Compound, Senapati Bapat Marg, Lower Parel, Mumbai, 400013, India
| | - Ashish Tripathi
- Epigeneres Biotech Pvt Ltd, Todi Mill Compound, Senapati Bapat Marg, Lower Parel, Mumbai, 400013, India
- TZAR Labs, 23Ikigai Pte Ltd., 30 Cecil Street, #21-08 Prudential Tower, Singapore, 049712, Singapore
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2
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Arjmand B, Mehran P, Badamchizadeh S, Alavi-Moghadam S, Arjmand R, Rezaei-Tavirani M, Aghayan HR, Larijani B, Vaezi M, Janbabaei G, Hajifathali A. The Role of Aging and Senescence in Bone Marrow Transplantation Outcome. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025. [PMID: 40259169 DOI: 10.1007/5584_2025_861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/23/2025]
Abstract
Bone marrow transplantation is considered a cornerstone in the treatment of hematologic malignancies and blood disorders. While it may offer the possibility of a cure through the use of high-dose chemotherapy and radiation, outcomes are significantly impacted by biological and medical factors. Herein, aging is associated with reduced hematopoiesis, immune function, and overall regenerative capacity of tissues. Growth arrest, a crucial property of cellular senescence, inhibits bone marrow function, lowers immune surveillance in aged adults, and reduces the efficiency of bone marrow transplantation. The clinical course for older recipients is further complicated by the presence of prolonged immunosuppression, slower recovery, and higher complication rates, including life-threatening graft-versus-host disease. Accordingly, there is increasing interest in explaining how aging, cellular senescence, and transplant outcomes are interrelated. The current chapter outlines the mechanisms whereby aging and senescence contribute to the immunological dysregulation and poor bone marrow transplantation outcomes observed in elderly cancer patients. The authors' goal is to suggest therapeutic approaches that will enhance the quality of life and survival rates of elderly bone marrow transplant recipients.
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Affiliation(s)
- Babak Arjmand
- Hematology-Oncology and Stem Cell Transplantation Research Center, Research Institute for Oncology, Hematology, and Cell Therapy, Tehran University of Medical Sciences, Tehran, Iran.
| | - Pouya Mehran
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Sepideh Alavi-Moghadam
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Rasta Arjmand
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Hamid Reza Aghayan
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohamad Vaezi
- Hematology-Oncology and Stem Cell Transplantation Research Center, Research Institute for Oncology, Hematology, and Cell Therapy, Tehran University of Medical Sciences, Tehran, Iran
| | - Ghasem Janbabaei
- Hematologic Malignancies Research Center, Research Institute for Oncology, Hematology, and Cell Therapy, Tehran University of Medical Sciences, Tehran, Iran
| | - Abbas Hajifathali
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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3
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Gao D, Yi WW, Liu B, Zhang CE, Yang CC, Zeng L, Li L, Luo G, Zhang L, Ju ZY, Wang JB. Tetrahydroxy stilbene glucoside rejuvenates aging hematopoietic stem cells with predilection for lymphoid differentiation via AMPK and Tet2. J Adv Res 2025; 70:515-529. [PMID: 38704089 PMCID: PMC11976424 DOI: 10.1016/j.jare.2024.04.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 03/26/2024] [Accepted: 04/26/2024] [Indexed: 05/06/2024] Open
Abstract
INTRODUCTION Aging of hematopoietic stem cells (HSCs) has emerged as an important challenge to human health. Recent advances have raised the prospect of rejuvenating aging HSCs via specific medical interventions, including pharmacological treatments. Nonetheless, efforts to develop such drugs are still in infancy until now. OBJECTIVES We aimed to screen the prospective agents that can rejuvenate aging HSCs and explore the potential mechanisms. METHODS We screened a set of natural anti-aging compounds through oral administration to sub-lethally irradiated mice, and identified 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) as a potent rejuvenating agent for aging HSCs. Then naturally aged mice were used for the follow-up assessment to determine the HSC rejuvenating potential of TSG. Finally, based on the transcriptome and DNA methylation analysis, we validated the role of the AMP-activated protein kinase (AMPK)-ten-eleven-translocation 2 (Tet2) axis (the AMPK-Tet2 axis) as the underlying mechanisms of TSG for ameliorating HSCs aging. RESULTS TSG treatment not only significantly increased the absolute number of common lymphoid progenitors (CLPs) along with B lymphocytes, but also boosted the HSCs/CLPs repopulation potential of aging mice. Further elaborated mechanism research demonstrated that TSG supplementation restored the stemness of aging HSCs, as well as promoted an epigenetic reprograming that was associated with an improved regenerative capacity and an increased rate of lymphopoiesis. Such effects were diminished when the mice were co-treated with an AMPK inhibitor, or when it was performed in Tet2 knockout mice as well as senescent cells assay. CONCLUSION TSG is effective in rejuvenating aging HSCs by modulating the AMPK- Tet2 axis and thus represents a potential candidate for developing effective HSC rejuvenating therapies.
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Affiliation(s)
- Dan Gao
- Department of Pharmacy, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing Engineering Research Center for Nervous System Drugs, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing 100053, China; Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, Guizhou Medical University, Guiyang 550004, China
| | - Wei-Wei Yi
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, Guangdong 510632, China
| | - Bo Liu
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, Guangdong 510632, China
| | - Cong-En Zhang
- Department of Pharmacy, Beijing Friendship Hospital of Capital Medical University, Beijing 100050, China
| | - Cui-Cui Yang
- Department of Pharmacy, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing Engineering Research Center for Nervous System Drugs, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing 100053, China
| | - Li Zeng
- Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, China
| | - Lin Li
- Department of Pharmacy, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing Engineering Research Center for Nervous System Drugs, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing 100053, China
| | - Guangbin Luo
- Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106-1712, USA; Centre for Translational Medicine, Shenzhen Bao'an Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen 518101, China.
| | - Lan Zhang
- Department of Pharmacy, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing Engineering Research Center for Nervous System Drugs, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing 100053, China.
| | - Zhen-Yu Ju
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, Guangdong 510632, China.
| | - Jia-Bo Wang
- School of Chinese Medicine, Capital Medical University, Beijing 100069, China.
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Yoon J, Sun S, Moon S, Yang H. Repeated Gonadotropin Administration Suppresses T Cell Development in the Mouse Thymus. Dev Reprod 2025; 29:1-11. [PMID: 40256124 PMCID: PMC12004010 DOI: 10.12717/dr.2025.29.1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 01/14/2025] [Accepted: 02/23/2025] [Indexed: 04/22/2025]
Abstract
Gonadotropins, such as follicle-stimulating hormone (FSH) and human chorionic gonadotropin (hCG), are widely used to induce ovarian hyperovulation during in vitro fertilization and embryo transfer (IVF-ET) for the treatment of infertility. However, the effects of repeated administration of these gonadotropins on immune function, particularly on T cell development in the thymus, remain poorly understood. This study investigated the effects of repeated administration of pregnant mare serum gonadotropin (PMSG) and hCG on thymic T cell development in mice. Histological analysis revealed structural changes in the thymus, including a blurred boundary between the medulla and cortex and reduced vascularization after repeated administration of PMSG and hCG. Quantitative real-time PCR showed increased expression of adipogenesis-related genes [phosphoenolpyruvate carboxykinase (PEPCK), adipocyte fatty acid-binding protein 2 (aP2), peroxisome proliferator-activated receptor gamma (PPARγ)] but no significant changes in thymic epithelial cell-related genes [autoimmune regulator (AIRE), epithelial V-like antigen (EVA), interleukin 7 (IL-7)]. Flow cytometry revealed a decrease in CD4+CD8+ T cells and an increase in CD4-CD8-T cells with altered CD25/CD44 subsets. In addition, CD4+ and CD8+ T cells in the spleen were significantly reduced. These findings suggest that repeated gonadotropin exposure may disrupt thymic T cell development and peripheral T cell populations, potentially impairing immune function. Further research is needed to elucidate the underlying mechanisms and broader immunologic consequences of gonadotropin use in infertility treatment.
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Affiliation(s)
- Jin Yoon
- Department of Biohealth Convergence, College of Science and Convergence Technology, Seoul Women’s University, Seoul 01797, Korea
| | - Sojung Sun
- Department of Biohealth Convergence, College of Science and Convergence Technology, Seoul Women’s University, Seoul 01797, Korea
| | - Soeun Moon
- Department of Biohealth Convergence, College of Science and Convergence Technology, Seoul Women’s University, Seoul 01797, Korea
| | - Hyunwon Yang
- Department of Biohealth Convergence, College of Science and Convergence Technology, Seoul Women’s University, Seoul 01797, Korea
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5
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Jahan-Mahin M, Askari R, Haghighi AH, Khaiyat O. The effect of three types of water-based training protocols on thymus atrophy and specific indicators of cellular immune senescence in aged male rats. Biogerontology 2025; 26:44. [PMID: 39832052 PMCID: PMC11747080 DOI: 10.1007/s10522-025-10183-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 01/02/2025] [Indexed: 01/22/2025]
Abstract
The collective detrimental impact of aged naive lymphocytes and thymus atrophy on the aging of the immune system can be mitigated by exercise. Hence, this research aims to explore the effects of three methods of water-based exercises on immune system aging and thymus atrophy in elderly rats. Thirty-two 24-month-old rats, with an average weight of 320 ± 5 g, were randomly allocated into four groups of endurance training (n = 8), resistance training (n = 8), combined training (n = 8), and control (n = 8).The training protocols (10 weeks) were conducted four times a week in a container measuring 50 × 50x100 cm filled with water at 30 ± 1 °C. The evaluation of naïve and memory T lymphocytes was conducted for the intervention groups based on the expression or lack of expression of the CD28 and CD57 markers in the subsets of CD4 + and CD8 + T cells. Naïve T cells were represented by CD28 + CD57- T lymphocytes, memory T cells were represented by CD28- CD57- T lymphocytes, aged naïve T cells were indicated by CD28 + CD57 + lymphocytes, and aged memory T cells were represented by CD28- CD57 + lymphocytes. The findings of the study showed that all three exercise protocols resulted in a significant decrease in levels of memory CD8, aged CD8, naive and naive CD4 and CD8, and aged memory, as well as an increase in levels of CD4, CD8, CD4 + , and naive CD8 when compared to the control group. It was observed that thymus atrophy, memory CD4, and aged CD4 had a significant decrease only in the combined exercise group compared to the control group, with no significant differences observed in these indicators for the resistance and endurance groups. Furthermore, the ratio of CD4 to CD8 remained unchanged across all groups. The findings of this study suggest greater efficacy of combined training in enhancing specific health indicators of cell immunity among elderly populations. Moreover, engaging in water exercises of all three types of combined, resistance, and endurance training are deemed safe activities for older individuals to bolster their immune system and mitigate the aging process of T cells.
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Affiliation(s)
- Mohammad Jahan-Mahin
- Department of Exercise Physiology, Faculty of Sport Science, Hakim Sabzevari University, Sabzevar, Iran
| | - Roya Askari
- Department of Exercise Physiology, Faculty of Sport Science, Hakim Sabzevari University, Sabzevar, Iran
| | - Amir Hossein Haghighi
- Department of Exercise Physiology, Faculty of Sport Science, Hakim Sabzevari University, Sabzevar, Iran
| | - Omid Khaiyat
- School of Health and Sport Sciences, Liverpool Hope University, Liverpool, UK.
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6
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Yang Y, Fan L, Li M, Wang Z. Immune senescence: A key player in cancer biology. Semin Cancer Biol 2025; 108:71-82. [PMID: 39675646 DOI: 10.1016/j.semcancer.2024.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 11/30/2024] [Accepted: 12/10/2024] [Indexed: 12/17/2024]
Abstract
With the rapid development of immunological techniques in recent years, our understanding of immune senescence has gradually deepened, but the role of immune senescence in cancer biology remains incompletely elucidated. Understanding these mechanisms and interactions is crucial for the development of tumor biology. This review examines five key areas: the classification and main features of immune senescence, factors influencing immune cell senescence in cancer, the reciprocal causal cycle between immune senescence and malignancy, and the potential of immune senescence as a target for cancer immunotherapy.
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Affiliation(s)
- Yanru Yang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Pathology, School of Basic Medicine and Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Linni Fan
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Pathology, School of Basic Medicine and Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Mingyang Li
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Pathology, School of Basic Medicine and Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Zhe Wang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Pathology, School of Basic Medicine and Xijing Hospital, Fourth Military Medical University, Xi'an, China.
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7
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Koh BI, Mohanakrishnan V, Jeong HW, Park H, Kruse K, Choi YJ, Nieminen-Kelhä M, Kumar R, Pereira RS, Adams S, Lee HJ, Bixel MG, Vajkoczy P, Krause DS, Adams RH. Adult skull bone marrow is an expanding and resilient haematopoietic reservoir. Nature 2024; 636:172-181. [PMID: 39537918 PMCID: PMC11618084 DOI: 10.1038/s41586-024-08163-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 10/07/2024] [Indexed: 11/16/2024]
Abstract
The bone marrow microenvironment is a critical regulator of haematopoietic stem cell self-renewal and fate1. Although it is appreciated that ageing, chronic inflammation and other insults compromise bone marrow function and thereby negatively affect haematopoiesis2, it is not known whether different bone compartments exhibit distinct microenvironmental properties and functional resilience. Here we use imaging, pharmacological approaches and mouse genetics to uncover specialized properties of bone marrow in adult and ageing skull. Specifically, we show that the skull bone marrow undergoes lifelong expansion involving vascular growth, which results in an increasing contribution to total haematopoietic output. Furthermore, skull is largely protected against major hallmarks of ageing, including upregulation of pro-inflammatory cytokines, adipogenesis and loss of vascular integrity. Conspicuous rapid and dynamic changes to the skull vasculature and bone marrow are induced by physiological alterations, namely pregnancy, but also pathological challenges, such as stroke and experimental chronic myeloid leukaemia. These responses are highly distinct from femur, the most extensively studied bone marrow compartment. We propose that skull harbours a protected and dynamically expanding bone marrow microenvironment, which is relevant for experimental studies and, potentially, for clinical treatments in humans.
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Affiliation(s)
- Bong Ihn Koh
- Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster, Germany.
| | - Vishal Mohanakrishnan
- Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster, Germany
| | - Hyun-Woo Jeong
- Sequencing Core Facility, Max Planck Institute for Molecular Biomedicine, Münster, Germany
| | - Hongryeol Park
- Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster, Germany
| | - Kai Kruse
- Bioinformatics Service Unit, Max Planck Institute for Molecular Biomedicine, Münster, Germany
| | - Young Jun Choi
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Melina Nieminen-Kelhä
- Department of Neurosurgery, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Rahul Kumar
- Institute of Transfusion Medicine, Transfusion Center, University Medicine Mainz, Mainz, Germany
| | - Raquel S Pereira
- Georg-Speyer-Haus Institute for Tumor Biology and Experimental Medicine and Goethe University Frankfurt, Frankfurt, Germany
| | - Susanne Adams
- Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster, Germany
| | - Hyuek Jong Lee
- Center for Vascular Research, Institute for Basic Science, Daejeon, Republic of Korea
| | - M Gabriele Bixel
- Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster, Germany
| | - Peter Vajkoczy
- Department of Neurosurgery, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Daniela S Krause
- Institute of Transfusion Medicine, Transfusion Center, University Medicine Mainz, Mainz, Germany
| | - Ralf H Adams
- Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster, Germany.
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8
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Katsantoni E. Molecular and cellular pathways of aging in hematopoiesis. FEBS Lett 2024; 598:2751-2754. [PMID: 39582202 DOI: 10.1002/1873-3468.15049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 10/18/2024] [Indexed: 11/26/2024]
Affiliation(s)
- Eleni Katsantoni
- Biomedical Research Foundation, Academy of Athens, Basic Research Center, Athens, Greece
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9
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Matteini F, Montserrat‐Vazquez S, Florian MC. Rejuvenating aged stem cells: therapeutic strategies to extend health and lifespan. FEBS Lett 2024; 598:2776-2787. [PMID: 38604982 PMCID: PMC11586596 DOI: 10.1002/1873-3468.14865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 02/03/2024] [Accepted: 03/07/2024] [Indexed: 04/13/2024]
Abstract
Aging is associated with a global decline in stem cell function. To date, several strategies have been proposed to rejuvenate aged stem cells: most of these result in functional improvement of the tissue where the stem cells reside, but the impact on the lifespan of the whole organism has been less clearly established. Here, we review some of the most recent work dealing with interventions that improve the regenerative capacity of aged somatic stem cells in mammals and that might have important translational possibilities. Overall, we underscore that somatic stem cell rejuvenation represents a strategy to improve tissue homeostasis upon aging and present some recent approaches with the potential to affect health span and lifespan of the whole organism.
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Affiliation(s)
- Francesca Matteini
- Stem Cell Aging Group, Regenerative Medicine ProgramThe Bellvitge Institute for Biomedical Research (IDIBELL)BarcelonaSpain
- Program for Advancing the Clinical Translation of Regenerative Medicine of Catalonia (P‐CMR[C])BarcelonaSpain
| | - Sara Montserrat‐Vazquez
- Stem Cell Aging Group, Regenerative Medicine ProgramThe Bellvitge Institute for Biomedical Research (IDIBELL)BarcelonaSpain
- Program for Advancing the Clinical Translation of Regenerative Medicine of Catalonia (P‐CMR[C])BarcelonaSpain
| | - M. Carolina Florian
- Stem Cell Aging Group, Regenerative Medicine ProgramThe Bellvitge Institute for Biomedical Research (IDIBELL)BarcelonaSpain
- Program for Advancing the Clinical Translation of Regenerative Medicine of Catalonia (P‐CMR[C])BarcelonaSpain
- Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER‐BBN)MadridSpain
- The Catalan Institution for Research and Advanced Studies (ICREA)BarcelonaSpain
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10
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Ye L, Tian C, Li Y, Pan H, Hu J, Shu L, Pan X. Hematopoietic aging: Cellular, molecular, and related mechanisms. Chin Med J (Engl) 2024; 137:1303-1312. [PMID: 37898877 PMCID: PMC11191024 DOI: 10.1097/cm9.0000000000002871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Indexed: 10/30/2023] Open
Abstract
ABSTRACT Aging is accompanied by significant inhibition of hematopoietic and immune system function and disruption of bone marrow structure. Aging-related alterations in the inflammatory response, immunity, and stem cell niches are at the root of hematopoietic aging. Understanding the molecular mechanisms underlying hematopoietic and bone marrow aging can aid the clinical treatment of aging-related diseases. In particular, it is unknown how the niche reprograms hematopoietic stem cells (HSCs) in an age-dependent manner to maintain normal hematopoiesis in elderly individuals. Recently, specific inhibitors and blood exchange methods have been shown to reshape the hematopoietic niche and reverse hematopoietic aging. Here, we present the latest scientific discoveries related to hematopoietic aging and hematopoietic system rejuvenation, discuss the relationships between hematopoietic niche aging and HSC aging, and describe related studies on stem cell-mediated regulation of hematopoietic aging, aiming to provide new ideas for further study.
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Affiliation(s)
- Li Ye
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Cell Therapy Technology Transfer Medical Key Laboratory of Yunnan Province, Kunming Key Laboratory of Stem Cell and Regenerative Medicine, Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, Yunnan 650032, China
- Department of Immunology of School of Basic Medicine of Guizhou Medical University, National and Local Joint Engineering Laboratory of Cell Engineering Biomedical Technology, Key Laboratory of Regenerative Medicine of Guizhou Province, State Key Laboratory of Efficacy and Utilization of Medicinal Plants Co-constructed by Province and Ministry, Key Laboratory of Translational Research of Adult Stem Cell of Chinese Academy of Medical Sciences, Guiyang, Guizhou 550025, China
| | - Chuan Tian
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Cell Therapy Technology Transfer Medical Key Laboratory of Yunnan Province, Kunming Key Laboratory of Stem Cell and Regenerative Medicine, Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, Yunnan 650032, China
| | - Ye Li
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Cell Therapy Technology Transfer Medical Key Laboratory of Yunnan Province, Kunming Key Laboratory of Stem Cell and Regenerative Medicine, Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, Yunnan 650032, China
- Department of Immunology of School of Basic Medicine of Guizhou Medical University, National and Local Joint Engineering Laboratory of Cell Engineering Biomedical Technology, Key Laboratory of Regenerative Medicine of Guizhou Province, State Key Laboratory of Efficacy and Utilization of Medicinal Plants Co-constructed by Province and Ministry, Key Laboratory of Translational Research of Adult Stem Cell of Chinese Academy of Medical Sciences, Guiyang, Guizhou 550025, China
| | - Hang Pan
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Cell Therapy Technology Transfer Medical Key Laboratory of Yunnan Province, Kunming Key Laboratory of Stem Cell and Regenerative Medicine, Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, Yunnan 650032, China
- Department of Immunology of School of Basic Medicine of Guizhou Medical University, National and Local Joint Engineering Laboratory of Cell Engineering Biomedical Technology, Key Laboratory of Regenerative Medicine of Guizhou Province, State Key Laboratory of Efficacy and Utilization of Medicinal Plants Co-constructed by Province and Ministry, Key Laboratory of Translational Research of Adult Stem Cell of Chinese Academy of Medical Sciences, Guiyang, Guizhou 550025, China
| | - Jinxiu Hu
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Cell Therapy Technology Transfer Medical Key Laboratory of Yunnan Province, Kunming Key Laboratory of Stem Cell and Regenerative Medicine, Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, Yunnan 650032, China
| | - Liping Shu
- Department of Immunology of School of Basic Medicine of Guizhou Medical University, National and Local Joint Engineering Laboratory of Cell Engineering Biomedical Technology, Key Laboratory of Regenerative Medicine of Guizhou Province, State Key Laboratory of Efficacy and Utilization of Medicinal Plants Co-constructed by Province and Ministry, Key Laboratory of Translational Research of Adult Stem Cell of Chinese Academy of Medical Sciences, Guiyang, Guizhou 550025, China
| | - Xinghua Pan
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Cell Therapy Technology Transfer Medical Key Laboratory of Yunnan Province, Kunming Key Laboratory of Stem Cell and Regenerative Medicine, Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, Yunnan 650032, China
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Jiang T, Zheng MT, Li RM, Ouyang NJ. The effects of matrix stiffness on immune cells in bone biology. MECHANOBIOLOGY IN MEDICINE 2024; 2:100046. [PMID: 40395853 PMCID: PMC12082311 DOI: 10.1016/j.mbm.2024.100046] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 02/16/2024] [Accepted: 02/17/2024] [Indexed: 05/22/2025]
Abstract
Bone and immune cells typically inhabit the same microenvironment and engage in mutual interactions to collectively execute the functions of the "osteoimmune system." Establishing a harmonized and enduring osteoimmune system significantly enhances bone regeneration, necessitating the maintenance of bone and immune homeostasis. Recently, mechanobiology has garnered increasing interest in bone tissue engineering, with matrix stiffness emerging as a crucial parameter that has been extensively investigated. The effect of matrix stiffness on bone homeostasis remains relatively clear. Soft substrates tend to significantly affect the chondrogenic differentiation of bone marrow mesenchymal stem cells, whereas increasing matrix stiffness is advantageous for osteogenic differentiation. Increased stiffness increases osteoclast differentiation and activity. Additionally, there is increasing emphasis on immune homeostasis, which necessitates dynamic communication between immune cells. Immune cells are crucial in initiating bone regeneration and driving early inflammatory responses. Functional changes induced by matrix stiffness are pivotal for determining the outcomes of engineered tissue mimics. However, inconsistent and incomparable findings regarding the responses of different immune cells to matrix stiffness can be perplexing owing to variations in the stiffness range, measurement methods, and other factors. Therefore, this study aimed to provide a comprehensive review of the specific effects of matrix stiffness on diverse immune cells, with a particular focus on its implications for bone regeneration, which would offer theoretical insights into the treatment of large segmental bony defects and assist in the clinical development of new engineering strategies.
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Affiliation(s)
- Ting Jiang
- Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, 200011, People's Republic of China
- Oral Bioengineering Lab, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, 200011, People's Republic of China
| | - Meng-Ting Zheng
- Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, 200011, People's Republic of China
- Oral Bioengineering Lab, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, 200011, People's Republic of China
| | - Ruo-Mei Li
- Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, 200011, People's Republic of China
- Oral Bioengineering Lab, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, 200011, People's Republic of China
| | - Ning-Juan Ouyang
- Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, 200011, People's Republic of China
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12
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Chinnapaka S, Malekzadeh H, Tirmizi Z, Ejaz A. Caloric restriction mitigates age-associated senescence characteristics in subcutaneous adipose tissue-derived stem cells. Aging (Albany NY) 2024; 16:7535-7552. [PMID: 38728252 PMCID: PMC11131987 DOI: 10.18632/aging.205812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 02/27/2024] [Indexed: 05/12/2024]
Abstract
Adipose tissue regulates metabolic balance, but aging disrupts it, shifting fat from insulin-sensitive subcutaneous to insulin-resistant visceral depots, impacting overall metabolic health. Adipose-derived stem cells (ASCs) are crucial for tissue regeneration, but aging diminishes their stemness and regeneration potential. Our findings reveal that aging is associated with a decrease in subcutaneous adipose tissue mass and an increase in the visceral fat depots mass. Aging is associated with increase in adipose tissue fibrosis but no significant change in adipocyte size was observed with age. Long term caloric restriction failed to prevent fibrotic changes but resulted in significant decrease in adipocytes size. Aged subcutaneous ASCs displayed an increased production of ROS. Using mitochondrial membrane activity as an indicator of stem cell quiescence and senescence, we observed a significant decrease in quiescence ASCs with age exclusively in subcutaneous adipose depot. In addition, aged subcutaneous adipose tissue accumulated more senescent ASCs having defective autophagy activity. However, long-term caloric restriction leads to a reduction in mitochondrial activity in ASCs. Furthermore, caloric restriction prevents the accumulation of senescent cells and helps retain autophagy activity in aging ASCs. These results suggest that caloric restriction and caloric restriction mimetics hold promise as a potential strategy to rejuvenate the stemness of aged ASCs. Further investigations, including in vivo evaluations using controlled interventions in animals and human studies, will be necessary to validate these findings and establish the clinical potential of this well-established approach for enhancing the stemness of aged stem cells.
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Affiliation(s)
- Somaiah Chinnapaka
- Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Hamid Malekzadeh
- Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Zayaan Tirmizi
- Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Asim Ejaz
- Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA 15261, USA
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13
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Ren Y, Cui YN, Wang HW. Effects of different concentrations of nicotinamide on hematopoietic stem cells cultured in vitro. World J Stem Cells 2024; 16:163-175. [PMID: 38455103 PMCID: PMC10915957 DOI: 10.4252/wjsc.v16.i2.163] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 12/14/2023] [Accepted: 01/12/2024] [Indexed: 02/26/2024] Open
Abstract
BACKGROUND In vitro expansion to increase numbers of hematopoietic stem cells (HSCs) in cord blood could improve clinical efficacy of this vital resource. Nicotinamide (NAM) can promote HSC expansion ex vivo, but its effect on hematopoietic stem and progenitor cells (HSPCs, CD34+CD38) and functional subtypes of HSCs - short-term repopulating HSCs (ST-HSCs, CD34+CD38CD45RACD49f+) and long-term repopulating HSCs (LT-HSCs, CD34+CD38CD45RACD49f+CD90+) is not yet known. As a sirtuin 1 (SIRT1) inhibitor, NAM participates in regulating cell adhesion, polarity, migration, proliferation, and differentiation. However, SIRT1 exhibits dual effects by promoting or inhibiting differentiation in different tissues or cells. We propose that the concentration of NAM may influence proliferation, differentiation, and SIRT1 signaling of HSCs. AIM To evaluate the effects and underlying mechanisms of action of different concentrations of NAM on HSC proliferation and differentiation. METHODS CD34+ cells were purified from umbilical cord blood using MacsCD34 beads, and cultured for 10-12 d in a serum-free medium supplemented with cytokines, with different concentrations of NAM added according to experimental requirements. Flow cytometry was used to detect phenotype, cell cycle distribution, and apoptosis of the cultured cells. Real-time polymerase chain reaction was used to detect the transcription levels of target genes encoding stemness-related factors, chemokines, components of hypoxia pathways, and antioxidant enzymes. Dichloro-dihydro-fluorescein diacetate probes were used to evaluate intracellular production of reactive oxygen species (ROS). Determination of the effect of different culture conditions on the balance of cytokine by cytometric bead array. RESULTS Compared with the control group, the proportion and expansion folds of HSPCs (CD34+CD38) incubated with 5 mmol/L or 10 mmol/L NAM were significantly increased (all P < 0.05). The ST-HSCs ratio and fold expansion of the 5 mmol/L NAM group were significantly higher than those of the control and 10 mmol/L NAM groups (all P < 0.001), whereas the LT-HSCs ratio and fold expansion of the 10 mmol/L NAM group were significantly higher than those of the other two groups (all P < 0.05). When the NAM concentration was > 10 mmol/L, cell viability significantly decreased. In addition, compared with the 5 mmol/L NAM group, the proportion of apoptotic cells in the 10 mmol/L NAM group increased and the proportion of cells in S and G2 phase decreased. Compared with the 5 mmol/L NAM group, the HSCs incubated with 10 mmol/L NAM exhibited significantly inhibited SIRT1 expression, increased intracellular ROS content, and downregulated expression of genes encoding antioxidant enzymes (superoxide dismutase 1, peroxiredoxin 1). CONCLUSION Low concentrations (5 mmol/L) of NAM can better regulate the balance between proliferation and differentiation, thereby promoting expansion of HSCs. These findings allow adjustment of NAM concentrations according to expansion needs.
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Affiliation(s)
- Yan Ren
- The Second Clinical Medical College, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
- Department of Hematology, The Second Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Yan-Ni Cui
- The Second Clinical Medical College, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
- Department of Hematology, The Second Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Hong-Wei Wang
- Department of Hematology, The Second Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
- Department of Hematology, Key Laboratory of Molecular Diagnosis and Treatment of Blood Diseases in Shanxi Province, Taiyuan 030001, Shanxi Province, China.
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14
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Lv J, Zhang C, Liu X, Gu C, Liu Y, Gao Y, Huang Z, Jiang Q, Chen B, He D, Wang T, Xu Z, Su W. An aging-related immune landscape in the hematopoietic immune system. Immun Ageing 2024; 21:3. [PMID: 38169405 PMCID: PMC10759628 DOI: 10.1186/s12979-023-00403-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 12/11/2023] [Indexed: 01/05/2024]
Abstract
BACKGROUND Aging is a holistic change that has a major impact on the immune system, and immunosenescence contributes to the overall progression of aging. The bone marrow is the most important hematopoietic immune organ, while the spleen, as the most important extramedullary hematopoietic immune organ, maintains homeostasis of the human hematopoietic immune system (HIS) in cooperation with the bone marrow. However, the overall changes in the HIS during aging have not been described. Here, we describe a hematopoietic immune map of the spleen and bone marrow of young and old mice using single-cell sequencing and flow cytometry techniques. RESULTS We observed extensive, complex changes in the HIS during aging. Compared with young mice, the immune cells of aged mice showed a marked tendency toward myeloid differentiation, with the neutrophil population accounting for a significant proportion of this response. In this change, hypoxia-inducible factor 1-alpha (Hif1α) was significantly overexpressed, and this enhanced the immune efficacy and inflammatory response of neutrophils. Our research revealed that during the aging process, hematopoietic stem cells undergo significant changes in function and composition, and their polymorphism and differentiation abilities are downregulated. Moreover, we found that the highly responsive CD62L + HSCs were obviously downregulated in aging, suggesting that they may play an important role in the aging process. CONCLUSIONS Overall, aging extensively alters the cellular composition and function of the HIS. These findings could potentially give high-dimensional insights and enable more accurate functional and developmental analyses as well as immune monitoring in HIS aging.
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Affiliation(s)
- Jianjie Lv
- State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, China
| | - Chun Zhang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Xiuxing Liu
- State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, China
| | - Chenyang Gu
- State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, China
| | - Yidan Liu
- State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, China
| | - Yuehan Gao
- State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, China
| | - Zhaohao Huang
- State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, China
| | - Qi Jiang
- State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, China
| | - Binyao Chen
- State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, China
| | - Daquan He
- State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, China
| | - Tianfu Wang
- State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, China
| | - Zhuping Xu
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Wenru Su
- State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, China.
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15
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Yan B, Yuan Q, Guryanova OA. Epigenetic Mechanisms in Hematologic Aging and Premalignant Conditions. EPIGENOMES 2023; 7:32. [PMID: 38131904 PMCID: PMC10743085 DOI: 10.3390/epigenomes7040032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 11/29/2023] [Accepted: 12/07/2023] [Indexed: 12/23/2023] Open
Abstract
Hematopoietic stem cells (HSCs) are essential for maintaining overall health by continuously generating blood cells throughout an individual's lifespan. However, as individuals age, the hematopoietic system undergoes significant functional decline, rendering them more susceptible to age-related diseases. Growing research evidence has highlighted the critical role of epigenetic regulation in this age-associated decline. This review aims to provide an overview of the diverse epigenetic mechanisms involved in the regulation of normal HSCs during the aging process and their implications in aging-related diseases. Understanding the intricate interplay of epigenetic mechanisms that contribute to aging-related changes in the hematopoietic system holds great potential for the development of innovative strategies to delay the aging process. In fact, interventions targeting epigenetic modifications have shown promising outcomes in alleviating aging-related phenotypes and extending lifespan in various animal models. Small molecule-based therapies and reprogramming strategies enabling epigenetic rejuvenation have emerged as effective approaches for ameliorating or even reversing aging-related conditions. By acquiring a deeper understanding of these epigenetic mechanisms, it is anticipated that interventions can be devised to prevent or mitigate the rates of hematologic aging and associated diseases later in life. Ultimately, these advancements have the potential to improve overall health and enhance the quality of life in aging individuals.
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Affiliation(s)
- Bowen Yan
- Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL 32610, USA;
| | | | - Olga A. Guryanova
- Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL 32610, USA;
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16
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Zhang X, Yue R. Stiffness matters: A soft bone marrow organoid rejuvenates hematopoietic stem cells. MECHANOBIOLOGY IN MEDICINE 2023; 1:100009. [PMID: 40395866 PMCID: PMC12082126 DOI: 10.1016/j.mbm.2023.100009] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Accepted: 06/25/2023] [Indexed: 05/22/2025]
Abstract
A recent study published in Cell Stem Cell [1] showed that matrix stiffness critically regulates hematopoietic stem cell (HSC) niche, and successfully engineered a soft bone marrow (BM) organoid to maintain and rejuvenate HSCs ex vivo. In addition, BM stiffening was also identified as a novel aging hallmark of the hematopoietic system. Together, these important findings implicate matrix stiffness as a fundamental biomechanical factor governing cell fate determination and aging of tissue-specific stem cells.
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Affiliation(s)
- Xiaoying Zhang
- Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Rui Yue
- Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
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17
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Chinnapaka S, Malekzadeh H, Tirmizi Z, Arellano JA, Ejaz A. Nicotinamide Riboside Improves Stemness of Human Adipose-Derived Stem Cells and Inhibits Terminal Adipocyte Differentiation. Pharmaceuticals (Basel) 2023; 16:1134. [PMID: 37631051 PMCID: PMC10458272 DOI: 10.3390/ph16081134] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Revised: 08/02/2023] [Accepted: 08/07/2023] [Indexed: 08/27/2023] Open
Abstract
Adipose tissue plays a crucial role in maintaining metabolic homeostasis by serving as a storage site for excess fat and protecting other organs from the detrimental effects of lipotoxicity. However, the aging process is accompanied by a redistribution of fat, characterized by a decrease in insulin-sensitive subcutaneous adipose depot and an increase in insulin-resistant visceral adipose depot. This age-related alteration in adipose tissue distribution has implications for metabolic health. Adipose-derived stem cells (ASCs) play a vital role in the regeneration of adipose tissue. However, aging negatively impacts the stemness and regenerative potential of ASCs. The accumulation of oxidative stress and mitochondrial dysfunction-associated cellular damage contributes to the decline in stemness observed in aged ASCs. Nicotinamide adenine dinucleotide (NAD+) is a crucial metabolite that is involved in maintaining cellular homeostasis and stemness. The dysregulation of NAD+ levels with age has been associated with metabolic disorders and the loss of stemness. In this study, we aimed to investigate the effects of nicotinamide riboside (NR), a precursor of NAD+, on the stemness of human ASCs in cell culture. Our findings reveal that adipogenesis is accompanied by an increase in mitochondrial activity and the production of reactive oxygen species (ROS). However, treatment with NR leads to a reduction in mitochondrial activity and ROS production in ASCs. Furthermore, NR administration improves the stemness-related genes expression in ASCs and mitigates their propensity for adipocyte differentiation. These results suggest that NR treatment holds promise as a potential strategy to rejuvenate the stemness of aged ASCs. Further investigations, including in vivo evaluations using animal models and human studies, will be necessary to validate these findings and establish the clinical potential of this well-established drug for enhancing the stemness of aged stem cells.
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Affiliation(s)
| | | | | | | | - Asim Ejaz
- Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA 15261, USA
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18
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Guilz NC, Ahn YO, Seo S, Mace EM. Unwinding the Role of the CMG Helicase in Inborn Errors of Immunity. J Clin Immunol 2023; 43:847-861. [PMID: 36809597 PMCID: PMC10789183 DOI: 10.1007/s10875-023-01437-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 01/20/2023] [Indexed: 02/23/2023]
Abstract
Inborn errors of immunity (IEI) are a collection of diseases resulting from genetic causes that impact the immune system through multiple mechanisms. Natural killer cell deficiency (NKD) is one such IEI where natural killer (NK) cells are the main immune lineage affected. Though rare, the deficiency of several genes has been described as underlying causes of NKD, including MCM4, GINS1, MCM10 , and GINS4 , all of which are involved in the eukaryotic CMG helicase. The CMG helicase is made up of C DC45 – M CM – G INS and accessory proteins including MCM10. The CMG helicase plays a critical role in DNA replication by unwinding the double helix and enabling access of polymerases to single-stranded DNA, and thus helicase proteins are active in any proliferating cell. Replication stress, DNA damage, and cell cycle arrest are among the cellular phenotypes attributed to loss of function variants in CMG helicase proteins. Despite the ubiquitous function of the CMG helicase, NK cells have an apparent susceptibility to the deficiency of helicase proteins. This review will examine the role of the CMG helicase in inborn errors of immunity through the lens of NKD and further discuss why natural killer cells can be so strongly affected by helicase deficiency.
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Affiliation(s)
- Nicole C Guilz
- Vagelos College of Physicians and Surgeons, Department of Pediatrics, Columbia University Irving Medical Center, 630 W 168th St., New York, NY, 10032, USA
| | - Yong-Oon Ahn
- Vagelos College of Physicians and Surgeons, Department of Pediatrics, Columbia University Irving Medical Center, 630 W 168th St., New York, NY, 10032, USA
| | - Seungmae Seo
- Vagelos College of Physicians and Surgeons, Department of Pediatrics, Columbia University Irving Medical Center, 630 W 168th St., New York, NY, 10032, USA
| | - Emily M Mace
- Vagelos College of Physicians and Surgeons, Department of Pediatrics, Columbia University Irving Medical Center, 630 W 168th St., New York, NY, 10032, USA.
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19
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Gullotta GS, De Feo D, Friebel E, Semerano A, Scotti GM, Bergamaschi A, Butti E, Brambilla E, Genchi A, Capotondo A, Gallizioli M, Coviello S, Piccoli M, Vigo T, Della Valle P, Ronchi P, Comi G, D'Angelo A, Maugeri N, Roveri L, Uccelli A, Becher B, Martino G, Bacigaluppi M. Age-induced alterations of granulopoiesis generate atypical neutrophils that aggravate stroke pathology. Nat Immunol 2023; 24:925-940. [PMID: 37188941 DOI: 10.1038/s41590-023-01505-1] [Citation(s) in RCA: 47] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Accepted: 04/06/2023] [Indexed: 05/17/2023]
Abstract
Aging accounts for increased risk and dismal outcome of ischemic stroke. Here, we investigated the impact of age-related changes in the immune system on stroke. Upon experimental stroke, compared with young mice, aged mice had increased neutrophil clogging of the ischemic brain microcirculation, leading to worse no-reflow and outcomes. Aged mice showed an enhanced granulopoietic response to stroke that led to the accumulation of CD101+CD62Llo mature and CD177hiCD101loCD62Llo and CD177loCD101loCD62Lhi immature atypical neutrophils in the blood, endowed with increased oxidative stress, phagocytosis and procoagulant features. Production of CXCL3 by CD62Llo neutrophils of the aged had a key role in the development and pathogenicity of aging-associated neutrophils. Hematopoietic stem cell rejuvenation reverted aging-associated neutropoiesis and improved stroke outcome. In elderly patients with ischemic stroke, single-cell proteome profile of blood leukocytes identified CD62Llo neutrophil subsets associated with worse reperfusion and outcome. Our results unveil how stroke in aging leads to a dysregulated emergency granulopoiesis impacting neurological outcome.
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Affiliation(s)
- Giorgia Serena Gullotta
- Neuroimmunology Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Hospital and Vita-Salute San Raffaele University, Milan, Italy
| | - Donatella De Feo
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Ekaterina Friebel
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Aurora Semerano
- Neuroimmunology Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Hospital and Vita-Salute San Raffaele University, Milan, Italy
- Neurology Department, IRCCS San Raffaele Hospital, Milan, Italy
| | | | - Andrea Bergamaschi
- Neuroimmunology Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Hospital and Vita-Salute San Raffaele University, Milan, Italy
| | - Erica Butti
- Neuroimmunology Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Hospital and Vita-Salute San Raffaele University, Milan, Italy
| | - Elena Brambilla
- Neuroimmunology Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Hospital and Vita-Salute San Raffaele University, Milan, Italy
| | - Angela Genchi
- Neuroimmunology Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Hospital and Vita-Salute San Raffaele University, Milan, Italy
- Neurology Department, IRCCS San Raffaele Hospital, Milan, Italy
| | - Alessia Capotondo
- Neuroimmunology Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Hospital and Vita-Salute San Raffaele University, Milan, Italy
| | - Mattia Gallizioli
- Neuroimmunology Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Hospital and Vita-Salute San Raffaele University, Milan, Italy
| | | | - Marco Piccoli
- Laboratory of Stem Cells for Tissue Engineering, IRCCS, Policlinico San Donato, Milan, Italy
| | - Tiziana Vigo
- IRCCS, Ospedale Policlinico San Martino, Genova, Italy
| | - Patrizia Della Valle
- Coagulation Service and Thrombosis Research Unit, IRCCS San Raffaele Hospital, Milan, Italy
| | - Paola Ronchi
- Division of Regenerative Medicine, Stem Cells and Gene Therapy, Telethon Institute for Gene Therapy (HSR-TIGET), IRCCS San Raffaele Hospital, Milan, Italy
| | - Giancarlo Comi
- Neurology Department, IRCCS San Raffaele Hospital, Milan, Italy
| | - Armando D'Angelo
- Coagulation Service and Thrombosis Research Unit, IRCCS San Raffaele Hospital, Milan, Italy
| | - Norma Maugeri
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Hospital and Vita-Salute San Raffaele University, Milan, Italy
| | - Luisa Roveri
- Neurology Department, IRCCS San Raffaele Hospital, Milan, Italy
| | - Antonio Uccelli
- IRCCS, Ospedale Policlinico San Martino, Genova, Italy
- Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genova, Genoa, Italy
| | - Burkhard Becher
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Gianvito Martino
- Neuroimmunology Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Hospital and Vita-Salute San Raffaele University, Milan, Italy
- Neurology Department, IRCCS San Raffaele Hospital, Milan, Italy
| | - Marco Bacigaluppi
- Neuroimmunology Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Hospital and Vita-Salute San Raffaele University, Milan, Italy.
- Neurology Department, IRCCS San Raffaele Hospital, Milan, Italy.
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20
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Lin DS, Trumpp A. Differential expression of endothelial protein C receptor (EPCR) in hematopoietic stem and multipotent progenitor cells in young and old mice. Cells Dev 2023; 174:203843. [PMID: 37080459 DOI: 10.1016/j.cdev.2023.203843] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/26/2023] [Accepted: 04/13/2023] [Indexed: 04/22/2023]
Abstract
Endothelial protein C receptor (EPCR) has emerged as one of the most conserved and reliable surface markers for the prospective identification and isolation of hematopoietic stem cells (HSCs). Prior studies have consistently demonstrated that EPCR expression enriches HSCs capable of long-term multilineage repopulation in both mouse and human across different hematopoietic tissues, including bone marrow (BM), fetal liver and ex vivo HSC expansion cultures. However, little is known about the expression profiles of EPCR in multipotent progenitor (MPP) populations located immediately downstream of HSCs in the hematopoietic hierarchy and which play a major role in sustaining lifelong blood cell production. Here, we incorporate EPCR antibody detection into a multi-parameter flow cytometric panel, which allows accurate identification of HSCs and five MPP subsets (MPP1-5) in mouse BM. Our data reveal that all MPP populations contain EPCR-expressing cells. Multipotent MPP1 and MPP5 contain higher proportion of EPCR+ cells compared to the more lineage-biased MPP2-4. Notably, high expression of EPCR enriches phenotypic HSC and MPP5, but not MPP1. Comparison of EPCR expression profiles between young and old BM reveals ageing mediated expansion of EPCR-expressing cells only in HSCs, but not in any of the MPP populations. Collectively, our study provides a comprehensive characterization of the surface expression pattern of EPCR in mouse HSC and MPP1-5 cells during normal and aged hematopoiesis.
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Affiliation(s)
- Dawn S Lin
- Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
| | - Andreas Trumpp
- Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany.
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21
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Shevyrev D, Tereshchenko V, Berezina TN, Rybtsov S. Hematopoietic Stem Cells and the Immune System in Development and Aging. Int J Mol Sci 2023; 24:ijms24065862. [PMID: 36982935 PMCID: PMC10056303 DOI: 10.3390/ijms24065862] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 03/13/2023] [Accepted: 03/16/2023] [Indexed: 03/30/2023] Open
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 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.
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Affiliation(s)
- Daniil Shevyrev
- Centre for Cell Technology and Immunology, Sirius University of Science and Technology, Sirius, 354340 Sochi, Russia
| | - Valeriy Tereshchenko
- Centre for Cell Technology and Immunology, Sirius University of Science and Technology, Sirius, 354340 Sochi, Russia
| | - Tatiana N Berezina
- Department of Scientific Basis of Extreme Psychology, Moscow State University of Psychology and Education, 127051 Moscow, Russia
| | - Stanislav Rybtsov
- Centre for Cell Technology and Immunology, Sirius University of Science and Technology, Sirius, 354340 Sochi, Russia
- Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, UK
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22
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Menéndez-Gutiérrez MP, Porcuna J, Nayak R, Paredes A, Niu H, Núñez V, Paranjpe A, Gómez MJ, Bhattacharjee A, Schnell DJ, Sánchez-Cabo F, Welch JS, Salomonis N, Cancelas JA, Ricote M. Retinoid X receptor promotes hematopoietic stem cell fitness and quiescence and preserves hematopoietic homeostasis. Blood 2023; 141:592-608. [PMID: 36347014 PMCID: PMC10082360 DOI: 10.1182/blood.2022016832] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 10/20/2022] [Accepted: 10/30/2022] [Indexed: 11/10/2022] Open
Abstract
Hematopoietic stem cells (HSCs) balance self-renewal and differentiation to maintain hematopoietic fitness throughout life. In steady-state conditions, HSC exhaustion is prevented by the maintenance of most HSCs in a quiescent state, with cells entering the cell cycle only occasionally. HSC quiescence is regulated by retinoid and fatty-acid ligands of transcriptional factors of the nuclear retinoid X receptor (RXR) family. Herein, we show that dual deficiency for hematopoietic RXRα and RXRβ induces HSC exhaustion, myeloid cell/megakaryocyte differentiation, and myeloproliferative-like disease. RXRα and RXRβ maintain HSC quiescence, survival, and chromatin compaction; moreover, transcriptome changes in RXRα;RXRβ-deficient HSCs include premature acquisition of an aging-like HSC signature, MYC pathway upregulation, and RNA intron retention. Fitness loss and associated RNA transcriptome and splicing alterations in RXRα;RXRβ-deficient HSCs are prevented by Myc haploinsufficiency. Our study reveals the critical importance of RXRs for the maintenance of HSC fitness and their protection from premature aging.
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Affiliation(s)
| | - Jesús Porcuna
- Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
| | - Ramesh Nayak
- Stem Cell Program, Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
- Hoxworth Blood Center, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Ana Paredes
- Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
| | - Haixia Niu
- Stem Cell Program, Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Vanessa Núñez
- Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
| | - Aditi Paranjpe
- Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Manuel J. Gómez
- Bioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
| | - Anukana Bhattacharjee
- Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Daniel J. Schnell
- Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Fátima Sánchez-Cabo
- Bioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
| | - John S. Welch
- Department of Internal Medicine, Washington University, St Louis, MO
| | - Nathan Salomonis
- Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
- Department of Internal Medicine, Washington University, St Louis, MO
| | - Jose A. Cancelas
- Stem Cell Program, Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
- Hoxworth Blood Center, University of Cincinnati College of Medicine, Cincinnati, OH
- Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Mercedes Ricote
- Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
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23
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Dong X, Tu H, Qin S, Bai X, Yang F, Li Z. Insights into the Roles of B Cells in Patients with Sepsis. J Immunol Res 2023; 2023:7408967. [PMID: 37128298 PMCID: PMC10148744 DOI: 10.1155/2023/7408967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 04/02/2023] [Accepted: 04/04/2023] [Indexed: 05/03/2023] Open
Abstract
Sepsis is a life-threatening yet common disease, still posing high mortality worldwide. Sepsis-related deaths primarily occur during immunosuppression; the disease can hamper the numbers and function of B cells, which mediate innate and adaptive immune responses to maintain immune homeostasis. Dysfunction of B cells, along with aggravated immunosuppression, are closely related to poor prognosis. However, B cells in patients with sepsis have garnered little attention. This article focuses on the significance of B-cell subsets, including regulatory B cells, in sepsis and how the counts and function of circulating B cells are affected in patients with sepsis. Finally, potential B-cell-related immunotherapies for sepsis are explored.
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Affiliation(s)
- Xijie Dong
- Trauma Center/Department of Emergency and Traumatic Surgery, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Hao Tu
- Trauma Center/Department of Emergency and Traumatic Surgery, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Shuang Qin
- Department of Radiation Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiangjun Bai
- Trauma Center/Department of Emergency and Traumatic Surgery, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Fan Yang
- Trauma Center/Department of Emergency and Traumatic Surgery, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Zhanfei Li
- Trauma Center/Department of Emergency and Traumatic Surgery, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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24
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Chen Z, Ju Z, Sun Y. Aging, Causes, and Rejuvenation of Hematopoietic Stem Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1442:201-210. [PMID: 38228966 DOI: 10.1007/978-981-99-7471-9_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2024]
Abstract
Hematopoietic stem cells (HSCs) undergo an age-related functional decline, which leads to a disruption of the blood system and contributes to the development of aging-associated hematopoietic diseases and malignancies. In this section, we provide a summary of the key hallmarks associated with HSC aging. We also examine the causal factors that contribute to HSC aging and emphasize potential approaches to mitigate HSC aging and age-related hematopoietic disorders.
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Affiliation(s)
- Zhiyang Chen
- Key Laboratory of Regenerative Medicine of Ministry of Education, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, Guangdong, China
| | - Zhenyu Ju
- Key Laboratory of Regenerative Medicine of Ministry of Education, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, Guangdong, China
| | - Yan Sun
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
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25
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Cai Y, Ji Z, Wang S, Zhang W, Qu J, Belmonte JCI, Liu GH. Genetic enhancement: an avenue to combat aging-related diseases. LIFE MEDICINE 2022; 1:307-318. [PMID: 39872744 PMCID: PMC11749557 DOI: 10.1093/lifemedi/lnac054] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 11/14/2022] [Indexed: 01/30/2025]
Abstract
Aging is a major risk factor for multiple diseases, including cardiovascular diseases, neurodegenerative disorders, osteoarthritis, and cancer. It is accompanied by the dysregulation of stem cells and other differentiated cells, and the impairment of their microenvironment. Cell therapies to replenish the abovementioned cells provide a promising approach to restore tissue homeostasis and alleviate aging and aging-related chronic diseases. Importantly, by leveraging gene editing technologies, genetic enhancement, an enhanced strategy for cell therapy, can be developed to improve the safety and efficacy of transplanted therapeutic cells. In this review, we provide an overview and discussion of the current progress in the genetic enhancement field, including genetic modifications of mesenchymal stem cells, neural stem cells, hematopoietic stem cells, vascular cells, and T cells to target aging and aging-associated diseases. We also outline questions regarding safety and current limitations that need to be addressed for the continued development of genetic enhancement strategies for cell therapy to enable its further applications in clinical trials to combat aging-related diseases.
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Affiliation(s)
- Yusheng Cai
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Zhejun Ji
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Si Wang
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Weiqi Zhang
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
- China National Center for Bioinformation, Beijing 100101, China
| | - Jing Qu
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | | | - Guang-Hui Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China
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26
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Hattori K, Takagi H, Ogata Y, Yamada T, Horiba H, Fukata K, Sakaida T, Yashiro Y, Hasegawa S, Tanaka H. Immunostimulatory effects of a subcritical water extract of Ganoderma. Biomed Rep 2022; 18:1. [PMID: 36544853 PMCID: PMC9756285 DOI: 10.3892/br.2022.1583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 10/11/2022] [Indexed: 11/10/2022] Open
Abstract
Ganoderma, a medicinal mushroom with various physiological activities, has been extensively investigated regarding its effectiveness. The aim of the present study was to examine the effects of a subcritical water extract of Ganoderma (SWEG) on the immune system. The use of subcritical water with a higher temperature and pressure than hot water allows efficient elution of components from natural products. As an evaluation of the effectiveness of SWEG, a cell proliferation and a cell differentiation test were carried out using A-6 cells, a model of hematopoietic stem cells. Furthermore, an oral administration test in mice was conducted to examine the effects of SWEG on the number and function of immune cells. As a result, SWEG was revealed to promote both self-renewal and differentiation into immune cells such as T cells and natural killer (NK) cells in experiments with A-6 cells. These results were not obtained in experiments using hot water extract of Ganoderma lucidum and Ganoderma sinense. The oral administration test in mice demonstrated that SWEG increased hematopoietic precursor cells, immature B cells, and NK cells in the bone marrow, and T cells in the thymus. In addition, SWEG enhanced the immune functions in the spleen by promoting granzyme B expression and NK cell activity. SWEG was demonstrated to be a food material that acts on HSCs and regulates immunity in vivo.
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Affiliation(s)
- Koji Hattori
- Research Laboratories, Nippon Menard Cosmetic Co., Ltd., Nagoya-shi, Aichi 451-0071, Japan
| | - Hiroshi Takagi
- Research Laboratories, Nippon Menard Cosmetic Co., Ltd., Nagoya-shi, Aichi 451-0071, Japan
| | - Yuichiro Ogata
- Research Laboratories, Nippon Menard Cosmetic Co., Ltd., Nagoya-shi, Aichi 451-0071, Japan
| | - Takaaki Yamada
- Research Laboratories, Nippon Menard Cosmetic Co., Ltd., Nagoya-shi, Aichi 451-0071, Japan
| | - Hiroki Horiba
- Research Laboratories, Nippon Menard Cosmetic Co., Ltd., Nagoya-shi, Aichi 451-0071, Japan
| | - Kousuke Fukata
- Research Laboratories, Nippon Menard Cosmetic Co., Ltd., Nagoya-shi, Aichi 451-0071, Japan
| | - Tsutomu Sakaida
- Research Laboratories, Nippon Menard Cosmetic Co., Ltd., Nagoya-shi, Aichi 451-0071, Japan
| | - Youichi Yashiro
- Research Laboratories, Nippon Menard Cosmetic Co., Ltd., Nagoya-shi, Aichi 451-0071, Japan
| | - Seiji Hasegawa
- Research Laboratories, Nippon Menard Cosmetic Co., Ltd., Nagoya-shi, Aichi 451-0071, Japan,Nagoya University-MENARD Collaborative Research Chair, Nagoya University Graduate School of Medicine, Nagoya-shi, Aichi 466-8550, Japan,Correspondence to: Dr Seiji Hasegawa, Research Laboratories, Nippon Menard Cosmetic Co., Ltd., 2-7 Torimi-cho, Nishi-ku, Nagoya-shi, Aichi 451-0071, Japan
| | - Hiroyuki Tanaka
- Laboratory of Immunobiology, Department of Biofunctional Analysis, Gifu Pharmaceutical University, Gifu 501-1196, Japan
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27
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Ma C, Liu H, Yang S, Li H, Liao X, Kang Y. The emerging roles and therapeutic potential of B cells in sepsis. Front Pharmacol 2022; 13:1034667. [PMID: 36425582 PMCID: PMC9679374 DOI: 10.3389/fphar.2022.1034667] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 10/26/2022] [Indexed: 01/03/2024] Open
Abstract
Sepsis is a life-threatening syndrome caused by anomalous host response to infection. The pathogenesis of sepsis is complex, and immune dysfunction is the central link in its occurrence and development. The sepsis immune response is not a local and transient process but a complex and continuous process involving all major cell types of innate and adaptive immunity. B cells are traditionally studied for their ability to produce antibodies in the context of mediating humoral immunity. However, over the past few years, B cells have been increasingly recognized as key modulators of adaptive and innate immunity, and they can participate in immune responses by presenting antigens, producing cytokines, and modulating other immune cells. Recently, increasing evidence links B-cell dysfunction to mechanisms of immune derangement in sepsis, which has drawn attention to the powerful properties of this unique immune cell type in sepsis. Here, we reviewed the dynamic alterations of B cells and their novel roles in animal models and patients with sepsis, and provided new perspectives for therapeutic strategies targeting B cells in sepsis.
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Affiliation(s)
- Chengyong Ma
- Center of Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Hanrui Liu
- Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Shuo Yang
- Center of Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Hong Li
- Center of Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Xuelian Liao
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Yan Kang
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
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28
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A stem cell aging framework, from mechanisms to interventions. Cell Rep 2022; 41:111451. [DOI: 10.1016/j.celrep.2022.111451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 09/04/2022] [Accepted: 09/14/2022] [Indexed: 11/19/2022] Open
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29
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Stolzenbach V, Woods DC, Tilly JL. Non-neutral clonal selection and its potential role in mammalian germline stem cell dysfunction with advancing age. Front Cell Dev Biol 2022; 10:942652. [PMID: 36081905 PMCID: PMC9445274 DOI: 10.3389/fcell.2022.942652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 07/20/2022] [Indexed: 11/13/2022] Open
Abstract
The concept of natural selection, or "survival of the fittest", refers to an evolutionary process in nature whereby traits emerge in individuals of a population through random gene alterations that enable those individuals to better adapt to changing environmental conditions. This genetic variance allows certain members of the population to gain an advantage over others in the same population to survive and reproduce in greater numbers under new environmental pressures, with the perpetuation of those advantageous traits in future progeny. Here we present that the behavior of adult stem cells in a tissue over time can, in many respects, be viewed in the same manner as evolution, with each stem cell clone being representative of an individual within a population. As stem cells divide or are subjected to cumulative oxidative damage over the lifespan of the organism, random genetic alterations are introduced into each clone that create variance in the population. These changes may occur in parallel to, or in response to, aging-associated changes in microenvironmental cues perceived by the stem cell population. While many of these alterations will be neutral or silent in terms of affecting cell function, a small fraction of these changes will enable certain clones to respond differently to shifts in microenvironmental conditions that arise with advancing age. In some cases, the same advantageous genetic changes that support survival and expansion of certain clones over others in the population (viz. non-neutral competition) could be detrimental to the downstream function of the differentiated stem cell descendants. In the context of the germline, such a situation would be devastating to successful propagation of the species across generations. However, even within a single generation, the “evolution” of stem cell lineages in the body over time can manifest into aging-related organ dysfunction and failure, as well as lead to chronic inflammation, hyperplasia, and cancer. Increased research efforts to evaluate stem cells within a population as individual entities will improve our understanding of how organisms age and how certain diseases develop, which in turn may open new opportunities for clinical detection and management of diverse pathologies.
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30
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Fujino T, Asada S, Goyama S, Kitamura T. Mechanisms involved in hematopoietic stem cell aging. Cell Mol Life Sci 2022; 79:473. [PMID: 35941268 PMCID: PMC11072869 DOI: 10.1007/s00018-022-04356-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 04/27/2022] [Accepted: 05/05/2022] [Indexed: 11/03/2022]
Abstract
Hematopoietic stem cells (HSCs) undergo progressive functional decline over time due to both internal and external stressors, leading to aging of the hematopoietic system. A comprehensive understanding of the molecular mechanisms underlying HSC aging will be valuable in developing novel therapies for HSC rejuvenation and to prevent the onset of several age-associated diseases and hematological malignancies. This review considers the general causes of HSC aging that range from cell-intrinsic factors to cell-extrinsic factors. In particular, epigenetics and inflammation have been implicated in the linkage of HSC aging, clonality, and oncogenesis. The challenges in clarifying mechanisms of HSC aging have accelerated the development of therapeutic interventions to rejuvenate HSCs, the major goal of aging research; these details are also discussed in this review.
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Affiliation(s)
- Takeshi Fujino
- Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan
| | - Shuhei Asada
- The Institute of Laboratory Animals, Tokyo Women's Medical University, Tokyo, 1628666, Japan
| | - Susumu Goyama
- Division of Molecular Oncology Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, 1088639, Japan
| | - Toshio Kitamura
- Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.
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31
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Abstract
Hematopoietic stem cell (HSC) regeneration is the remarkable process by which extremely rare, normally inactive cells of the bone marrow can replace an entire organ if called to do so by injury or harnessed by transplantation. HSC research is arguably the first quantitative single-cell science and the foundation of adult stem cell biology. Bone marrow transplant is the oldest and most refined technique of regenerative medicine. Here we review the intertwined history of the discovery of HSCs and bone marrow transplant, the molecular and cellular mechanisms of HSC self-renewal, and the use of HSCs and their derivatives for cell therapy.
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Affiliation(s)
- Mitch Biermann
- Department of Medicine, University of California San Diego, La Jolla, California 92093
| | - Tannishtha Reya
- Department of Medicine, University of California San Diego, La Jolla, California 92093
- Department of Pharmacology, University of California San Diego, La Jolla, California 92093
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32
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Leonov A, Feldman R, Piano A, Arlia-Ciommo A, Junio JAB, Orfanos E, Tafakori T, Lutchman V, Mohammad K, Elsaser S, Orfali S, Rajen H, Titorenko VI. Diverse geroprotectors differently affect a mechanism linking cellular aging to cellular quiescence in budding yeast. Oncotarget 2022; 13:918-943. [PMID: 35937500 PMCID: PMC9348708 DOI: 10.18632/oncotarget.28256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 07/01/2022] [Indexed: 11/25/2022] Open
Affiliation(s)
- Anna Leonov
- Department of Biology, Concordia University, Montreal, Quebec H4B 1R6, Canada
| | - Rachel Feldman
- Department of Biology, Concordia University, Montreal, Quebec H4B 1R6, Canada
| | - Amanda Piano
- Department of Biology, Concordia University, Montreal, Quebec H4B 1R6, Canada
| | | | | | - Emmanuel Orfanos
- Department of Biology, Concordia University, Montreal, Quebec H4B 1R6, Canada
| | - Tala Tafakori
- Department of Biology, Concordia University, Montreal, Quebec H4B 1R6, Canada
| | - Vicky Lutchman
- Department of Biology, Concordia University, Montreal, Quebec H4B 1R6, Canada
| | - Karamat Mohammad
- Department of Biology, Concordia University, Montreal, Quebec H4B 1R6, Canada
| | - Sarah Elsaser
- Department of Biology, Concordia University, Montreal, Quebec H4B 1R6, Canada
| | - Sandra Orfali
- Department of Biology, Concordia University, Montreal, Quebec H4B 1R6, Canada
| | - Harshvardhan Rajen
- Department of Biology, Concordia University, Montreal, Quebec H4B 1R6, Canada
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Emerging Evidence of the Significance of Thioredoxin-1 in Hematopoietic Stem Cell Aging. Antioxidants (Basel) 2022; 11:antiox11071291. [PMID: 35883782 PMCID: PMC9312246 DOI: 10.3390/antiox11071291] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 06/22/2022] [Accepted: 06/28/2022] [Indexed: 02/04/2023] Open
Abstract
The United States is undergoing a demographic shift towards an older population with profound economic, social, and healthcare implications. The number of Americans aged 65 and older will reach 80 million by 2040. The shift will be even more dramatic in the extremes of age, with a projected 400% increase in the population over 85 years old in the next two decades. Understanding the molecular and cellular mechanisms of ageing is crucial to reduce ageing-associated disease and to improve the quality of life for the elderly. In this review, we summarized the changes associated with the ageing of hematopoietic stem cells (HSCs) and what is known about some of the key underlying cellular and molecular pathways. We focus here on the effects of reactive oxygen species and the thioredoxin redox homeostasis system on ageing biology in HSCs and the HSC microenvironment. We present additional data from our lab demonstrating the key role of thioredoxin-1 in regulating HSC ageing.
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Fichtel P, von Bonin M, Kuhnert R, Möbus K, Bornhäuser M, Wobus M. Mesenchymal Stromal Cell-Derived Extracellular Vesicles Modulate Hematopoietic Stem and Progenitor Cell Viability and the Expression of Cell Cycle Regulators in an Age-dependent Manner. Front Bioeng Biotechnol 2022; 10:892661. [PMID: 35721867 PMCID: PMC9198480 DOI: 10.3389/fbioe.2022.892661] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 05/18/2022] [Indexed: 11/13/2022] Open
Abstract
Aging of the hematopoietic system is characterized by an expansion of hematopoietic stem and progenitor cells (HSPCs) with reduced capacity for engraftment, self-renewal, and lymphoid differentiation, resulting in myeloid-biased hematopoiesis. This process is mediated by both HSPC intrinsic and extrinsic factors, e.g., the stromal environment. A relevant cellular component of the bone marrow (BM) microenvironment are mesenchymal stromal cells (MSCs) which regulate fate and differentiation of HSPCs. The bi-directional communication with HSPCs is mediated either by direct cell-cell contacts or by extracellular vesicles (EVs) which carry bioactive substances such as small RNA, DNA, lipids and proteins. So far, the impact of MSC-derived EVs on human hematopoietic aging is poorly investigated. BM MSCs were isolated from young (n = 3, median age: 22 years) and aged (n = 3, median age: 70 years) donors and the EVs were isolated after culturing the confluent cell layer in serum-free medium for 48 h. CD34+ HSPCs were purified from peripheral blood of healthy donors (n = 3, median age: 65 years) by magnetic sorting. Nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM) and western blot detection of EV markers CD63, CD81 and Flotillin-1 revealed no significant differences between young and aged MSC-EVs. Interestingly, young MSCs secreted a significantly higher miRNA concentration than aged cells. However, the amount of distinct miRNAs such as miR-29a and miR-34a was significantly higher in aged MSC-EVs. HSPCs incubated with young EVs showed a significant increase in cell number and a higher viability. The expression of the tumor suppressors PTEN, a known target of mir-29a, and CDKN2A was increased in HSPCs incubated with young EVs. The clonogenic assay demonstrated a decreased colony number of CFU-GM after treatment with young EVs and an increased number of BFU-E/CFU-E after incubation with aged MSC-EVs. Xenogenic transplantation experiments showed no significant differences concerning the engraftment of lymphoid or myeloid cell compartments, but the overall human chimerism 8–16 weeks after transplantation was higher after EV treatment. In conclusion, our data suggest that HSPC characteristics such as cell cycle activity and clonogenicity can be modulated by MSC-derived EVs. Further studies have to elucidate the potential therapeutic relevance of our findings.
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Affiliation(s)
- Pascal Fichtel
- Department of Medicine I, University Hospital Carl Gustav Carus, Technische Universität, Dresden, Germany
| | - Malte von Bonin
- Department of Medicine I, University Hospital Carl Gustav Carus, Technische Universität, Dresden, Germany
| | - Robert Kuhnert
- Department of Medicine I, University Hospital Carl Gustav Carus, Technische Universität, Dresden, Germany
| | - Kristin Möbus
- Department of Medicine I, University Hospital Carl Gustav Carus, Technische Universität, Dresden, Germany
| | - Martin Bornhäuser
- Department of Medicine I, University Hospital Carl Gustav Carus, Technische Universität, Dresden, Germany
- Center for Regenerative Therapies, Technische Universität, Dresden, Germany
| | - Manja Wobus
- Department of Medicine I, University Hospital Carl Gustav Carus, Technische Universität, Dresden, Germany
- Center for Regenerative Therapies, Technische Universität, Dresden, Germany
- *Correspondence: Manja Wobus,
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Hageb A, Thalheim T, Nattamai KJ, Möhrle B, Saçma M, Sakk V, Thielecke L, Cornils K, Grandy C, Port F, Gottschalk KE, Mallm JP, Glauche I, Galle J, Mulaw MA, Geiger H. Reduced adhesion of aged intestinal stem cells contributes to an accelerated clonal drift. Life Sci Alliance 2022; 5:5/8/e202201408. [PMID: 35487692 PMCID: PMC9057243 DOI: 10.26508/lsa.202201408] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 04/11/2022] [Accepted: 04/12/2022] [Indexed: 11/30/2022] Open
Abstract
Analysis of clonal dynamics of intestinal stem cells supports an accelerated clonal drift upon aging, likely because of reduced adhesion of aged ISCs because of reduced canonical Wnt signaling. Upon aging, the function of the intestinal epithelium declines with a concomitant increase in aging-related diseases. ISCs play an important role in this process. It is known that ISC clonal dynamics follow a neutral drift model. However, it is not clear whether the drift model is still valid in aged ISCs. Tracking of clonal dynamics by clonal tracing revealed that aged crypts drift into monoclonality substantially faster than young ones. However, ISC tracing experiments, in vivo and ex vivo, implied a similar clonal expansion ability of both young and aged ISCs. Single-cell RNA sequencing for 1,920 high Lgr5 ISCs from young and aged mice revealed increased heterogeneity among subgroups of aged ISCs. Genes associated with cell adhesion were down-regulated in aged ISCs. ISCs of aged mice indeed show weaker adhesion to the matrix. Simulations applying a single cell–based model of the small intestinal crypt demonstrated an accelerated clonal drift at reduced adhesion strength, implying a central role for reduced adhesion for affecting clonal dynamics upon aging.
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Affiliation(s)
- Ali Hageb
- Institute of Molecular Medicine, Ulm University, Ulm, Germany
| | - Torsten Thalheim
- Interdisciplinary Centre for Bioinformatics, University Leipzig, Leipzig, Germany
| | - Kalpana J Nattamai
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH, USA
| | - Bettina Möhrle
- Institute of Molecular Medicine, Ulm University, Ulm, Germany
| | - Mehmet Saçma
- Institute of Molecular Medicine, Ulm University, Ulm, Germany
| | - Vadim Sakk
- Institute of Molecular Medicine, Ulm University, Ulm, Germany
| | - Lars Thielecke
- Institute for Medical Informatics and Biometry, Technische Universität Dresden, Dresden, Germany
| | - Kerstin Cornils
- Clinic of Pediatric Hematology and Oncology, Division of Pediatric Stem Cell Transplantation and Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Research Institute Children's Cancer Center Hamburg, Hamburg, Germany
| | - Carolin Grandy
- Institute for Experimental Physics, Ulm University, Ulm, Germany
| | - Fabian Port
- Institute for Experimental Physics, Ulm University, Ulm, Germany
| | - Kay-E Gottschalk
- Institute for Experimental Physics, Ulm University, Ulm, Germany
| | - Jan-Philipp Mallm
- Division of Chromatin Networks, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Ingmar Glauche
- Institute for Medical Informatics and Biometry, Technische Universität Dresden, Dresden, Germany
| | - Jörg Galle
- Interdisciplinary Centre for Bioinformatics, University Leipzig, Leipzig, Germany
| | - Medhanie A Mulaw
- Central Unit Single Cell Sequencing, Medical Faculty, Ulm University, Ulm, Germany
| | - Hartmut Geiger
- Institute of Molecular Medicine, Ulm University, Ulm, Germany
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36
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Ou MY, Zhang H, Tan PC, Zhou SB, Li QF. Adipose tissue aging: mechanisms and therapeutic implications. Cell Death Dis 2022; 13:300. [PMID: 35379822 PMCID: PMC8980023 DOI: 10.1038/s41419-022-04752-6] [Citation(s) in RCA: 118] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/03/2022] [Accepted: 03/18/2022] [Indexed: 01/10/2023]
Abstract
Adipose tissue, which is the crucial energy reservoir and endocrine organ for the maintenance of systemic glucose, lipid, and energy homeostasis, undergoes significant changes during aging. These changes cause physiological declines and age-related disease in the elderly population. Here, we review the age-related changes in adipose tissue at multiple levels and highlight the underlying mechanisms regulating the aging process. We also discuss the pathogenic pathways of age-related fat dysfunctions and their systemic negative consequences, such as dyslipidemia, chronic general inflammation, insulin resistance, and type 2 diabetes (T2D). Age-related changes in adipose tissue involve redistribution of deposits and composition, in parallel with the functional decline of adipocyte progenitors and accumulation of senescent cells. Multiple pathogenic pathways induce defective adipogenesis, inflammation, aberrant adipocytokine production, and insulin resistance, leading to adipose tissue dysfunction. Changes in gene expression and extracellular signaling molecules regulate the aging process of adipose tissue through various pathways. In addition, adipose tissue aging impacts other organs that are infiltrated by lipids, which leads to systemic inflammation, metabolic system disruption, and aging process acceleration. Moreover, studies have indicated that adipose aging is an early onset event in aging and a potential target to extend lifespan. Together, we suggest that adipose tissue plays a key role in the aging process and is a therapeutic target for the treatment of age-related disease, which deserves further study to advance relevant knowledge.
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Affiliation(s)
- Min-Yi Ou
- Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 200011, Shanghai, China
| | - Hao Zhang
- Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 200011, Shanghai, China
| | - Poh-Ching Tan
- Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 200011, Shanghai, China
| | - Shuang-Bai Zhou
- Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 200011, Shanghai, China.
| | - Qing-Feng Li
- Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 200011, Shanghai, China.
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37
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Montazersaheb S, Ehsani A, Fathi E, Farahzadi R. Cellular and Molecular Mechanisms Involved in Hematopoietic Stem Cell Aging as a Clinical Prospect. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:2713483. [PMID: 35401928 PMCID: PMC8993567 DOI: 10.1155/2022/2713483] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 02/28/2022] [Accepted: 03/22/2022] [Indexed: 11/17/2022]
Abstract
There is a hot topic in stem cell research to investigate the process of hematopoietic stem cell (HSC) aging characterized by decreased self-renewal ability, myeloid-biased differentiation, impaired homing, and other abnormalities related to hematopoietic repair function. It is of crucial importance that HSCs preserve self-renewal and differentiation ability to maintain hematopoiesis under homeostatic states over time. Although HSC numbers increase with age in both mice and humans, this cannot compensate for functional defects of aged HSCs. The underlying mechanisms regarding HSC aging have been studied from various perspectives, but the exact molecular events remain unclear. Several cell-intrinsic and cell-extrinsic factors contribute to HSC aging including DNA damage responses, reactive oxygen species (ROS), altered epigenetic profiling, polarity, metabolic alterations, impaired autophagy, Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, nuclear factor- (NF-) κB pathway, mTOR pathway, transforming growth factor-beta (TGF-β) pathway, and wingless-related integration site (Wnt) pathway. To determine how deficient HSCs develop during aging, we provide an overview of different hallmarks, age-related signaling pathways, and epigenetic modifications in young and aged HSCs. Knowing how such changes occur and progress will help researchers to develop medications and promote the quality of life for the elderly and possibly alleviate age-associated hematopoietic disorders. The present review is aimed at discussing the latest advancements of HSC aging and the role of HSC-intrinsic factors and related events of a bone marrow niche during HSC aging.
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Affiliation(s)
- Soheila Montazersaheb
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Ehsani
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ezzatollah Fathi
- Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Raheleh Farahzadi
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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38
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Hematopoiesis, Inflammation and Aging-The Biological Background and Clinical Impact of Anemia and Increased C-Reactive Protein Levels on Elderly Individuals. J Clin Med 2022; 11:jcm11030706. [PMID: 35160156 PMCID: PMC8836692 DOI: 10.3390/jcm11030706] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/21/2022] [Accepted: 01/24/2022] [Indexed: 01/27/2023] Open
Abstract
Anemia and systemic signs of inflammation are common in elderly individuals and are associated with decreased survival. The common biological context for these two states is then the hallmarks of aging, i.e., genomic instability, telomere shortening, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intercellular communication. Such aging-associated alterations of hematopoietic stem cells are probably caused by complex mechanisms and depend on both the aging of hematopoietic (stem) cells and on the supporting stromal cells. The function of inflammatory or immunocompetent cells is also altered by aging. The intracellular signaling initiated by soluble proinflammatory mediators (e.g., IL1, IL6 and TNFα) is altered during aging and contributes to the development of both the inhibition of erythropoiesis with anemia as well as to the development of the acute-phase reaction as a systemic sign of inflammation with increased CRP levels. Both anemia and increased CRP levels are associated with decreased overall survival and increased cardiovascular mortality. The handling of elderly patients with inflammation and/or anemia should in our opinion be individualized; all of them should have a limited evaluation with regard to the cause of the abnormalities, but the extent of additional and especially invasive diagnostic evaluation should be based on an overall clinical evaluation and the possible therapeutic consequences.
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39
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Pan Y, Zuo H, Wen F, Huang F, Zhu Y, Cao L, Sha QQ, Li Y, Zhang H, Shi M, Liang C, Huang J, Zou L, Fan HY, Ju Z, Wang H, Shen L. HMCES safeguards genome integrity and long-term self-renewal of hematopoietic stem cells during stress responses. Leukemia 2022; 36:1123-1131. [PMID: 35039639 DOI: 10.1038/s41375-021-01499-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 12/04/2021] [Accepted: 12/10/2021] [Indexed: 12/28/2022]
Abstract
Hematopoietic stress drives quiescent hematopoietic stem cells (HSCs) to proliferate, generating reactive oxygen species (ROS) and oxidative DNA damage including abasic sites. Such a coupling between rapid DNA replication and a burst of abasic site formation during HSC stress responses, however, presents a challenge to accurately repair abasic sites located in replication-associated single-stranded DNA. Here we show that HMCES, a novel shield of abasic sites, plays pivotal roles in overcoming this challenge upon HSC activation. While HMCES was dispensable for steady-state hematopoiesis, Hmces-deficient HSCs exhibited compromised long-term self-renewal capacity in response to hematopoietic stress such as myeloablation and transplantation. Loss of HMCES resulted in accumulation of DNA lesions due to impaired resolution of abasic sites generated by activation-induced ROS in activated HSCs and broad downregulation of DNA damage response and repair pathways. Moreover, Hmces-deficient mice died from bone marrow failure after exposure to sublethal irradiation, which also produces ROS. Notably, dysregulation of HMCES occurs frequently in acute lymphocytic leukemia (ALL) and is associated with poor clinical outcomes. Together, our findings not only highlighted HMCES as a novel genome protector in activated HSCs, but also position it as a potential selective target against ALL while sparing normal hematopoiesis.
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Affiliation(s)
- Yinghao Pan
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Hongna Zuo
- MOE Key Laboratory of Regenerative Medicine, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, China
| | - Fei Wen
- MOE Key Laboratory of Regenerative Medicine, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, China
| | - Fei Huang
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Yezhang Zhu
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Lanrui Cao
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Qian-Qian Sha
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Yang Li
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Huiying Zhang
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Miao Shi
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Chengzhen Liang
- Department of Orthopedics Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jun Huang
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Lin Zou
- Clinical Research Unit, Children's Hospital of Shanghai Jiaotong University, Shanghai, China
| | - Heng-Yu Fan
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Zhenyu Ju
- MOE Key Laboratory of Regenerative Medicine, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, China.
| | - Hu Wang
- Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Institute of Ageing Research, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China.
| | - Li Shen
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China. .,Department of Orthopedics Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. .,Hangzhou Innovation Center, Zhejiang University, Hangzhou, China.
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40
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Sun Y, Lin X, Liu B, Zhang Y, Li W, Zhang S, He F, Tian H, Zhu X, Liu X, Wu J, Cai J, Li M. Loss of ATF4 leads to functional aging-like attrition of adult hematopoietic stem cells. SCIENCE ADVANCES 2021; 7:eabj6877. [PMID: 34936448 PMCID: PMC8694622 DOI: 10.1126/sciadv.abj6877] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/02/2023]
Abstract
Aging of hematopoietic stem cells (HSCs) directly contributes to dysfunction of hematopoietic and immune systems due to aging-associated alterations in HSC features. How the function of adult HSCs is regulated during aging so that relevant pathologic abnormalities may occur, however, remains incompletely understood. Here, we report that ATF4 deficiency provokes severe HSC defects with multifaceted aging-like phenotype via cell-autonomous mechanisms. ATF4 deletion caused expansion of phenotypical HSCs with functional attrition, characterized by defective repopulating and self-renewal capacities and myeloid bias. Moreover, the ATF4−/− HSC defects were associated with elevated mitochondrial ROS production by targeting HIF1α. In addition, loss of ATF4 significantly delayed leukemogenesis in the MLL-AF9–induced leukemia model. Mechanistically, ATF4 deficiency impaired HSC function with aging-like phenotype and alleviated leukemogenesis by regulating HIF1α and p16Ink4a. Together, our findings suggest a possibility of developing new strategies for the prevention and management of HSC aging and related pathological conditions.
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Affiliation(s)
- Yan Sun
- Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
- Corresponding author. (M.L.); (Y.S.); (J.C.)
| | - Xiaolin Lin
- Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Bangdong Liu
- Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Yaxuan Zhang
- Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Wei Li
- Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Sheng Zhang
- Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Falian He
- Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Han Tian
- Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Xun Zhu
- Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Ximeng Liu
- Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Jueheng Wu
- Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Junchao Cai
- Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
- Corresponding author. (M.L.); (Y.S.); (J.C.)
| | - Mengfeng Li
- Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
- Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
- Corresponding author. (M.L.); (Y.S.); (J.C.)
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41
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Kandi R, Senger K, Grigoryan A, Soller K, Sakk V, Schuster T, Eiwen K, Menon MB, Gaestel M, Zheng Y, Florian MC, Geiger H. Cdc42-Borg4-Septin7 axis regulates HSC polarity and function. EMBO Rep 2021; 22:e52931. [PMID: 34661963 PMCID: PMC8647144 DOI: 10.15252/embr.202152931] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 09/13/2021] [Accepted: 09/17/2021] [Indexed: 01/03/2023] Open
Abstract
Aging of hematopoietic stem cells (HSCs) is caused by the elevated activity of the small RhoGTPase Cdc42 and an apolar distribution of proteins. Mechanisms by which Cdc42 activity controls polarity of HSCs are not known. Binder of RhoGTPases proteins (Borgs) are known effector proteins of Cdc42 that are able to regulate the cytoskeletal Septin network. Here, we show that Cdc42 interacts with Borg4, which in turn interacts with Septin7 to regulate the polar distribution of Cdc42, Borg4, and Septin7 within HSCs. Genetic deletion of either Borg4 or Septin7 results in a reduced frequency of HSCs polar for Cdc42 or Borg4 or Septin7, a reduced engraftment potential and decreased lymphoid‐primed multipotent progenitor (LMPP) frequency in the bone marrow. Taken together, our data identify a Cdc42‐Borg4‐Septin7 axis essential for the maintenance of polarity within HSCs and for HSC function and provide a rationale for further investigating the role of Borgs and Septins in the regulation of compartmentalization within stem cells.
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Affiliation(s)
- Ravinder Kandi
- Institute of Molecular Medicine, Ulm University, Ulm, Germany
| | | | - Ani Grigoryan
- Institute of Molecular Medicine, Ulm University, Ulm, Germany
| | - Karin Soller
- Institute of Molecular Medicine, Ulm University, Ulm, Germany
| | - Vadim Sakk
- Institute of Molecular Medicine, Ulm University, Ulm, Germany
| | - Tanja Schuster
- Institute of Molecular Medicine, Ulm University, Ulm, Germany
| | - Karina Eiwen
- Institute of Molecular Medicine, Ulm University, Ulm, Germany
| | - Manoj B Menon
- Institute of Cell Biochemistry, Hannover Medical School, Hannover, Germany.,Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, New Delhi, India
| | - Matthias Gaestel
- Institute of Cell Biochemistry, Hannover Medical School, Hannover, Germany
| | - Yi Zheng
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | | | - Hartmut Geiger
- Institute of Molecular Medicine, Ulm University, Ulm, Germany
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42
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Aging, Bone Marrow and Next-Generation Sequencing (NGS): Recent Advances and Future Perspectives. Int J Mol Sci 2021; 22:ijms222212225. [PMID: 34830107 PMCID: PMC8620539 DOI: 10.3390/ijms222212225] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/07/2021] [Accepted: 11/09/2021] [Indexed: 12/28/2022] Open
Abstract
The aging of bone marrow (BM) remains a very imperative and alluring subject, with an ever-increasing interest among fellow scientists. A considerable amount of progress has been made in this field with the established ‘hallmarks of aging’ and continued efforts to investigate the age-related changes observed within the BM. Inflammaging is considered as a low-grade state of inflammation associated with aging, and whilst the possible mechanisms by which aging occurs are now largely understood, the processes leading to the underlying changes within aged BM remain elusive. The ability to identify these changes and detect such alterations at the genetic level are key to broadening the knowledgebase of aging BM. Next-generation sequencing (NGS) is an important molecular-level application presenting the ability to not only determine genomic base changes but provide transcriptional profiling (RNA-seq), as well as a high-throughput analysis of DNA–protein interactions (ChIP-seq). Utilising NGS to explore the genetic alterations occurring over the aging process within alterative cell types facilitates the comprehension of the molecular and cellular changes influencing the dynamics of aging BM. Thus, this review prospects the current landscape of BM aging and explores how NGS technology is currently being applied within this ever-expanding field of research.
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43
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Rejuvenating the Immune System: Insights for Anti-Neurodegeneration Strategies. Neurosci Bull 2021; 38:107-109. [PMID: 34748186 PMCID: PMC8782958 DOI: 10.1007/s12264-021-00787-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 08/19/2021] [Indexed: 01/03/2023] Open
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Isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomic analysis of mRNA splicing relevant proteins in aging HSPCs. Aging Clin Exp Res 2021; 33:3123-3134. [PMID: 32141009 DOI: 10.1007/s40520-020-01509-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Accepted: 02/10/2020] [Indexed: 10/24/2022]
Abstract
BACKGROUND HSPC (hematopoietic stem/progenitor cell) aging was closely associated with the organism aging, senile diseases and hematopoietic related diseases. Therefore, study on HSPC aging is of great significance to further elucidate the mechanisms of aging and to treat hematopoietic disease resulting from HSPC aging. Little attention had been paid to mRNA splicing as a mechanism underlying HSPC senescence. RESULTS We used our lab's patented in vitro aging model of HSPCs to analyze mRNA splicing relevant protein alterations with iTRAQ-based proteomic analysis. We found that not only the notable mRNA splicing genes such as SR, hnRNP, WBP11, Sf3b1, Ptbp1 and U2AF1 but also the scarcely reported mRNA splicing relevant genes such as Rbmxl1, Dhx16, Pcbp2, Pabpc1 were significantly down-regulated. We further verified their gene expressions by qRT-PCR. In addition, we reported the effect of Spliceostatin A (SSA), which inhibits mRNA splicing in vivo and in vitro, on HSPC aging. CONCLUSIONS It was concluded that mRNA splicing emerged as an important factor for the vulnerability of HSPC aging. This study improved our understanding of the role of mRNA splicing in the HSPC aging process.
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de Mol J, Kuiper J, Tsiantoulas D, Foks AC. The Dynamics of B Cell Aging in Health and Disease. Front Immunol 2021; 12:733566. [PMID: 34675924 PMCID: PMC8524000 DOI: 10.3389/fimmu.2021.733566] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 09/16/2021] [Indexed: 12/30/2022] Open
Abstract
Aging is considered to be an important risk factor for several inflammatory diseases. B cells play a major role in chronic inflammatory diseases by antibody secretion, antigen presentation and T cell regulation. Different B cell subsets have been implicated in infections and multiple autoimmune diseases. Since aging decreases B cell numbers, affects B cell subsets and impairs antibody responses, the aged B cell is expected to have major impacts on the development and progression of these diseases. In this review, we summarize the role of B cells in health and disease settings, such as atherosclerotic disease. Furthermore, we provide an overview of age-related changes in B cell development and function with respect to their impact in chronic inflammatory diseases.
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Affiliation(s)
- Jill de Mol
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands
| | - Johan Kuiper
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands
| | | | - Amanda C. Foks
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands
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Vaughan KL, Franchini AM, Kern HG, Lawrence BP. The Aryl Hydrocarbon Receptor Modulates Murine Hematopoietic Stem Cell Homeostasis and Influences Lineage-Biased Stem and Progenitor Cells. Stem Cells Dev 2021; 30:970-980. [PMID: 34428990 PMCID: PMC8851211 DOI: 10.1089/scd.2021.0096] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 08/09/2021] [Indexed: 12/24/2022] Open
Abstract
The core function of hematopoietic stem and progenitor cells (HSPCs) is to provide lifelong production of all lineages of the blood and immune cells. The mechanisms that modulate HSPC homeostasis and lineage biasing are not fully understood. Growing evidence implicates the aryl hydrocarbon receptor (AHR), an environment-sensing transcription factor, as a regulator of hematopoiesis. AHR ligands modulate the frequency of mature hematopoietic cells in the bone marrow and periphery, while HSPCs from mice lacking AHR (AHR KO) have increased proliferation. Yet, whether AHR modulates HSPC lineage potential and directs differentiation toward specific lineage-biased progenitors is not well understood. This study revealed that AHR KO mice have an increased proportion of myeloid-biased HSCs and myeloid-biased multipotent progenitor (MPP3) cells. Utilizing inducible AHR knockout mice (iAHR KO), it was discovered that acute deletion of AHR doubled the number of MPP3 cells and altered the composition of downstream lineage-committed progenitors, such as increased frequency of pregranulocyte/premonocyte committed progenitors. Furthermore, in vivo antagonism of the AHR led to a 2.5-fold increase in the number of MPP3 cells and promoted myeloid-biased differentiation. Using hematopoietic-specific conditional AHR knockout mice (AHRVav1) revealed that increased frequency of myeloid-biased HSCs and myeloid-biased progenitors is driven by AHR signaling that is intrinsic to the hematopoietic compartment. These findings demonstrate that the AHR plays a pivotal role in regulating steady-state hematopoiesis, influencing HSPC homeostasis and lineage potential. In addition, the data presented provide potential insight into how deliberate modulation of AHR signaling could help with the treatment of a broad range of diseases that require the hematopoietic compartment.
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Affiliation(s)
- Keegan L. Vaughan
- Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Anthony M. Franchini
- Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Harrison G. Kern
- Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - B. Paige Lawrence
- Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
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Duah M, Li L, Shen J, Lan Q, Pan B, Xu K. Thymus Degeneration and Regeneration. Front Immunol 2021; 12:706244. [PMID: 34539637 PMCID: PMC8442952 DOI: 10.3389/fimmu.2021.706244] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 08/16/2021] [Indexed: 01/08/2023] Open
Abstract
The immune system’s ability to resist the invasion of foreign pathogens and the tolerance to self-antigens are primarily centered on the efficient functions of the various subsets of T lymphocytes. As the primary organ of thymopoiesis, the thymus performs a crucial role in generating a self-tolerant but diverse repertoire of T cell receptors and peripheral T cell pool, with the capacity to recognize a wide variety of antigens and for the surveillance of malignancies. However, cells in the thymus are fragile and sensitive to changes in the external environment and acute insults such as infections, chemo- and radiation-therapy, resulting in thymic injury and degeneration. Though the thymus has the capacity to self-regenerate, it is often insufficient to reconstitute an intact thymic function. Thymic dysfunction leads to an increased risk of opportunistic infections, tumor relapse, autoimmunity, and adverse clinical outcome. Thus, exploiting the mechanism of thymic regeneration would provide new therapeutic options for these settings. This review summarizes the thymus’s development, factors causing thymic injury, and the strategies for improving thymus regeneration.
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Affiliation(s)
- Maxwell Duah
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China.,Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
| | - Lingling Li
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China.,Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
| | - Jingyi Shen
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China.,Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
| | - Qiu Lan
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China.,Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
| | - Bin Pan
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China.,Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
| | - Kailin Xu
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China.,Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
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48
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Lai X, Guo Y, Chen M, Wei Y, Yi W, Shi Y, Xiong L. Caveolin1: its roles in normal and cancer stem cells. J Cancer Res Clin Oncol 2021; 147:3459-3475. [PMID: 34498146 DOI: 10.1007/s00432-021-03793-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 09/03/2021] [Indexed: 12/09/2022]
Abstract
PURPOSE Stem cells are characterized by the capability of self-renewal and multi-differentiation. Normal stem cells, which are important for tissue repair and tissue regeneration, can be divided into embryonic stem cells (ESCs) and somatic stem cells (SSCs) depending on their origin. As a subpopulation of cells within cancer, cancer stem cells (CSCs) are at the root of therapeutic resistance. Tumor-initiating cells (TICs) are necessary for tumor initiation. Caveolin1 (Cav1), a membrane protein located at the caveolae, participates in cell lipid transport, cell migration, cell proliferation, and cell signal transduction. The purpose of this review was to explore the relationship between Cav1 and stem cells. RESULTS In ESCs, Cav1 is beneficial for self-renewal, proliferation, and migration. In SSCs, Cav1 exhibits positive or/and negative effects on stem cell self-renewal, differentiation, proliferation, migration, and angiogenic capacity. Cav1 deficiency impairs normal stem cell-based tissue repair. In CSCs, Cav1 inhibits or/and promotes CSC self-renewal, differentiation, invasion, migration, tumorigenicity ability, and CSC formation. And suppressing Cav1 promotes chemo-sensitivity in CSCs and TICs. CONCLUSION Cav1 shows dual roles in stem cell biology. Targeting the Cav1-stem cell axis would be a new way for tissue repair and cancer drug resistance.
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Affiliation(s)
- Xingning Lai
- Department of Pathophysiology, Medical College, Nanchang University, 461 Bayi Road, Nanchang, China.,Second Clinical Medical College, Nanchang University, Nanchang, 330006, China
| | - Yiling Guo
- Department of Pathophysiology, Medical College, Nanchang University, 461 Bayi Road, Nanchang, China.,Second Clinical Medical College, Nanchang University, Nanchang, 330006, China
| | - Miaomiao Chen
- Department of Pathophysiology, Medical College, Nanchang University, 461 Bayi Road, Nanchang, China.,First Clinical Medical College, Nanchang University, Nanchang, 330006, China
| | - Yuxuan Wei
- Department of Pathophysiology, Medical College, Nanchang University, 461 Bayi Road, Nanchang, China.,Queen Mary School, Jiangxi Medical College of Nanchang University, Nanchang, 330006, China
| | - Wanting Yi
- Department of Pathophysiology, Medical College, Nanchang University, 461 Bayi Road, Nanchang, China.,First Clinical Medical College, Nanchang University, Nanchang, 330006, China
| | - Yubo Shi
- Department of Pathophysiology, Medical College, Nanchang University, 461 Bayi Road, Nanchang, China.,Queen Mary School, Jiangxi Medical College of Nanchang University, Nanchang, 330006, China
| | - Lixia Xiong
- Department of Pathophysiology, Medical College, Nanchang University, 461 Bayi Road, Nanchang, China. .,Jiangxi Province Key Laboratory of Tumor Pathogenesis and Molecular Pathology, Nanchang, 330006, China.
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Belyavsky A, Petinati N, Drize N. Hematopoiesis during Ontogenesis, Adult Life, and Aging. Int J Mol Sci 2021; 22:ijms22179231. [PMID: 34502137 PMCID: PMC8430730 DOI: 10.3390/ijms22179231] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 08/13/2021] [Accepted: 08/24/2021] [Indexed: 12/17/2022] Open
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 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.
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Affiliation(s)
- Alexander Belyavsky
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia;
| | | | - Nina Drize
- National Research Center for Hematology, 125167 Moscow, Russia;
- Correspondence:
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Luan J, Xu H, Jin Z, Guan H, Gao X, Gou X, Xu L. Analysis of the dynamic changes in the proportion of immune cells and the proportion of cells with stem cell characteristics in the corresponding immune cell population of C57 mice during the natural aging process. Immunol Res 2021; 69:520-532. [PMID: 34415527 DOI: 10.1007/s12026-021-09229-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Accepted: 08/14/2021] [Indexed: 01/17/2023]
Abstract
The aging of the immune system is not only an inevitable result but also an important cause of physical aging. The aging of the immune system is rooted in the aging of hematopoietic cells (HSCs), which manifests as decreasing functionality of the adaptive immune system and the innate immune system. C57BL/6 mice of different ages were collected in this study to better understand the changes in the structures of the innate and adaptive immune systems in individuals of different ages and the distribution and changes in immune cells with stem cell properties. The immune cells of the innate and adaptive immune systems, including DCs, monocytes, macrophages, CD4+ T lymphocytes, CD8+ T lymphocytes, and B lymphocytes, were assessed, and the proportions of cells with stem cell properties among these immune cell populations were also tested. Overall, immune cells in the peripheral blood, spleen, and bone marrow of mice exhibit certain regular properties with increasing age. The trend of changes in immune cells in different immune organs differs with age. The changes in lymphocytes in the peripheral blood are more sensitive. Their proportions increase slowly with age and then decrease rapidly to a very low level (less than 5%) after a certain point (9 or 13 months old). Nine to 13 months of age is the most critical time point for assessing changes in the immune system of mice and the most critical time point for detecting changes in the proportion of stem cells. After 13 months of age, the balance and stability of stem cells in mice are disrupted, and animals begin to age rapidly. The ratio of Ly6A to E+CD117+ cells in the peripheral blood, particularly lymphocytes involved in adaptive immunity, represents a specific marker for predicting immune senescence and body senescence.
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Affiliation(s)
- Jing Luan
- Department of Anesthesiology, School of Stomatology, Fourth Military Medical University, Xi'an, China.,Shaanxi Key Laboratory of Brain Disorders and Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, 710021, Shaanxi, China.,Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, China
| | - Hao Xu
- Institution of Basic Medical Science, Xi'an Medical University, Xi'an, China
| | - Zhang Jin
- Department of Anesthesiology, School of Stomatology, Fourth Military Medical University, Xi'an, China
| | - Hua Guan
- Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, China
| | - Xingchun Gao
- Institution of Basic Medical Science, Xi'an Medical University, Xi'an, China
| | - Xingchun Gou
- Shaanxi Key Laboratory of Brain Disorders and Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, 710021, Shaanxi, China.
| | - Lixian Xu
- Department of Anesthesiology, School of Stomatology, Fourth Military Medical University, Xi'an, China.
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