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1
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Wang B, Bian Q. Regulation of 3D genome organization during T cell activation. FEBS J 2025; 292:1833-1852. [PMID: 38944686 DOI: 10.1111/febs.17211] [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: 01/04/2024] [Revised: 04/23/2024] [Accepted: 06/14/2024] [Indexed: 07/01/2024]
Abstract
Within the three-dimensional (3D) nuclear space, the genome organizes into a series of orderly structures that impose important influences on gene regulation. T lymphocytes, crucial players in adaptive immune responses, undergo intricate transcriptional remodeling upon activation, leading to differentiation into specific effector and memory T cell subsets. Recent evidence suggests that T cell activation is accompanied by dynamic changes in genome architecture at multiple levels, providing a unique biological context to explore the functional relevance and molecular mechanisms of 3D genome organization. Here, we summarize recent advances that link the reorganization of genome architecture to the remodeling of transcriptional programs and conversion of cell fates during T cell activation and differentiation. We further discuss how various chromatin architecture regulators, including CCCTC-binding factor and several transcription factors, collectively modulate the genome architecture during this process.
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Affiliation(s)
- Bao Wang
- Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, China
- Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, China
| | - Qian Bian
- Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, China
- Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, China
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2
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Karatepe K, Mafra de Faria B, Zhang J, Chen X, Pinto H, Fyodorov D, Sefik E, Willcockson M, Flavell R, Skoultchi A, Guo S. Linker histone regulates the myeloid versus lymphoid bifurcation of multipotent hematopoietic stem and progenitors. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.16.613227. [PMID: 39345411 PMCID: PMC11429722 DOI: 10.1101/2024.09.16.613227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
Myeloid-biased differentiation of multipotent hematopoietic stem and progenitor cells (HSPCs) occurs with aging or exhaustion. The molecular mechanism(s) responsible for this fate bias remain unclear. Here we report that linker histone regulates HSPC fate choice at the lymphoid versus myeloid bifurcation. HSPCs expressing H1.0 from a doxycycline (dox) inducible transgene favor the lymphoid fate, display strengthened nucleosome organization and reduced chromatin accessibility at genomic regions hosting key myeloid fate drivers. The transcription factor Hlf is located in one of such regions, where chromatin accessibility and gene expression is reduced in H1.0 high HSPCs. Furthermore, H1.0 protein in HSPCs decreases in an aspartyl protease dependent manner, a process enhanced in response to interferon alpha (IFNα) signaling. Aspartyl protease inhibitors preserve endogenous H1.0 levels and promote the lymphoid fate of wild type HSPCs. Thus, our work uncovers a point of intervention to mitigate myeloid skewed hematopoiesis.
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3
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Qi W, Bai J, Wang R, Zeng X, Zhang L. SATB1, senescence and senescence-related diseases. J Cell Physiol 2024; 239:e31327. [PMID: 38801120 DOI: 10.1002/jcp.31327] [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: 01/31/2024] [Revised: 05/06/2024] [Accepted: 05/15/2024] [Indexed: 05/29/2024]
Abstract
Aging leads to an accumulation of cellular mutations and damage, increasing the risk of senescence, apoptosis, and malignant transformation. Cellular senescence, which is pivotal in aging, acts as both a guard against cellular transformation and as a check against cancer progression. It is marked by stable cell cycle arrest, widespread macromolecular changes, a pro-inflammatory profile, and altered gene expression. However, it remains to be determined whether these differing subsets of senescent cells result from unique intrinsic programs or are influenced by their environmental contexts. Multiple transcription regulators and chromatin modifiers contribute to these alterations. Special AT-rich sequence-binding protein 1 (SATB1) stands out as a crucial regulator in this process, orchestrating gene expression by structuring chromatin into loop domains and anchoring DNA elements. This review provides an overview of cellular senescence and delves into the role of SATB1 in senescence-related diseases. It highlights SATB1's potential in developing antiaging and anticancer strategies, potentially contributing to improved quality of life and addressing aging-related diseases.
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Affiliation(s)
- Wenjing Qi
- Department of Bioscience, Changchun Normal University, Changchun, Jilin, China
- Key Laboratory of Molecular Epigenetics of Ministry of Education, College of Life Sciences, Northeast Normal University, Changchun, Jilin, China
| | - Jinping Bai
- Department of Bioscience, Changchun Normal University, Changchun, Jilin, China
| | - Ruoxi Wang
- Center for Cell Structure and Function, College of Life Sciences, Key Laboratory of Animal Resistance Biology of Shandong Province, Shandong Normal University, Jinan, Shandong, China
| | - Xianlu Zeng
- Key Laboratory of Molecular Epigenetics of Ministry of Education, College of Life Sciences, Northeast Normal University, Changchun, Jilin, China
| | - Lihui Zhang
- Department of Bioscience, Changchun Normal University, Changchun, Jilin, China
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4
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Kim Y, Calderon AA, Favaro P, Glass DR, Tsai AG, Ho D, Borges L, Greenleaf WJ, Bendall SC. Terminal deoxynucleotidyl transferase and CD84 identify human multi-potent lymphoid progenitors. Nat Commun 2024; 15:5910. [PMID: 39003273 PMCID: PMC11246490 DOI: 10.1038/s41467-024-49883-w] [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: 12/02/2022] [Accepted: 06/24/2024] [Indexed: 07/15/2024] Open
Abstract
Lymphoid specification in human hematopoietic progenitors is not fully understood. To better associate lymphoid identity with protein-level cell features, we conduct a highly multiplexed single-cell proteomic screen on human bone marrow progenitors. This screen identifies terminal deoxynucleotidyl transferase (TdT), a specialized DNA polymerase intrinsic to VDJ recombination, broadly expressed within CD34+ progenitors prior to B/T cell emergence. While these TdT+ cells coincide with granulocyte-monocyte progenitor (GMP) immunophenotype, their accessible chromatin regions show enrichment for lymphoid-associated transcription factor (TF) motifs. TdT expression on GMPs is inversely related to the SLAM family member CD84. Prospective isolation of CD84lo GMPs demonstrates robust lymphoid potentials ex vivo, while still retaining significant myeloid differentiation capacity, akin to LMPPs. This multi-omic study identifies human bone marrow lymphoid-primed progenitors, further defining the lympho-myeloid axis in human hematopoiesis.
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Affiliation(s)
- YeEun Kim
- Immunology Graduate Program, Stanford University, Stanford, CA, USA
- Department of Pathology, Stanford University, Stanford, CA, USA
| | - Ariel A Calderon
- Immunology Graduate Program, Stanford University, Stanford, CA, USA
- Department of Pathology, Stanford University, Stanford, CA, USA
| | - Patricia Favaro
- Department of Pathology, Stanford University, Stanford, CA, USA
| | - David R Glass
- Immunology Graduate Program, Stanford University, Stanford, CA, USA
- Department of Pathology, Stanford University, Stanford, CA, USA
| | - Albert G Tsai
- Department of Pathology, Stanford University, Stanford, CA, USA
| | - Daniel Ho
- Department of Pathology, Stanford University, Stanford, CA, USA
| | - Luciene Borges
- Department of Pathology, Stanford University, Stanford, CA, USA
| | | | - Sean C Bendall
- Department of Pathology, Stanford University, Stanford, CA, USA.
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5
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Alhaj Hussen K, Louis V, Canque B. A new model of human lymphopoiesis across development and aging. Trends Immunol 2024; 45:495-510. [PMID: 38908962 DOI: 10.1016/j.it.2024.05.007] [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: 05/06/2024] [Revised: 05/25/2024] [Accepted: 05/26/2024] [Indexed: 06/24/2024]
Abstract
Over the past decade our research has implemented a multimodal approach to human lymphopoiesis, combining clonal-scale mapping of lymphoid developmental architecture with the monitoring of dynamic changes in the pattern of lymphocyte generation across ontogeny. We propose that lymphopoiesis stems from founder populations of CD127/interleukin (IL)7R- or CD127/IL7R+ early lymphoid progenitors (ELPs) polarized respectively toward the T-natural killer (NK)/innate lymphoid cell (ILC) or B lineages, arising from newly characterized CD117lo multi-lymphoid progenitors (MLPs). Recent data on the lifelong lymphocyte dynamics of healthy donors suggest that, after birth, lymphopoiesis may become increasingly oriented toward the production of B lymphocytes. Stemming from this, we posit that there are three major developmental transitions, the first occurring during the neonatal period, the next at puberty, and the last during aging.
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Affiliation(s)
- Kutaiba Alhaj Hussen
- Service de Biochimie, Université de Paris Saclay, Hôpital Paul Brousse, AP-HP, Paris, France
| | - Valentine Louis
- INSERM 1151, Université de Paris, École Pratique des Hautes Études/PSL Research University, Institut Necker Enfants Malades (INEM), Paris, France
| | - Bruno Canque
- INSERM 1151, Université de Paris, École Pratique des Hautes Études/PSL Research University, Institut Necker Enfants Malades (INEM), Paris, France.
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6
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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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7
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Song T, Yao Y, Papoin J, Sherry B, Diamond B, Gu H, Blanc L, Zou YR. Host factor TIMP1 sustains long-lasting myeloid-biased hematopoiesis after severe infection. J Exp Med 2023; 220:e20230018. [PMID: 37851372 PMCID: PMC10585121 DOI: 10.1084/jem.20230018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 07/10/2023] [Accepted: 10/03/2023] [Indexed: 10/19/2023] Open
Abstract
Infection is able to promote innate immunity by enhancing a long-term myeloid output even after the inciting infectious agent has been cleared. However, the mechanisms underlying such a regulation are not fully understood. Using a mouse polymicrobial peritonitis (sepsis) model, we show that severe infection leads to increased, sustained myelopoiesis after the infection is resolved. In post-infection mice, the tissue inhibitor of metalloproteinases 1 (TIMP1) is constitutively upregulated. TIMP1 antagonizes the function of ADAM10, an essential cleavage enzyme for the activation of the Notch signaling pathway, which suppresses myelopoiesis. While TIMP1 is dispensable for myelopoiesis under the steady state, increased TIMP1 enhances myelopoiesis after infection. Thus, our data establish TIMP1 as a molecular reporter of past infection in the host, sustaining hyper myelopoiesis and serving as a potential therapeutic target for modulating HSPC cell fate.
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Affiliation(s)
- Tengfei Song
- Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, USA
| | - Yonghong Yao
- Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, USA
| | - Julien Papoin
- Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, USA
| | - Barbara Sherry
- Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, USA
- Department of Molecular Medicine, Zucker School of Medicine at Hofstra-Northwell, Hempstead, NY, USA
| | - Betty Diamond
- Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, USA
- Department of Molecular Medicine, Zucker School of Medicine at Hofstra-Northwell, Hempstead, NY, USA
| | - Hua Gu
- Laboratory of Molecular Immunology, Institut de Recherches Cliniques de Montréal, Montréal, Canada
| | - Lionel Blanc
- Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, USA
- Department of Molecular Medicine, Zucker School of Medicine at Hofstra-Northwell, Hempstead, NY, USA
| | - Yong-Rui Zou
- Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, USA
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8
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Kasbekar M, Mitchell CA, Proven MA, Passegué E. Hematopoietic stem cells through the ages: A lifetime of adaptation to organismal demands. Cell Stem Cell 2023; 30:1403-1420. [PMID: 37865087 PMCID: PMC10842631 DOI: 10.1016/j.stem.2023.09.013] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Revised: 09/20/2023] [Accepted: 09/28/2023] [Indexed: 10/23/2023]
Abstract
Hematopoietic stem cells (HSCs), which govern the production of all blood lineages, transition through a series of functional states characterized by expansion during fetal development, functional quiescence in adulthood, and decline upon aging. We describe central features of HSC regulation during ontogeny to contextualize how adaptive responses over the life of the organism ultimately form the basis for HSC functional degradation with age. We particularly focus on the role of cell cycle regulation, inflammatory response pathways, epigenetic changes, and metabolic regulation. We then explore how the knowledge of age-related changes in HSC regulation can inform strategies for the rejuvenation of old HSCs.
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Affiliation(s)
- Monica Kasbekar
- Columbia Stem Cell Initiative, Department of Genetics and Development, Columbia University, New York, NY 10032, USA; Division of Hematology and Medical Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Carl A Mitchell
- Columbia Stem Cell Initiative, Department of Genetics and Development, Columbia University, New York, NY 10032, USA
| | - Melissa A Proven
- Columbia Stem Cell Initiative, Department of Genetics and Development, Columbia University, New York, NY 10032, USA
| | - Emmanuelle Passegué
- Columbia Stem Cell Initiative, Department of Genetics and Development, Columbia University, New York, NY 10032, USA.
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Guo J, Chen Z, Xiao Y, Yu G, Li Y. SATB1 promotes osteogenic differentiation of diabetic rat BMSCs through MAPK signalling activation. Oral Dis 2023; 29:3610-3619. [PMID: 35608610 DOI: 10.1111/odi.14265] [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: 10/03/2021] [Revised: 04/28/2022] [Accepted: 05/10/2022] [Indexed: 11/27/2022]
Abstract
OBJECTIVE Special AT-rich binding protein 1 (SATB1), a chromatin organizer and global transcriptional regulator, plays an important role in tumorigenesis and immune response. However, its function in the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) remains unknown. Therefore, this study aimed to explore the role of SATB1 in osteogenesis. METHODS BMSCs were collected from the type 2 diabetes rat model and the protein and gene expression of SATB1 and osteospecific genes were evaluated post osteogenic induction. RESULTS SATB1 protein expression significantly decreased in diabetic rat BMSCs whereas it increased in BMSCs following osteogenic induction. SATB1 knockdown significantly suppressed the expression of osteospecific genes, including alkaline phosphatase (Alp), runt-related transcription factor 2, and osteocalcin, and reduced the number of mineral deposits and ALP activity, whereas SATB1 overexpression yielded the opposite results. Moreover, SATB1 knockdown suppressed activation of the MAPK signalling pathway (phosphorylation of p38 and ERK), and MAPK pathway inhibitors could reverse the inhibitory effect of SATB1 knockdown on osteogenic differentiation of BMSCs. CONCLUSION SATB1 plays a key role in the osteogenic differentiation of BMSCs via the p38 MAPK and ERK MAPK signalling pathways. These findings may provide a new strategy for the application of BMSCs in bone regeneration.
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Affiliation(s)
- Jing Guo
- The Affiliated Stomatological Hospital of Nanchang University, Nanchang, China
- The Key Laboratory of Oral Biomedicine, Nanchang, China
- Jiangxi Province Clinical Research Center for Oral Diseases, Nanchang, China
| | - Zhuochen Chen
- The Second Clinical Medical College, Nanchang University, Nanchang, China
| | - Yue Xiao
- The First Clinical Medical College, Nanchang University, Nanchang, China
| | - Guiyuan Yu
- Department of Anesthesiology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yong Li
- Department of Anesthesiology, The First Affiliated Hospital of Nanchang University, Nanchang, China
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10
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Thomas M, Bruzeau C, Martin OA, Pollet J, Bender S, Carrion C, Le Noir S, Pinaud E. A dual function for the chromatin organizer Special A-T rich Binding Protein 1 in B-lineage cells. Cell Mol Immunol 2023; 20:1114-1126. [PMID: 37544964 PMCID: PMC10541883 DOI: 10.1038/s41423-023-01069-y] [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: 11/10/2022] [Accepted: 07/17/2023] [Indexed: 08/08/2023] Open
Abstract
SATB1 (Special A-T rich Binding protein 1) is a cell type-specific factor that regulates the genetic network in developing T cells and neurons. In T cells, SATB1 is required for lineage commitment, VDJ recombination, development and maturation. Considering that its expression varies during B-cell differentiation, the involvement of SATB1 needs to be clarified in this lineage. Using a KO mouse model in which SATB1 was deleted from the pro-B-cell stage, we examined the consequences of SATB1 deletion in naive and activated B-cell subsets. Our model indicates first, unlike its essential function in T cells, that SATB1 is dispensable for B-cell development and the establishment of a broad IgH repertoire. Second, we show that SATB1 exhibits an ambivalent function in mature B cells, acting sequentially as a positive and negative regulator of Ig gene transcription in naive and activated cells, respectively. Third, our study indicates that the negative regulatory function of SATB1 in B cells extends to the germinal center response, in which this factor limits somatic hypermutation of Ig genes.
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Affiliation(s)
- Morgane Thomas
- Laboratoire Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Université de Limoges, CNRS Unité Mixte de Recherche 7276, Inserm Unité 1262, Limoges, France
- Laboratoire Suivi des Thérapies Innovantes, Institut de Génétique Humaine, UMR 9002 CNRS-UM, Montpellier, France
| | - Charlotte Bruzeau
- Laboratoire Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Université de Limoges, CNRS Unité Mixte de Recherche 7276, Inserm Unité 1262, Limoges, France
| | - Ophélie Alyssa Martin
- Laboratoire Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Université de Limoges, CNRS Unité Mixte de Recherche 7276, Inserm Unité 1262, Limoges, France
| | - Justine Pollet
- Laboratoire Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Université de Limoges, CNRS Unité Mixte de Recherche 7276, Inserm Unité 1262, Limoges, France
| | - Sébastien Bender
- Laboratoire Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Université de Limoges, CNRS Unité Mixte de Recherche 7276, Inserm Unité 1262, Limoges, France
- Centre Hospitalier Universitaire Dupuytren, Service d'Immunopathologie, Limoges, France
- Centre Hospitalier Universitaire de Limoges, Centre National de l'Amylose AL et Autres Maladies par Dépôt d'Immunoglobulines Monoclonales, Limoges, France
| | - Claire Carrion
- Laboratoire Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Université de Limoges, CNRS Unité Mixte de Recherche 7276, Inserm Unité 1262, Limoges, France
| | - Sandrine Le Noir
- Laboratoire Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Université de Limoges, CNRS Unité Mixte de Recherche 7276, Inserm Unité 1262, Limoges, France.
| | - Eric Pinaud
- Laboratoire Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Université de Limoges, CNRS Unité Mixte de Recherche 7276, Inserm Unité 1262, Limoges, France.
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11
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Wang M, Brandt LTL, Wang X, Russell H, Mitchell E, Kamimae-Lanning AN, Brown JM, Dingler FA, Garaycoechea JI, Isobe T, Kinston SJ, Gu M, Vassiliou GS, Wilson NK, Göttgens B, Patel KJ. Genotoxic aldehyde stress prematurely ages hematopoietic stem cells in a p53-driven manner. Mol Cell 2023; 83:2417-2433.e7. [PMID: 37348497 PMCID: PMC7614878 DOI: 10.1016/j.molcel.2023.05.035] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 04/18/2023] [Accepted: 05/25/2023] [Indexed: 06/24/2023]
Abstract
Aged hematopoietic stem cells (HSCs) display diminished self-renewal and a myeloid differentiation bias. However, the drivers and mechanisms that underpin this fundamental switch are not understood. HSCs produce genotoxic formaldehyde that requires protection by the detoxification enzymes ALDH2 and ADH5 and the Fanconi anemia (FA) DNA repair pathway. We find that the HSCs in young Aldh2-/-Fancd2-/- mice harbor a transcriptomic signature equivalent to aged wild-type HSCs, along with increased epigenetic age, telomere attrition, and myeloid-biased differentiation quantified by single HSC transplantation. In addition, the p53 response is vigorously activated in Aldh2-/-Fancd2-/- HSCs, while p53 deletion rescued this aged HSC phenotype. To further define the origins of the myeloid differentiation bias, we use a GFP genetic reporter to find a striking enrichment of Vwf+ myeloid and megakaryocyte-lineage-biased HSCs. These results indicate that metabolism-derived formaldehyde-DNA damage stimulates the p53 response in HSCs to drive accelerated aging.
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Affiliation(s)
- Meng Wang
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA; Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK; MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, UK.
| | - Laura T L Brandt
- MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, UK
| | - Xiaonan Wang
- Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK; School of Public Health, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Holly Russell
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Emily Mitchell
- Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK; Wellcome Sanger Institute, Hinxton, UK
| | - Ashley N Kamimae-Lanning
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Jill M Brown
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Felix A Dingler
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Juan I Garaycoechea
- Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Center, Utrecht, the Netherlands
| | - Tomoya Isobe
- Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
| | - Sarah J Kinston
- Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
| | - Muxin Gu
- Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
| | - George S Vassiliou
- Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
| | - Nicola K Wilson
- Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
| | - Berthold Göttgens
- Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
| | - Ketan J Patel
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
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12
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Keita S, Diop S, Lekiashvili S, Chabaane E, Nelson E, Strullu M, Arfeuille C, Guimiot F, Domet T, Duchez S, Evrard B, Darde T, Larghero J, Verhoeyen E, Cumano A, Macintyre EA, Kasraian Z, Jouen F, Goodhardt M, Garrick D, Chalmel F, Alhaj Hussen K, Canque B. Distinct subsets of multi-lymphoid progenitors support ontogeny-related changes in human lymphopoiesis. Cell Rep 2023; 42:112618. [PMID: 37294633 DOI: 10.1016/j.celrep.2023.112618] [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: 02/16/2023] [Revised: 04/13/2023] [Accepted: 05/22/2023] [Indexed: 06/11/2023] Open
Abstract
Changes in lymphocyte production patterns occurring across human ontogeny remain poorly defined. In this study, we demonstrate that human lymphopoiesis is supported by three waves of embryonic, fetal, and postnatal multi-lymphoid progenitors (MLPs) differing in CD7 and CD10 expression and their output of CD127-/+ early lymphoid progenitors (ELPs). In addition, our results reveal that, like the fetal-to-adult switch in erythropoiesis, transition to postnatal life coincides with a shift from multilineage to B lineage-biased lymphopoiesis and an increase in production of CD127+ ELPs, which persists until puberty. A further developmental transition is observed in elderly individuals whereby B cell differentiation bypasses the CD127+ compartment and branches directly from CD10+ MLPs. Functional analyses indicate that these changes are determined at the level of hematopoietic stem cells. These findings provide insights for understanding identity and function of human MLPs and the establishment and maintenance of adaptative immunity.
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Affiliation(s)
- Seydou Keita
- INSERM U976, Université de Paris, École Pratique des Hautes Études/PSL Research University, Institut de Recherche Saint Louis, Paris, France
| | - Samuel Diop
- INSERM U976, Université de Paris, École Pratique des Hautes Études/PSL Research University, Institut de Recherche Saint Louis, Paris, France; Laboratoire Cognitions Humaine et Artificielle (CHArt) EA 4004 FED 4246, École Pratique des Hautes Études/PSL Research University, Paris, France
| | - Shalva Lekiashvili
- INSERM U976, Université de Paris, École Pratique des Hautes Études/PSL Research University, Institut de Recherche Saint Louis, Paris, France
| | - Emna Chabaane
- INSERM U976, Université de Paris, École Pratique des Hautes Études/PSL Research University, Institut de Recherche Saint Louis, Paris, France
| | - Elisabeth Nelson
- INSERM U976, Université de Paris, École Pratique des Hautes Études/PSL Research University, Institut de Recherche Saint Louis, Paris, France
| | - Marion Strullu
- Service d'Hémato-Immunologie Pédiatrique, Inserm U1131, Université de Paris, Hôpital Robert-Debré, AP-HP, Paris, France
| | - Chloé Arfeuille
- Service d'Hémato-Immunologie Pédiatrique, Inserm U1131, Université de Paris, Hôpital Robert-Debré, AP-HP, Paris, France
| | - Fabien Guimiot
- INSERM UMR 1141, Service de Biologie du Développement, Université de Paris, Hôpital Robert-Debré, AP-HP, Paris, France
| | - Thomas Domet
- AP-HP, Hôpital Saint-Louis, Unité de Thérapie Cellulaire, CIC de Biothérapies, Université de Paris, INSERM U976, Paris, France
| | - Sophie Duchez
- Plateforme d'Imagerie et de Tri Cellulaire, Institut de Recherche Saint Louis, Paris, France
| | - Bertrand Evrard
- INSERM, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, University Rennes, Rennes, France
| | | | - Jerome Larghero
- AP-HP, Hôpital Saint-Louis, Unité de Thérapie Cellulaire, CIC de Biothérapies, Université de Paris, INSERM U976, Paris, France
| | - Els Verhoeyen
- CIRI, International Center for Infectiology Research, Université de Lyon, INSERM U1111, Lyon, France; Centre Mediterranéen de Médecine Moléculaire (C3M), INSERM U1065, Nice, France
| | - Ana Cumano
- Unit of Lymphopoiesis, Immunology Department, Institut Pasteur, Paris, France
| | - Elizabeth A Macintyre
- Institut Necker Enfants-Malades, Team 2, INSERM Unité 1151, Hôpital Necker Enfants-Malades, Laboratoire d'Onco-Hématologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Université de Paris, Paris, France
| | - Zeinab Kasraian
- Institut Necker Enfants-Malades, Team 2, INSERM Unité 1151, Hôpital Necker Enfants-Malades, Laboratoire d'Onco-Hématologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Université de Paris, Paris, France
| | - François Jouen
- Laboratoire Cognitions Humaine et Artificielle (CHArt) EA 4004 FED 4246, École Pratique des Hautes Études/PSL Research University, Paris, France
| | - Michele Goodhardt
- INSERM U976, Université de Paris, École Pratique des Hautes Études/PSL Research University, Institut de Recherche Saint Louis, Paris, France
| | - David Garrick
- INSERM U976, Université de Paris, École Pratique des Hautes Études/PSL Research University, Institut de Recherche Saint Louis, Paris, France
| | - Frederic Chalmel
- INSERM, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, University Rennes, Rennes, France
| | - Kutaiba Alhaj Hussen
- INSERM U976, Université de Paris, École Pratique des Hautes Études/PSL Research University, Institut de Recherche Saint Louis, Paris, France; Service de Biochimie, Université de Paris Saclay, Hôpital Paul Brousse, AP-HP, Paris, France.
| | - Bruno Canque
- INSERM U976, Université de Paris, École Pratique des Hautes Études/PSL Research University, Institut de Recherche Saint Louis, Paris, France.
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13
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Wilkes MC, Chae HD, Scanlon V, Cepika AM, Wentworth EP, Saxena M, Eskin A, Chen Z, Glader B, Grazia Roncarolo M, Nelson SF, Sakamoto KM. SATB1 Chromatin Loops Regulate Megakaryocyte/Erythroid Progenitor Expansion by Facilitating HSP70 and GATA1 Induction. Stem Cells 2023; 41:560-569. [PMID: 36987811 PMCID: PMC10267687 DOI: 10.1093/stmcls/sxad025] [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: 12/22/2022] [Accepted: 02/21/2023] [Indexed: 03/30/2023]
Abstract
Diamond Blackfan anemia (DBA) is an inherited bone marrow failure syndrome associated with severe anemia, congenital malformations, and an increased risk of developing cancer. The chromatin-binding special AT-rich sequence-binding protein-1 (SATB1) is downregulated in megakaryocyte/erythroid progenitors (MEPs) in patients and cell models of DBA, leading to a reduction in MEP expansion. Here we demonstrate that SATB1 expression is required for the upregulation of the critical erythroid factors heat shock protein 70 (HSP70) and GATA1 which accompanies MEP differentiation. SATB1 binding to specific sites surrounding the HSP70 genes promotes chromatin loops that are required for the induction of HSP70, which, in turn, promotes GATA1 induction. This demonstrates that SATB1, although gradually downregulated during myelopoiesis, maintains a biological function in early myeloid progenitors.
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Affiliation(s)
- Mark C Wilkes
- Division of Hematology/Oncology, Department of Pediatrics, Stanford University, Stanford, CA, USA
| | - Hee-Don Chae
- Division of Hematology/Oncology, Department of Pediatrics, Stanford University, Stanford, CA, USA
| | - Vanessa Scanlon
- Department of Laboratory Medicine, Yale Stem Cell Center, Yale Cooperative Center of Excellence in Hematology, Yale School of Medicine, New Haven, CT, USA
| | - Alma-Martina Cepika
- Institute for Stem Cell Biology and Regenerative Medicine, Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Ethan P Wentworth
- Division of Hematology/Oncology, Department of Pediatrics, Stanford University, Stanford, CA, USA
| | - Mallika Saxena
- Division of Hematology/Oncology, Department of Pediatrics, Stanford University, Stanford, CA, USA
| | - Ascia Eskin
- Department of Pathology and Laboratory Medicine¸ David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Zugen Chen
- Department of Pathology and Laboratory Medicine¸ David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Bert Glader
- Division of Hematology/Oncology, Department of Pediatrics, Stanford University, Stanford, CA, USA
| | - Maria Grazia Roncarolo
- Institute for Stem Cell Biology and Regenerative Medicine, Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Stanley F Nelson
- Department of Pathology and Laboratory Medicine¸ David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Kathleen M Sakamoto
- Division of Hematology/Oncology, Department of Pediatrics, Stanford University, Stanford, CA, USA
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14
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Wang B, Ji L, Bian Q. SATB1 regulates 3D genome architecture in T cells by constraining chromatin interactions surrounding CTCF-binding sites. Cell Rep 2023; 42:112323. [PMID: 37000624 DOI: 10.1016/j.celrep.2023.112323] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 01/20/2023] [Accepted: 03/16/2023] [Indexed: 04/01/2023] Open
Abstract
Special AT-rich sequence binding protein 1 (SATB1) has long been proposed to act as a global chromatin loop organizer in T cells. However, the exact functions of SATB1 in spatial genome organization remain elusive. Here we show that the depletion of SATB1 in human and murine T cells leads to transcriptional dysregulation for genes involved in T cell activation, as well as alterations of 3D genome architecture at multiple levels, including compartments, topologically associating domains, and loops. Importantly, SATB1 extensively colocalizes with CTCF throughout the genome. Depletion of SATB1 leads to increased chromatin contacts among and across the SATB1/CTCF co-occupied sites, thereby affecting the transcription of critical regulators of T cell activation. The loss of SATB1 does not affect CTCF occupancy but significantly reduces the retention of CTCF in the nuclear matrix. Collectively, our data show that SATB1 contributes to 3D genome organization by constraining chromatin topology surrounding CTCF-binding sites.
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Affiliation(s)
- Bao Wang
- Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China; Shanghai Institute of Precision Medicine, Shanghai 200125, China
| | - Luzhang Ji
- Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China; Shanghai Institute of Precision Medicine, Shanghai 200125, China
| | - Qian Bian
- Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China; Shanghai Institute of Precision Medicine, Shanghai 200125, China; Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
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15
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Lieske A, Agyeman-Duah E, Selich A, Dörpmund N, Talbot SR, Schambach A, Maetzig T. A pro B cell population forms the apex of the leukemic hierarchy in Hoxa9/Meis1-dependent AML. Leukemia 2023; 37:79-90. [PMID: 36517672 PMCID: PMC9883166 DOI: 10.1038/s41375-022-01775-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 11/21/2022] [Accepted: 11/23/2022] [Indexed: 12/15/2022]
Abstract
Relapse is a major challenge to therapeutic success in acute myeloid leukemia (AML) and can be partly associated with heterogeneous leukemic stem cell (LSC) properties. In the murine Hoxa9/Meis1-dependent (H9M) AML model, LSC potential lies in three defined immunophenotypes, including Lin-cKit+ progenitor cells (Lin-), Gr1+CD11b+cKit+ myeloid cells, and lymphoid cells (Lym+). Previous reports demonstrated their interconversion and distinct drug sensitivities. In contrast, we here show that H9M AML is hierarchically organized. We, therefore, tracked the developmental potential of LSC phenotypes. This unexpectedly revealed a substantial fraction of Lin- LSCs that failed to regenerate Lym+ LSCs, and that harbored reduced leukemogenic potential. However, Lin- LSCs capable of producing Lym+ LSCs as well as Lym+ LSCs triggered rapid disease development suggestive of their high relapse-driving potential. Transcriptional analyses revealed that B lymphoid master regulators, including Sox4 and Bach2, correlated with Lym+ LSC development and presumably aggressive disease. Lentiviral overexpression of Sox4 and Bach2 induced dedifferentiation of H9M cells towards a lineage-negative state in vitro as the first step of lineage conversion. This work suggests that the potency to initiate a partial B lymphoid primed transcriptional program as present in infant AML correlates with aggressive disease and governs the H9M LSC hierarchy.
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Affiliation(s)
- Anna Lieske
- Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany
- Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
| | - Eric Agyeman-Duah
- Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
| | - Anton Selich
- Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany
| | - Nicole Dörpmund
- Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
| | - Steven R Talbot
- Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany
| | - Axel Schambach
- Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany
- Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Tobias Maetzig
- Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
- Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
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16
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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: 21] [Impact Index Per Article: 7.0] [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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17
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Arif T. Lysosomes and Their Role in Regulating the Metabolism of Hematopoietic Stem Cells. BIOLOGY 2022; 11:1410. [PMID: 36290314 PMCID: PMC9598322 DOI: 10.3390/biology11101410] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/22/2022] [Accepted: 09/23/2022] [Indexed: 11/26/2022]
Abstract
Hematopoietic stem cells (HSCs) have the capacity to renew blood cells at all stages of life and are largely quiescent at a steady state. It is essential to understand the processes that govern quiescence in HSCs to enhance bone marrow transplantation. It is hypothesized that in their quiescent state, HSCs primarily use glycolysis for energy production rather than mitochondrial oxidative phosphorylation (OXPHOS). In addition, the HSC switch from quiescence to activation occurs along a continuous developmental path that is driven by metabolism. Specifying the metabolic regulation pathway of HSC quiescence will provide insights into HSC homeostasis for therapeutic application. Therefore, understanding the metabolic demands of HSCs at a steady state is key to developing innovative hematological therapeutics. Lysosomes are the major degradative organelle in eukaryotic cells. Catabolic, anabolic, and lysosomal function abnormalities are connected to an expanding list of diseases. In recent years, lysosomes have emerged as control centers of cellular metabolism, particularly in HSC quiescence, and essential regulators of cell signaling have been found on the lysosomal membrane. In addition to autophagic processes, lysosomal activities have been shown to be crucial in sustaining quiescence by restricting HSCs access to a nutritional reserve essential for their activation into the cell cycle. Lysosomal activity may preserve HSC quiescence by altering glycolysis-mitochondrial biogenesis. The understanding of HSC metabolism has significantly expanded over the decade, revealing previously unknown requirements of HSCs in both their dividing (active) and quiescent states. Therefore, understanding the role of lysosomes in HSCs will allow for the development of innovative treatment methods based on HSCs to fight clonal hematopoiesis and HSC aging.
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Affiliation(s)
- Tasleem Arif
- Department of Cell, Developmental & Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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18
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Chromatin organizer SATB1 controls the cell identity of CD4 + CD8 + double-positive thymocytes by regulating the activity of super-enhancers. Nat Commun 2022; 13:5554. [PMID: 36138028 PMCID: PMC9500044 DOI: 10.1038/s41467-022-33333-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 09/14/2022] [Indexed: 11/19/2022] Open
Abstract
CD4+ and CD8+ double-positive (DP) thymocytes play a crucial role in T cell development in the thymus. DP cells rearrange the T cell receptor gene Tcra to generate T cell receptors with TCRβ. DP cells differentiate into CD4 or CD8 single-positive (SP) thymocytes, regulatory T cells, or invariant nature kill T cells (iNKT) in response to TCR signaling. Chromatin organizer SATB1 is highly expressed in DP cells and is essential in regulating Tcra rearrangement and differentiation of DP cells. Here we explored the mechanism of SATB1 orchestrating gene expression in DP cells. Single-cell RNA sequencing shows that Satb1 deletion changes the cell identity of DP thymocytes and down-regulates genes specifically and highly expressed in DP cells. Super-enhancers regulate the expressions of DP-specific genes, and our Hi-C data show that SATB1 deficiency in thymocytes reduces super-enhancer activity by specifically decreasing interactions among super-enhancers and between super-enhancers and promoters. Our results reveal that SATB1 plays a critical role in thymocyte development to promote the establishment of DP cell identity by globally regulating super-enhancers of DP cells at the chromatin architectural level.
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19
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Ding P, Tan Q, Wei Z, Chen Q, Wang C, Qi L, Wen L, Zhang C, Yao C. Toll-like receptor 9 deficiency induces osteoclastic bone loss via gut microbiota-associated systemic chronic inflammation. Bone Res 2022; 10:42. [PMID: 35624094 PMCID: PMC9142495 DOI: 10.1038/s41413-022-00210-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 02/06/2022] [Accepted: 03/13/2022] [Indexed: 02/08/2023] Open
Abstract
Toll-like receptors (TLRs) play pivotal roles in inflammation and provide important links between the immune and skeletal systems. Although the activation of TLRs may affect osteoclast differentiation and bone metabolism, whether and how TLRs are required for normal bone remodeling remains to be fully explored. In the current study, we show for the first time that TLR9-/- mice exhibit a low bone mass and low-grade systemic chronic inflammation, which is characterized by the expansion of CD4+ T cells and increased levels of inflammatory cytokines, including TNFα, RANKL, and IL1β. The increased levels of these cytokines significantly promote osteoclastogenesis and induce bone loss. Importantly, TLR9 deletion alters the gut microbiota, and this dysbiosis is the basis of the systemic inflammation and bone loss observed in TLR9-/- mice. Furthermore, through single-cell RNA sequencing, we identified myeloid-biased hematopoiesis in the bone marrow of TLR9-/- mice and determined that the increase in myelopoiesis, likely caused by the adaptation of hematopoietic stem cells to systemic inflammation, also contributes to inflammation-induced osteoclastogenesis and subsequent bone loss in TLR9-/- mice. Thus, our study provides novel evidence that TLR9 signaling connects the gut microbiota, immune system, and bone and is critical in maintaining the homeostasis of inflammation, hematopoiesis, and bone metabolism under normal conditions.
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Affiliation(s)
- Peng Ding
- Department of Orthopedic Surgery, Shanghai Jiaotong University affiliated Sixth People's Hospital, Shanghai, China
| | - Qiyuan Tan
- Department of Endocrinology and Metabolism, Shanghai Jiaotong University affiliated Sixth People's Hospital, Shanghai, China
| | - Zhanying Wei
- Department of Osteoporosis and Skeletal Disorders, Shanghai Jiaotong University affiliated Sixth People's Hospital, Shanghai, China
| | - Qiyu Chen
- Department of Orthopedic Surgery, Shanghai Jiaotong University affiliated Sixth People's Hospital, Shanghai, China
| | - Chun Wang
- Department of Osteoporosis and Skeletal Disorders, Shanghai Jiaotong University affiliated Sixth People's Hospital, Shanghai, China
| | - Luyue Qi
- Department of Endocrinology and Metabolism, Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Li Wen
- Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, USA
| | - Changqing Zhang
- Department of Orthopedic Surgery, Shanghai Jiaotong University affiliated Sixth People's Hospital, Shanghai, China.
| | - Chen Yao
- Department of Orthopedic Surgery, Shanghai Jiaotong University affiliated Sixth People's Hospital, Shanghai, China.
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20
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Wilkes MC, Scanlon V, Shibuya A, Celika AM, Eskin A, Chen Z, Narla A, Glader B, Roncarolo MG, Nelson SF, Sakamoto KM. Downregulation of SATB1 by miRNAs Reduces Megakaryocyte/Erythroid Progenitor Expansion in pre-clinical models of Diamond Blackfan Anemia. Exp Hematol 2022; 111:66-78. [PMID: 35460833 PMCID: PMC9255422 DOI: 10.1016/j.exphem.2022.04.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 04/12/2022] [Accepted: 04/13/2022] [Indexed: 11/27/2022]
Abstract
Diamond Blackfan Anemia (DBA) is an inherited bone marrow failure syndrome that is associated with anemia, congenital anomalies, and cancer predisposition. It is categorized as a ribosomopathy, because over 80% or patients have haploinsufficiency of either a small or large subunit-associated ribosomal protein (RP). The erythroid pathology is predominantly due to a block and delay in early committed erythropoiesis with reduced Megakaryocyte/Erythroid Progenitors (MEPs). To understand the molecular pathways leading to pathogenesis of DBA, we performed RNA-seq on mRNA and miRNA from RPS19-deficient human hematopoietic stem and progenitor cells (HSPCs) and compared an existing database documenting transcript fluctuations across stages of early normal erythropoiesis. We determined the chromatin regulator, SATB1 was prematurely downregulated through the coordinated action of upregulated miR-34 and miR-30 during differentiation in ribosomal-insufficiency. Restoration of SATB1 rescued MEP expansion, leading to a modest improvement in erythroid and megakaryocyte expansion in RPS19-insufficiency. However, SATB1 expression did not impact expansion of committed erythroid progenitors, indicating ribosomal insufficiency impacts multiple stages during erythroid differentiation.
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Affiliation(s)
- Mark C Wilkes
- Division of Hematology/Oncology, Department of Pediatrics, Stanford University, Stanford, California 94305, USA
| | - Vanessa Scanlon
- Yale Stem Cell Center, Department of Pathology, Yale School of Medicine, Yale University, New Haven, Connecticut 06509, USA
| | - Aya Shibuya
- Division of Hematology/Oncology, Department of Pediatrics, Stanford University, Stanford, California 94305, USA
| | - Alma-Martina Celika
- Institute for Stem Cell Biology and Regenerative Medicine, Department of Genetics, Stanford University School of Medicine, Stanford, California 94305 USA
| | - Ascia Eskin
- Department of Pathology and Laboratory Medicine¸ David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - Zugen Chen
- Department of Pathology and Laboratory Medicine¸ David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - Anupama Narla
- Division of Hematology/Oncology, Department of Pediatrics, Stanford University, Stanford, California 94305, USA
| | - Bert Glader
- Division of Hematology/Oncology, Department of Pediatrics, Stanford University, Stanford, California 94305, USA
| | - Maria Grazia Roncarolo
- Institute for Stem Cell Biology and Regenerative Medicine, Department of Genetics, Stanford University School of Medicine, Stanford, California 94305 USA
| | - Stanley F Nelson
- Department of Pathology and Laboratory Medicine¸ David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - Kathleen M Sakamoto
- Division of Hematology/Oncology, Department of Pediatrics, Stanford University, Stanford, California 94305, USA.
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21
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Ozawa T, Fujii K, Sudo T, Doi Y, Nakai R, Shingai Y, Ueda T, Baba Y, Hosen N, Yokota T. Special AT-Rich Sequence-Binding Protein 1 Supports Survival and Maturation of Naive B Cells Stimulated by B Cell Receptors. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 208:1937-1946. [PMID: 35379742 DOI: 10.4049/jimmunol.2101097] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 02/09/2022] [Indexed: 11/19/2022]
Abstract
Epigenetic mechanisms underpin the elaborate activities of essential transcription factors in lymphocyte development. Special AT-rich sequence-binding protein 1 (SATB1) is a chromatin remodeler that orchestrates the spatial and temporal actions of transcription factors. Previous studies have revealed the significance of SATB1 in T cell lineage. However, whether and how SATB1 controls B cell lineage development is yet to be clarified. In this study, we show that SATB1 is an important factor during splenic B cell maturation. By analyzing SATB1/Tomato reporter mice, we determined the dynamic fluctuation of SATB1 expression in the B cell lineage. Although SATB1 expression decreased to minimal levels during B cell differentiation in the bone marrow, it resurged markedly in naive B cells in the spleen. The expression was dramatically downregulated upon Ag-induced activation. Splenic naive B cells were subdivided into two categories, namely SATB1high and SATB1-/low, according to their SATB1 expression levels. SATB1high naive B cells were less susceptible to death and greater proliferative than were SATB1-/low cells during incubation with an anti-IgM Ab. Additionally, SATB1high cells tended to induce the expression of MHC class II, CD86, and CD83. Accordingly, naive B cells from B lineage-specific SATB1 conditional knockout mice were more susceptible to apoptosis than that in the control group upon anti-IgM Ab stimulation in vitro. Furthermore, conditional knockout mice were less capable of producing Ag-specific B cells after immunization. Collectively, our findings suggest that SATB1 expression increases in naive B cells and plays an important role in their survival and maturation.
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Affiliation(s)
- Takayuki Ozawa
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Kentaro Fujii
- Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka, Japan
| | - Takao Sudo
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yukiko Doi
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Ritsuko Nakai
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yasuhiro Shingai
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Tomoaki Ueda
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yoshihiro Baba
- Division of Immunology and Genome Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Naoki Hosen
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan.,Laboratory of Cellular Immunotherapy, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan; and.,Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan
| | - Takafumi Yokota
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan;
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22
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Tanaka Y, Onozato M, Mikami T, Kohwi-Shigematsu T, Fukushima T, Kondo M. Increased Indoleamine 2,3-Dioxygenase Levels at the Onset of Sjögren's Syndrome in SATB1-Conditional Knockout Mice. Int J Mol Sci 2021; 22:10125. [PMID: 34576286 PMCID: PMC8468825 DOI: 10.3390/ijms221810125] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 09/10/2021] [Accepted: 09/17/2021] [Indexed: 01/16/2023] Open
Abstract
Sjögren's syndrome (SS) is a chronic autoimmune disease characterized by dysfunction of salivary and lacrimal glands, resulting in xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes). Autoantibodies, such as anti-SSA and anti-SSB antibodies, are hallmarks and important diagnostic factors for SS. In our previous study, we demonstrated that SS-like xerostomia was observed in SATB1 conditional knockout (SATB1cKO) mice, in which the floxed SATB1 gene was specifically deleted in hematopoietic cells as early as 4 weeks of age. In these mice, autoantibodies were not detected until 8 weeks of age in SATB1cKO mice, although exocrine gland function reached its lowest at this age. Therefore, other markers may be necessary for the diagnosis of SS in the early phase. Here, we found that mRNA expression of the interferonγ (IFN-γ) gene and the IFN-responsive indoleamine 2,3-dioxygenase (IDO) gene is upregulated in the salivary glands of SATB1cKO mice after 3 and 4 weeks of age, respectively. We detected l-kynurenine (l-KYN), an intermediate of l-tryptophan (l-Trp) metabolism mediated by IDO, in the serum of SATB1cKO mice after 4 weeks of age. In addition, the upregulation of IDO expression was significantly suppressed by the administration of IFN-γ neutralizing antibodies in SATB1cKO mice. These results suggest that the induction of IFN-dependent IDO expression is an initial event that occurs immediately after the onset of SS in SATB1cKO mice. These results also imply that serum l-KYN could be used as a marker for SS diagnosis in the early phases of the disease before autoantibodies are detectable.
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Grants
- JP24390121 to M.K. and Y.T., JP26670240 to M.K., 18K07075 to Y.T. MEXT/JSPS KAKENHI
- Strategic Research Foundation Grant-aided Project for Private Schools at Heisei 26th (S1411015 ) Ministry of Education, Culture, Sports, Science and Technology
- Research Promotion Grant (14-02) Toho University Graduate School of Medicine
- Project Research Grants (23-4 and 26-22 to Y.T.) Toho University School of Medicine
- N/A Public Foundation of the Vaccination Research Center
- Joint research Fund to M.K., Y.T., M.O. and K.F. Toho University
- Initiative for Realizing Diversity in the Research Environment Japan Science and Technology Agency
- R37CA39681 to T.K.-S. NIH HHS
- Grant-in Aid for Private University Research Branding Project Ministry of Education, Culture, Sports, Science and Technology
- Grant for Research Initiative Program Toho University
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Affiliation(s)
- Yuriko Tanaka
- Department of Molecular Immunology, Toho University School of Medicine, Tokyo 143-8540, Japan;
| | - Mayu Onozato
- Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Toho University, Chiba 274-8510, Japan; (M.O.); (T.F.)
| | - Tetuo Mikami
- Department of Pathology, Toho University School of Medicine, Tokyo 143-8540, Japan;
| | - Terumi Kohwi-Shigematsu
- Department of Orofacial Sciences, University of California San Francisco School of Dentistry, San Francisco, CA 94143, USA;
| | - Takeshi Fukushima
- Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Toho University, Chiba 274-8510, Japan; (M.O.); (T.F.)
| | - Motonari Kondo
- Department of Molecular Immunology, Toho University School of Medicine, Tokyo 143-8540, Japan;
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23
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Opportunities and Challenges in Stem Cell Aging. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1341:143-175. [PMID: 33748933 DOI: 10.1007/5584_2021_624] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Studying aging, as a physiological process that can cause various pathological phenotypes, has attracted lots of attention due to its increasing burden and prevalence. Therefore, understanding its mechanism to find novel therapeutic alternatives for age-related disorders such as neurodegenerative and cardiovascular diseases is essential. Stem cell senescence plays an important role in aging. In the context of the underlying pathways, mitochondrial dysfunction, epigenetic and genetic alterations, and other mechanisms have been studied and as a consequence, several rejuvenation strategies targeting these mechanisms like pharmaceutical interventions, genetic modification, and cellular reprogramming have been proposed. On the other hand, since stem cells have great potential for disease modeling, they have been useful for representing aging and its associated disorders. Accordingly, the main mechanisms of senescence in stem cells and promising ways of rejuvenation, along with some examples of stem cell models for aging are introduced and discussed. This review aims to prepare a comprehensive summary of the findings by focusing on the most recent ones to shine a light on this area of research.
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24
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Yang D, de Haan G. Inflammation and Aging of Hematopoietic Stem Cells in Their Niche. Cells 2021; 10:1849. [PMID: 34440618 PMCID: PMC8391820 DOI: 10.3390/cells10081849] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 07/15/2021] [Accepted: 07/16/2021] [Indexed: 12/30/2022] Open
Abstract
Hematopoietic stem cells (HSCs) sustain the lifelong production of all blood cell lineages. The functioning of aged HSCs is impaired, including a declined repopulation capacity and myeloid and platelet-restricted differentiation. Both cell-intrinsic and microenvironmental extrinsic factors contribute to HSC aging. Recent studies highlight the emerging role of inflammation in contributing to HSC aging. In this review, we summarize the recent finding of age-associated changes of HSCs and the bone marrow niche in which they lodge, and discuss how inflammation may drive HSC aging.
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Affiliation(s)
- Daozheng Yang
- European Research Institute for the Biology of Ageing (ERIBA), University Medical Center Groningen, University of Groningen, 9713 AV Groningen, The Netherlands;
| | - Gerald de Haan
- European Research Institute for the Biology of Ageing (ERIBA), University Medical Center Groningen, University of Groningen, 9713 AV Groningen, The Netherlands;
- Sanquin Research, Landsteiner Laboratory, Amsterdam UMC, 1006 AD Amsterdam, The Netherlands
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25
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Abstract
The regulatory circuits that define developmental decisions of thymocytes are still incompletely resolved. SATB1 protein is predominantly expressed at the CD4+CD8+cell stage exerting its broad transcription regulation potential with both activatory and repressive roles. A series of post-translational modifications and the presence of potential SATB1 protein isoforms indicate the complexity of its regulatory potential. The most apparent mechanism of its involvement in gene expression regulation is via the orchestration of long-range chromatin loops between genes and their regulatory elements. Multiple SATB1 perturbations in mice uncovered a link to autoimmune diseases while clinical investigations on cancer research uncovered that SATB1 has a promoting role in several types of cancer and can be used as a prognostic biomarker. SATB1 is a multivalent tissue-specific factor with a broad and yet undetermined regulatory potential. Future investigations on this protein could further uncover T cell-specific regulatory pathways and link them to (patho)physiology.
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Affiliation(s)
- Tomas Zelenka
- Department of Biology, University of Crete , Heraklion, Crete, Greece.,Gene Regulation & Genomics, Institute of Molecular Biology and Biotechnology-Foundation for Research and Technology Hellas , Heraklion, Crete, Greece
| | - Charalampos Spilianakis
- Department of Biology, University of Crete , Heraklion, Crete, Greece.,Gene Regulation & Genomics, Institute of Molecular Biology and Biotechnology-Foundation for Research and Technology Hellas , Heraklion, Crete, Greece
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26
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Ho TT, Dellorusso PV, Verovskaya EV, Bakker ST, Flach J, Smith LK, Ventura PB, Lansinger OM, Hérault A, Zhang SY, Kang YA, Mitchell CA, Villeda SA, Passegué E. Aged hematopoietic stem cells are refractory to bloodborne systemic rejuvenation interventions. J Exp Med 2021; 218:212183. [PMID: 34032859 PMCID: PMC8155813 DOI: 10.1084/jem.20210223] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 03/24/2021] [Accepted: 04/15/2021] [Indexed: 01/13/2023] Open
Abstract
While young blood can restore many aged tissues, its effects on the aged blood system itself and old hematopoietic stem cells (HSCs) have not been determined. Here, we used transplantation, parabiosis, plasma transfer, exercise, calorie restriction, and aging mutant mice to understand the effects of age-regulated systemic factors on HSCs and their bone marrow (BM) niche. We found that neither exposure to young blood, nor long-term residence in young niches after parabiont separation, nor direct heterochronic transplantation had any observable rejuvenating effects on old HSCs. Likewise, exercise and calorie restriction did not improve old HSC function, nor old BM niches. Conversely, young HSCs were not affected by systemic pro-aging conditions, and HSC function was not impacted by mutations influencing organismal aging in established long-lived or progeroid genetic models. Therefore, the blood system that carries factors with either rejuvenating or pro-aging properties for many other tissues is itself refractory to those factors.
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Affiliation(s)
- Theodore T Ho
- The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Medicine, Hematology/Oncology Division, University of California, San Francisco, San Francisco, CA
| | - Paul V Dellorusso
- Columbia Stem Cell Initiative, Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY
| | - Evgenia V Verovskaya
- The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Medicine, Hematology/Oncology Division, University of California, San Francisco, San Francisco, CA.,Columbia Stem Cell Initiative, Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY
| | - Sietske T Bakker
- The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Medicine, Hematology/Oncology Division, University of California, San Francisco, San Francisco, CA
| | - Johanna Flach
- The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Medicine, Hematology/Oncology Division, University of California, San Francisco, San Francisco, CA
| | - Lucas K Smith
- Department of Anatomy, University of California, San Francisco, San Francisco, CA
| | - Patrick B Ventura
- Department of Anatomy, University of California, San Francisco, San Francisco, CA
| | - Olivia M Lansinger
- The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Medicine, Hematology/Oncology Division, University of California, San Francisco, San Francisco, CA
| | - Aurélie Hérault
- The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Medicine, Hematology/Oncology Division, University of California, San Francisco, San Francisco, CA
| | - Si Yi Zhang
- The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Medicine, Hematology/Oncology Division, University of California, San Francisco, San Francisco, CA
| | - Yoon-A Kang
- The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Medicine, Hematology/Oncology Division, University of California, San Francisco, San Francisco, CA.,Columbia Stem Cell Initiative, Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY
| | - Carl A Mitchell
- Columbia Stem Cell Initiative, Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY
| | - Saul A Villeda
- Department of Anatomy, University of California, San Francisco, San Francisco, CA
| | - Emmanuelle Passegué
- The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Medicine, Hematology/Oncology Division, University of California, San Francisco, San Francisco, CA.,Columbia Stem Cell Initiative, Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY
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27
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Ota M, Nagafuchi Y, Hatano H, Ishigaki K, Terao C, Takeshima Y, Yanaoka H, Kobayashi S, Okubo M, Shirai H, Sugimori Y, Maeda J, Nakano M, Yamada S, Yoshida R, Tsuchiya H, Tsuchida Y, Akizuki S, Yoshifuji H, Ohmura K, Mimori T, Yoshida K, Kurosaka D, Okada M, Setoguchi K, Kaneko H, Ban N, Yabuki N, Matsuki K, Mutoh H, Oyama S, Okazaki M, Tsunoda H, Iwasaki Y, Sumitomo S, Shoda H, Kochi Y, Okada Y, Yamamoto K, Okamura T, Fujio K. Dynamic landscape of immune cell-specific gene regulation in immune-mediated diseases. Cell 2021; 184:3006-3021.e17. [PMID: 33930287 DOI: 10.1016/j.cell.2021.03.056] [Citation(s) in RCA: 183] [Impact Index Per Article: 45.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 01/25/2021] [Accepted: 03/28/2021] [Indexed: 02/07/2023]
Abstract
Genetic studies have revealed many variant loci that are associated with immune-mediated diseases. To elucidate the disease pathogenesis, it is essential to understand the function of these variants, especially under disease-associated conditions. Here, we performed a large-scale immune cell gene-expression analysis, together with whole-genome sequence analysis. Our dataset consists of 28 distinct immune cell subsets from 337 patients diagnosed with 10 categories of immune-mediated diseases and 79 healthy volunteers. Our dataset captured distinctive gene-expression profiles across immune cell types and diseases. Expression quantitative trait loci (eQTL) analysis revealed dynamic variations of eQTL effects in the context of immunological conditions, as well as cell types. These cell-type-specific and context-dependent eQTLs showed significant enrichment in immune disease-associated genetic variants, and they implicated the disease-relevant cell types, genes, and environment. This atlas deepens our understanding of the immunogenetic functions of disease-associated variants under in vivo disease conditions.
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Affiliation(s)
- Mineto Ota
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Department of Functional Genomics and Immunological Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
| | - Yasuo Nagafuchi
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Department of Functional Genomics and Immunological Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
| | - Hiroaki Hatano
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
| | - Kazuyoshi Ishigaki
- Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Chikashi Terao
- Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan
| | - Yusuke Takeshima
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Department of Functional Genomics and Immunological Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
| | - Haruyuki Yanaoka
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
| | - Satomi Kobayashi
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
| | - Mai Okubo
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
| | - Harumi Shirai
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
| | - Yusuke Sugimori
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
| | - Junko Maeda
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
| | - Masahiro Nakano
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
| | - Saeko Yamada
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
| | - Ryochi Yoshida
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
| | - Haruka Tsuchiya
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
| | - Yumi Tsuchida
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
| | - Shuji Akizuki
- Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
| | - Hajime Yoshifuji
- Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
| | - Koichiro Ohmura
- Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
| | - Tsuneyo Mimori
- Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
| | - Ken Yoshida
- Division of Rheumatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 105-8461, Japan
| | - Daitaro Kurosaka
- Division of Rheumatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 105-8461, Japan
| | - Masato Okada
- Immuno-Rheumatology Center, St. Luke's International Hospital, Tokyo 104-8560, Japan
| | - Keigo Setoguchi
- Division of Collagen Disease, Department of Medicine, Tokyo Metropolitan Komagome Hospital, Tokyo 113-0021, Japan
| | - Hiroshi Kaneko
- Division of Rheumatic Diseases, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
| | - Nobuhiro Ban
- Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan
| | - Nami Yabuki
- Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan
| | - Kosuke Matsuki
- Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan
| | - Hironori Mutoh
- Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan
| | - Sohei Oyama
- Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan
| | - Makoto Okazaki
- Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan
| | - Hiroyuki Tsunoda
- Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan
| | - Yukiko Iwasaki
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
| | - Shuji Sumitomo
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
| | - Hirofumi Shoda
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
| | - Yuta Kochi
- Department of Genomic Function and Diversity, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan; Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan
| | - Yukinori Okada
- Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Kazuhiko Yamamoto
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan
| | - Tomohisa Okamura
- Department of Functional Genomics and Immunological Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
| | - Keishi Fujio
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
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28
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A comprehensive transcriptome signature of murine hematopoietic stem cell aging. Blood 2021; 138:439-451. [PMID: 33876187 DOI: 10.1182/blood.2020009729] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 04/02/2021] [Indexed: 01/11/2023] Open
Abstract
We surveyed 16 published and unpublished data sets to determine whether a consistent pattern of transcriptional deregulation in aging murine hematopoietic stem cells (HSC) exists. Despite substantial heterogeneity between individual studies, we uncovered a core and robust HSC aging signature. We detected increased transcriptional activation in aged HSCs, further confirmed by chromatin accessibility analysis. Unexpectedly, using two independent computational approaches, we established that deregulated aging genes consist largely of membrane-associated transcripts, including many cell surface molecules previously not associated with HSC biology. We show that Selp, the most consistent deregulated gene, is not merely a marker for aged HSCs but is associated with HSC functional decline. Additionally, single-cell transcriptomics analysis revealed increased heterogeneity of the aged HSC pool. We identify the presence of transcriptionally "young-like" HSCs in aged bone marrow. We share our results as an online resource and demonstrate its utility by confirming that exposure to sympathomimetics, and deletion of Dnmt3a/b, molecularly resembles HSC rejuvenation or aging, respectively.
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29
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Zilenaite D, Rasmusson A, Augulis R, Besusparis J, Laurinaviciene A, Plancoulaine B, Ostapenko V, Laurinavicius A. Independent Prognostic Value of Intratumoral Heterogeneity and Immune Response Features by Automated Digital Immunohistochemistry Analysis in Early Hormone Receptor-Positive Breast Carcinoma. Front Oncol 2020; 10:950. [PMID: 32612954 PMCID: PMC7308549 DOI: 10.3389/fonc.2020.00950] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Accepted: 05/14/2020] [Indexed: 12/11/2022] Open
Abstract
Immunohistochemistry (IHC) for ER, PR, HER2, and Ki67 is used to predict outcome and therapy response in breast cancer patients. The current IHC assessment, visual or digital, is based mostly on global biomarker expression levels in the tissue sample. In our study, we explored the prognostic value of digital image analysis of conventional breast cancer IHC biomarkers supplemented with their intratumoral heterogeneity and tissue immune response indicators. Surgically excised tumor samples from 101 female patients with hormone receptor-positive breast cancer (HRBC) were stained for ER, PR, HER2, Ki67, SATB1, CD8, and scanned at 20x. Digital image analysis was performed using the HALO™ platform. Subsequently, hexagonal tiling was used to compute intratumoral heterogeneity indicators for ER, PR and Ki67 expression. Multiple Cox regression analysis revealed three independent predictors of the patient's overall survival: Haralick's texture entropy of PR (HR = 0.19, p = 0.0005), Ki67 Ashman's D bimodality (HR = 3.0, p = 0.01), and CD8+SATB1+ cell density in tumor tissue (HR = 0.32, p = 0.02). Remarkably, the PR and Ki67 intratumoral heterogeneity indicators were prognostically more informative than the rates of their expression. In particular, a distinct non-linear relationship between the rate of PR expression and its intratumoral heterogeneity was observed and revealed a non-linear prognostic effect of PR expression. The independent prognostic significance of CD8+SATB1+ cells infiltrating the tumor could indicate their role in anti-tumor immunity. In conclusion, we suggest that prognostic modeling, based entirely on the computational image-based IHC biomarkers, is possible in HRBC patients. The intratumoral heterogeneity and immune response indicators outperformed both conventional breast cancer IHC and clinicopathological variables while markedly increasing the power of the model.
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Affiliation(s)
- Dovile Zilenaite
- Department of Pathology, Forensic Medicine and Pharmacology, Faculty of Medicine, Institute of Biomedical Sciences, Vilnius University, Vilnius, Lithuania.,National Centre of Pathology, Affiliate of Vilnius University Hospital Santaros Clinics, Vilnius, Lithuania
| | - Allan Rasmusson
- Department of Pathology, Forensic Medicine and Pharmacology, Faculty of Medicine, Institute of Biomedical Sciences, Vilnius University, Vilnius, Lithuania.,National Centre of Pathology, Affiliate of Vilnius University Hospital Santaros Clinics, Vilnius, Lithuania
| | - Renaldas Augulis
- Department of Pathology, Forensic Medicine and Pharmacology, Faculty of Medicine, Institute of Biomedical Sciences, Vilnius University, Vilnius, Lithuania.,National Centre of Pathology, Affiliate of Vilnius University Hospital Santaros Clinics, Vilnius, Lithuania
| | - Justinas Besusparis
- Department of Pathology, Forensic Medicine and Pharmacology, Faculty of Medicine, Institute of Biomedical Sciences, Vilnius University, Vilnius, Lithuania.,National Centre of Pathology, Affiliate of Vilnius University Hospital Santaros Clinics, Vilnius, Lithuania
| | - Aida Laurinaviciene
- Department of Pathology, Forensic Medicine and Pharmacology, Faculty of Medicine, Institute of Biomedical Sciences, Vilnius University, Vilnius, Lithuania.,National Centre of Pathology, Affiliate of Vilnius University Hospital Santaros Clinics, Vilnius, Lithuania
| | - Benoit Plancoulaine
- Department of Pathology, Forensic Medicine and Pharmacology, Faculty of Medicine, Institute of Biomedical Sciences, Vilnius University, Vilnius, Lithuania.,ANTICIPE, Inserm (UMR 1086), Cancer Center F. Baclesse, Normandy University, Caen, France
| | - Valerijus Ostapenko
- Department of Breast Surgery and Oncology, National Cancer Institute, Vilnius, Lithuania
| | - Arvydas Laurinavicius
- Department of Pathology, Forensic Medicine and Pharmacology, Faculty of Medicine, Institute of Biomedical Sciences, Vilnius University, Vilnius, Lithuania.,National Centre of Pathology, Affiliate of Vilnius University Hospital Santaros Clinics, Vilnius, Lithuania
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30
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Li X, Zeng X, Xu Y, Wang B, Zhao Y, Lai X, Qian P, Huang H. Mechanisms and rejuvenation strategies for aged hematopoietic stem cells. J Hematol Oncol 2020; 13:31. [PMID: 32252797 PMCID: PMC7137344 DOI: 10.1186/s13045-020-00864-8] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 03/27/2020] [Indexed: 12/18/2022] Open
Abstract
Hematopoietic stem cell (HSC) aging, which is accompanied by reduced self-renewal ability, impaired homing, myeloid-biased differentiation, and other defects in hematopoietic reconstitution function, is a hot topic in stem cell research. Although the number of HSCs increases with age in both mice and humans, the increase cannot compensate for the defects of aged HSCs. Many studies have been performed from various perspectives to illustrate the potential mechanisms of HSC aging; however, the detailed molecular mechanisms remain unclear, blocking further exploration of aged HSC rejuvenation. To determine how aged HSC defects occur, we provide an overview of differences in the hallmarks, signaling pathways, and epigenetics of young and aged HSCs as well as of the bone marrow niche wherein HSCs reside. Notably, we summarize the very recent studies which dissect HSC aging at the single-cell level. Furthermore, we review the promising strategies for rejuvenating aged HSC functions. Considering that the incidence of many hematological malignancies is strongly associated with age, our HSC aging review delineates the association between functional changes and molecular mechanisms and may have significant clinical relevance.
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Affiliation(s)
- Xia Li
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang, People's Republic of China
| | - Xiangjun Zeng
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang, People's Republic of China
| | - Yulin Xu
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang, People's Republic of China
| | - Binsheng Wang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang, People's Republic of China
| | - Yanmin Zhao
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang, People's Republic of China
| | - Xiaoyu Lai
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang, People's Republic of China
| | - Pengxu Qian
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang, People's Republic of China
| | - He Huang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China. .,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China. .,Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang, People's Republic of China.
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31
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Guderyon MJ, Chen C, Bhattacharjee A, Ge G, Fernandez RA, Gelfond JAL, Gorena KM, Cheng CJ, Li Y, Nelson JF, Strong RJ, Hornsby PJ, Clark RA, Li S. Mobilization-based transplantation of young-donor hematopoietic stem cells extends lifespan in mice. Aging Cell 2020; 19:e13110. [PMID: 32012439 PMCID: PMC7059148 DOI: 10.1111/acel.13110] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 12/18/2019] [Accepted: 01/05/2020] [Indexed: 12/25/2022] Open
Abstract
Mammalian aging is associated with reduced tissue regeneration and loss of physiological integrity. With age, stem cells diminish in their ability to regenerate adult tissues, likely contributing to age-related morbidity. Thus, we replaced aged hematopoietic stem cells (HSCs) with young-donor HSCs using a novel mobilization-enabled hematopoietic stem cell transplantation (HSCT) technology as an alternative to the highly toxic conditioning regimens used in conventional HSCT. Using this approach, we are the first to report an increase in median lifespan (12%) and a decrease in overall mortality hazard (HR: 0.42, CI: 0.273-0.638) in aged mice following transplantation of young-donor HSCs. The increase in longevity was accompanied by reductions of frailty measures and increases in food intake and body weight of aged recipients. Young-donor HSCs not only preserved youthful function within the aged bone marrow stroma, but also at least partially ameliorated dysfunctional hematopoietic phenotypes of aged recipients. This compelling evidence that mammalian health and lifespan can be extended through stem cell therapy adds a new category to the very limited list of successful anti-aging/life-extending interventions. Our findings have implications for further development of stem cell therapies for increasing health and lifespan.
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Affiliation(s)
| | - Cang Chen
- Department of MedicineUT Health San AntonioSan AntonioTXUSA
| | | | - Guo Ge
- Department of MedicineUT Health San AntonioSan AntonioTXUSA
| | - Roman A. Fernandez
- Department of Epidemiology and BiostatisticsUT Health San AntonioSan AntonioTXUSA
| | | | - Karla M. Gorena
- Flow Cytometry Core FacilityUT Health San AntonioSan AntonioTXUSA
| | - Catherine J. Cheng
- Department of Cell Systems and AnatomyUT Health San AntonioSan AntonioTXUSA
- Barshop Institute for Longevity and Aging StudiesUT Health San AntonioSan AntonioTXUSA
| | - Yang Li
- Department of Pathology and Laboratory MedicinePerelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA
| | - James F. Nelson
- Barshop Institute for Longevity and Aging StudiesUT Health San AntonioSan AntonioTXUSA
- Department of Cellular and Integrative PhysiologyUT Health San AntonioSan AntonioTXUSA
| | - Randy J. Strong
- Barshop Institute for Longevity and Aging StudiesUT Health San AntonioSan AntonioTXUSA
- Department of PharmacologyUT Health San AntonioSan AntonioTXUSA
- Research ServiceSouth Texas Veterans Health Care SystemSan AntonioTXUSA
| | - Peter J. Hornsby
- Barshop Institute for Longevity and Aging StudiesUT Health San AntonioSan AntonioTXUSA
- Department of Cellular and Integrative PhysiologyUT Health San AntonioSan AntonioTXUSA
| | - Robert A. Clark
- Department of MedicineUT Health San AntonioSan AntonioTXUSA
- Research ServiceSouth Texas Veterans Health Care SystemSan AntonioTXUSA
| | - Senlin Li
- Department of MedicineUT Health San AntonioSan AntonioTXUSA
- Barshop Institute for Longevity and Aging StudiesUT Health San AntonioSan AntonioTXUSA
- Department of PharmacologyUT Health San AntonioSan AntonioTXUSA
- Research ServiceSouth Texas Veterans Health Care SystemSan AntonioTXUSA
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32
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Zhang Y, Zheng L, Le M, Nakano Y, Chan B, Huang Y, Torbaty PM, Kohwi Y, Marcucio R, Habelitz S, Den Besten PK, Kohwi-Shigematsu T. SATB1 establishes ameloblast cell polarity and regulates directional amelogenin secretion for enamel formation. BMC Biol 2019; 17:104. [PMID: 31830989 PMCID: PMC6909472 DOI: 10.1186/s12915-019-0722-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Accepted: 11/13/2019] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Polarity is necessary for epithelial cells to perform distinct functions at their apical and basal surfaces. Oral epithelial cell-derived ameloblasts at secretory stage (SABs) synthesize large amounts of enamel matrix proteins (EMPs), largely amelogenins. EMPs are unidirectionally secreted into the enamel space through their apical cytoplasmic protrusions, or Tomes' processes (TPs), to guide the enamel formation. Little is known about the transcriptional regulation underlying the establishment of cell polarity and unidirectional secretion of SABs. RESULTS The higher-order chromatin architecture of eukaryotic genome plays important roles in cell- and stage-specific transcriptional programming. A genome organizer, special AT-rich sequence-binding protein 1 (SATB1), was discovered to be significantly upregulated in ameloblasts compared to oral epithelial cells using a whole-transcript microarray analysis. The Satb1-/- mice possessed deformed ameloblasts and a thin layer of hypomineralized and non-prismatic enamel. Remarkably, Satb1-/- ameloblasts at the secretory stage lost many morphological characteristics found at the apical surface of wild-type (wt) SABs, including the loss of Tomes' processes, defective inter-ameloblastic adhesion, and filamentous actin architecture. As expected, the secretory function of Satb1-/- SABs was compromised as amelogenins were largely retained in cells. We found the expression of epidermal growth factor receptor pathway substrate 8 (Eps8), a known regulator for actin filament assembly and small intestinal epithelial cytoplasmic protrusion formation, to be SATB1 dependent. In contrast to wt SABs, EPS8 could not be detected at the apical surface of Satb1-/- SABs. Eps8 expression was greatly reduced in small intestinal epithelial cells in Satb1-/- mice as well, displaying defective intestinal microvilli. CONCLUSIONS Our data show that SATB1 is essential for establishing secretory ameloblast cell polarity and for EMP secretion. In line with the deformed apical architecture, amelogenin transport to the apical secretory front and secretion into enamel space were impeded in Satb1-/- SABs resulting in a massive cytoplasmic accumulation of amelogenins and a thin layer of hypomineralized enamel. Our studies strongly suggest that SATB1-dependent Eps8 expression plays a critical role in cytoplasmic protrusion formation in both SABs and in small intestines. This study demonstrates the role of SATB1 in the regulation of amelogenesis and the potential application of SATB1 in ameloblast/enamel regeneration.
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Affiliation(s)
- Yan Zhang
- Department of Orofacial Sciences, University of California, San Francisco, USA.
| | - Liwei Zheng
- Department of Orofacial Sciences, University of California, San Francisco, USA
| | - Michael Le
- Department of Orofacial Sciences, University of California, San Francisco, USA
| | - Yukiko Nakano
- Department of Orofacial Sciences, University of California, San Francisco, USA
| | - Barry Chan
- Department of Orofacial Sciences, University of California, San Francisco, USA
| | - Yulei Huang
- Department of Orofacial Sciences, University of California, San Francisco, USA
| | | | - Yoshinori Kohwi
- Department of Orofacial Sciences, University of California, San Francisco, USA
| | - Ralph Marcucio
- Department of Orthopaedic Surgery, University of California, San Francisco, USA
| | - Stefan Habelitz
- Preventive and Restorative Dental Sciences, University of California, San Francisco, USA
| | - Pamela K Den Besten
- Department of Orofacial Sciences, University of California, San Francisco, USA
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33
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Doi Y, Yokota T, Satoh Y, Okuzaki D, Tokunaga M, Ishibashi T, Sudo T, Ueda T, Shingai Y, Ichii M, Tanimura A, Ezoe S, Shibayama H, Kohwi-Shigematsu T, Takeda J, Oritani K, Kanakura Y. Variable SATB1 Levels Regulate Hematopoietic Stem Cell Heterogeneity with Distinct Lineage Fate. Cell Rep 2019; 23:3223-3235. [PMID: 29898394 DOI: 10.1016/j.celrep.2018.05.042] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Revised: 04/05/2018] [Accepted: 05/14/2018] [Indexed: 12/18/2022] Open
Abstract
Hematopoietic stem cells (HSCs) comprise a heterogeneous population exhibiting self-renewal and differentiation capabilities; however, the mechanisms involved in maintaining this heterogeneity remain unclear. Here, we show that SATB1 is involved in regulating HSC heterogeneity. Results in conditional Satb1-knockout mice revealed that SATB1 was important for the self-renewal and lymphopoiesis of adult HSCs. Additionally, HSCs from Satb1/Tomato-knockin reporter mice were classified based on SATB1/Tomato intensity, with transplantation experiments revealing stronger differentiation toward the lymphocytic lineage along with high SATB1 levels, whereas SATB1- HSCs followed the myeloid lineage in agreement with genome-wide transcription and cell culture studies. Importantly, SATB1- and SATB1+ HSC populations were interconvertible upon transplantation, with SATB1+ HSCs showing higher reconstituting and lymphopoietic potentials in primary recipients relative to SATB1- HSCs, whereas both HSCs exhibited equally efficient reconstituted lympho-hematopoiesis in secondary recipients. These results suggest that SATB1 levels regulate the maintenance of HSC multipotency, with variations contributing to HSC heterogeneity.
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Affiliation(s)
- Yukiko Doi
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Takafumi Yokota
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Japan.
| | - Yusuke Satoh
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Japan; Department of Lifestyle Studies, Kobe Shoin Women's University, Kobe, Japan
| | - Daisuke Okuzaki
- DNA-chip Development Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, Suita, Japan
| | - Masahiro Tokunaga
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tomohiko Ishibashi
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Japan; Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan
| | - Takao Sudo
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Japan; Department of Immunology and Cell Biology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tomoaki Ueda
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yasuhiro Shingai
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Michiko Ichii
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Akira Tanimura
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Sachiko Ezoe
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Hirohiko Shibayama
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Terumi Kohwi-Shigematsu
- Department of Orofacial Sciences, University of California, San Francisco, San Francisco, CA, USA
| | - Junji Takeda
- Department of Genome Biology Graduate School of Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| | - Kenji Oritani
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yuzuru Kanakura
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Japan
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34
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"Hierarchy" and "Holacracy"; A Paradigm of the Hematopoietic System. Cells 2019; 8:cells8101138. [PMID: 31554248 PMCID: PMC6830102 DOI: 10.3390/cells8101138] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 09/20/2019] [Accepted: 09/23/2019] [Indexed: 02/06/2023] Open
Abstract
The mammalian hematopoietic system has long been viewed as a hierarchical paradigm in which a small number of hematopoietic stem cells (HSCs) are located at the apex. HSCs were traditionally thought to be homogeneous and quiescent in a homeostatic state. However, recent observations, through extramedullary hematopoiesis and clonal assays, have cast doubt on the validity of the conventional interpretation. A key issue is understanding the characteristics of HSCs from different viewpoints, including dynamic physics and social network theory. The aim of this literature review is to propose a new paradigm of our hematopoietic system, in which individual HSCs are actively involved.
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35
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Park H, Shin MS, Kim M, Bilsborrow JB, Mohanty S, Montgomery RR, Shaw AC, You S, Kang I. Transcriptomic analysis of human IL-7 receptor alpha low and high effector memory CD8 + T cells reveals an age-associated signature linked to influenza vaccine response in older adults. Aging Cell 2019; 18:e12960. [PMID: 31044512 PMCID: PMC6612637 DOI: 10.1111/acel.12960] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Accepted: 03/10/2019] [Indexed: 12/20/2022] Open
Abstract
Here, we investigated the relationship of the age‐associated expansion of IL‐7 receptor alpha low (IL‐7Rαlow) effector memory (EM) CD8+ T cells with the global transcriptomic profile of peripheral blood cells in humans. We found 231 aging signature genes of IL‐7Rαlow EM CD8+ T cells that corresponded to 15% of the age‐associated genes (231/1,497) reported by a meta‐analysis study on human peripheral whole blood from approximately 15,000 individuals, having high correlation with chronological age. These aging signature genes were the target genes of several transcription factors including MYC, SATB1, and BATF, which also belonged to the 231 genes, supporting the upstream regulatory role of these transcription factors in altering the gene expression profile of peripheral blood cells with aging. We validated the differential expression of these transcription factors between IL‐7Rαlow and high EM CD8+ T cells as well as in peripheral blood mononuclear cells (PBMCs) of young and older adults. Finally, we found a significant association with influenza vaccine responses in older adults, suggesting the possible biological significance of the aging signature genes of IL‐7Rαlow EM CD8+ T cells. The results of our study support the relationship of the expansion of IL‐7Rαlow EM CD8+ T cells with the age‐associated changes in the gene expression profile of peripheral blood cells and its possible biological implications.
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Affiliation(s)
- Hong‐Jai Park
- Department of Internal Medicine Yale University School of Medicine New Haven Connecticut
| | - Min Sun Shin
- Department of Internal Medicine Yale University School of Medicine New Haven Connecticut
| | - Minhyung Kim
- Departments of Surgery and Biomedical Sciences Cedars‐Sinai Medical Center Los Angeles California
| | - Joshua B. Bilsborrow
- Department of Internal Medicine Yale University School of Medicine New Haven Connecticut
| | - Subhasis Mohanty
- Department of Internal Medicine Yale University School of Medicine New Haven Connecticut
| | - Ruth R. Montgomery
- Department of Internal Medicine Yale University School of Medicine New Haven Connecticut
| | - Albert C. Shaw
- Department of Internal Medicine Yale University School of Medicine New Haven Connecticut
| | - Sungyong You
- Departments of Surgery and Biomedical Sciences Cedars‐Sinai Medical Center Los Angeles California
- Samuel Oschin Comprehensive Cancer Institute Cedars‐Sinai Medical Center Los Angeles California
| | - Insoo Kang
- Department of Internal Medicine Yale University School of Medicine New Haven Connecticut
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Wang MJ, Chen J, Chen F, Liu Q, Sun Y, Yan C, Yang T, Bao Y, Hu YP. Rejuvenating Strategies of Tissue-specific Stem Cells for Healthy Aging. Aging Dis 2019; 10:871-882. [PMID: 31440391 PMCID: PMC6675530 DOI: 10.14336/ad.2018.1119] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Accepted: 11/19/2018] [Indexed: 12/22/2022] Open
Abstract
Although aging is a physiological process, it has raised interest in the science of aging and rejuvenation because of the increasing burden on the rapidly aging global population. With advanced age, there is a decline in homeostatic maintenance and regenerative responsiveness to the injury of various tissues, thereby contributing to the incidence of age-related diseases. The primary cause of the functional declines that occur along with aging is considered to be the exhaustion of stem cell functions in their corresponding tissues. Age-related changes in the systemic environment, the niche, and stem cells contribute to this loss. Thus, the reversal of stem cell aging at the cellular level might lead to the rejuvenation of the animal at an organismic level and the prevention of aging, which would be critical for developing new therapies for age-related dysfunction and diseases. Here, we will explore the effects of aging on stem cells in different tissues. The focus of this discussion is on pro-youth interventions that target intrinsic stem cell properties, environmental niche component, systemic factors, and senescent cellular clearance, which are promising for developing strategies related to the reversal of aged stem cell function and optimizing tissue repair processes.
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Affiliation(s)
- Min-Jun Wang
- 1Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, Shanghai 200433, China
| | - Jiajia Chen
- 1Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, Shanghai 200433, China
| | - Fei Chen
- 1Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, Shanghai 200433, China
| | - Qinggui Liu
- 1Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, Shanghai 200433, China
| | - Yu Sun
- 1Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, Shanghai 200433, China
| | - Chen Yan
- 1Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, Shanghai 200433, China
| | - Tao Yang
- 1Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, Shanghai 200433, China
| | - Yiwen Bao
- 1Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, Shanghai 200433, China.,2Department of Diagnostic radiology, University of Hong Kong, Hong Kong 999077, China
| | - Yi-Ping Hu
- 1Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, Shanghai 200433, China
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37
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Lee J, Yoon SR, Choi I, Jung H. Causes and Mechanisms of Hematopoietic Stem Cell Aging. Int J Mol Sci 2019; 20:ijms20061272. [PMID: 30871268 PMCID: PMC6470724 DOI: 10.3390/ijms20061272] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 03/08/2019] [Accepted: 03/09/2019] [Indexed: 12/11/2022] Open
Abstract
Many elderly people suffer from hematological diseases known to be highly age-dependent. Hematopoietic stem cells (HSCs) maintain the immune system by producing all blood cells throughout the lifetime of an organism. Recent reports have suggested that HSCs are susceptible to age-related stress and gradually lose their self-renewal and regeneration capacity with aging. HSC aging is driven by cell-intrinsic and -extrinsic factors that result in the disruption of the immune system. Thus, the study of HSC aging is important to our understanding of age-related immune diseases and can also provide potential strategies to improve quality of life in the elderly. In this review, we delineate our understanding of the phenotypes, causes, and molecular mechanisms involved in HSC aging.
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Affiliation(s)
- Jungwoon Lee
- Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Korea.
| | - Suk Ran Yoon
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Korea.
- Department of Functional Genomics, University of Science and Technology (UST), 113 Gwahak-ro, Yuseong-gu, Daejeon 34113, Korea.
| | - Inpyo Choi
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Korea.
- Department of Functional Genomics, University of Science and Technology (UST), 113 Gwahak-ro, Yuseong-gu, Daejeon 34113, Korea.
| | - Haiyoung Jung
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Korea.
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38
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Naik R, Galande S. SATB family chromatin organizers as master regulators of tumor progression. Oncogene 2019; 38:1989-2004. [PMID: 30413763 DOI: 10.1038/s41388-018-0541-4] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Revised: 08/30/2018] [Accepted: 09/02/2018] [Indexed: 02/07/2023]
Abstract
SATB (Special AT-rich binding protein) family proteins have emerged as key regulators that integrate higher-order chromatin organization with the regulation of gene expression. Studies over the past decade have elucidated the specific roles of SATB1 and SATB2, two closely related members of this family, in cancer progression. SATB family chromatin organizers play diverse and important roles in regulating the dynamic equilibrium of apoptosis, cell invasion, metastasis, proliferation, angiogenesis, and immune modulation. This review highlights cellular and molecular events governed by SATB1 influencing the structural organization of chromatin and interacting with several co-activators and co-repressors of transcription towards tumor progression. SATB1 expression across tumor cell types generates cellular and molecular heterogeneity culminating in tumor relapse and metastasis. SATB1 exhibits dynamic expression within intratumoral cell types regulated by the tumor microenvironment, which culminates towards tumor progression. Recent studies suggested that cell-specific expression of SATB1 across tumor recruited dendritic cells (DC), cytotoxic T lymphocytes (CTL), T regulatory cells (Tregs) and tumor epithelial cells along with tumor microenvironment act as primary determinants of tumor progression and tumor inflammation. In contrast, SATB2 is differentially expressed in an array of cancer types and is involved in tumorigenesis. Survival analysis for patients across an array of cancer types correlated with expression of SATB family chromatin organizers suggested tissue-specific expression of SATB1 and SATB2 contributing to disease prognosis. In this context, it is pertinent to understand molecular players, cellular pathways, genetic and epigenetic mechanisms governed by cell types within tumors regulated by SATB proteins. We propose that patient survival analysis based on the expression profile of SATB chromatin organizers would facilitate their unequivocal establishment as prognostic markers and therapeutic targets for cancer therapy.
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Affiliation(s)
- Rutika Naik
- Centre of Excellence in Epigenetics, Department of Biology, Indian Institute of Science Education and Research, Pune, 411008, India
| | - Sanjeev Galande
- Centre of Excellence in Epigenetics, Department of Biology, Indian Institute of Science Education and Research, Pune, 411008, India.
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39
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Hosokawa H, Ungerbäck J, Wang X, Matsumoto M, Nakayama KI, Cohen SM, Tanaka T, Rothenberg EV. Transcription Factor PU.1 Represses and Activates Gene Expression in Early T Cells by Redirecting Partner Transcription Factor Binding. Immunity 2019; 48:1119-1134.e7. [PMID: 29924977 DOI: 10.1016/j.immuni.2018.04.024] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 02/21/2018] [Accepted: 04/19/2018] [Indexed: 01/09/2023]
Abstract
Transcription factors normally regulate gene expression through their action at sites where they bind to DNA. However, the balance of activating and repressive functions that a transcription factor can mediate is not completely understood. Here, we showed that the transcription factor PU.1 regulated gene expression in early T cell development both by recruiting partner transcription factors to its own binding sites and by depleting them from the binding sites that they preferred when PU.1 was absent. The removal of partner factors Satb1 and Runx1 occurred primarily from sites where PU.1 itself did not bind. Genes linked to sites of partner factor "theft" were enriched for genes that PU.1 represses despite lack of binding, both in a model cell line system and in normal T cell development. Thus, system-level competitive recruitment dynamics permit PU.1 to affect gene expression both through its own target sites and through action at a distance.
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Affiliation(s)
- Hiroyuki Hosokawa
- Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Jonas Ungerbäck
- Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA, USA; Division of Molecular Hematology, Lund University, Sweden
| | - Xun Wang
- Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Masaki Matsumoto
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Japan
| | - Keiichi I Nakayama
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Japan
| | - Sarah M Cohen
- Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Tomoaki Tanaka
- Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Japan; AMED-CREST, AMED, Japan Agency for Medical Research and Development, Tokyo, Japan
| | - Ellen V Rothenberg
- Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
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40
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Yasuda K, Kitagawa Y, Kawakami R, Isaka Y, Watanabe H, Kondoh G, Kohwi-Shigematsu T, Sakaguchi S, Hirota K. Satb1 regulates the effector program of encephalitogenic tissue Th17 cells in chronic inflammation. Nat Commun 2019; 10:549. [PMID: 30710091 PMCID: PMC6358604 DOI: 10.1038/s41467-019-08404-w] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 01/07/2019] [Indexed: 12/15/2022] Open
Abstract
The genome organizer, special AT-rich sequence-binding protein-1 (Satb1), plays a pivotal role in the regulation of global gene networks in a cell type-dependent manner and is indispensable for the development of multiple cell types, including mature CD4+ T, CD8+ T, and Foxp3+ regulatory T cells in the thymus. However, it remains unknown how the differentiation and effector program of the Th subsets in the periphery are regulated by Satb1. Here, we demonstrate that Satb1 differentially regulates gene expression profiles in non-pathogenic and pathogenic Th17 cells and promotes the pathogenic effector program of encephalitogenic Th17 cells by regulating GM-CSF via Bhlhe40 and inhibiting PD-1 expression. However, Satb1 is dispensable for the differentiation and non-pathogenic functions of Th17 cells. These results indicate that Satb1 regulates the specific gene expression and function of effector Th17 cells in tissue inflammation.
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Affiliation(s)
- Keiko Yasuda
- Laboratory of Experimental Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
- Department of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Yohko Kitagawa
- Department of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan
| | - Ryoji Kawakami
- Department of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan
| | - Yoshitaka Isaka
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Hitomi Watanabe
- Laboratory of Integrative Biological Science, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
| | - Gen Kondoh
- Laboratory of Integrative Biological Science, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
| | | | - Shimon Sakaguchi
- Laboratory of Experimental Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
- Department of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
| | - Keiji Hirota
- Department of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
- Laboratory of Integrative Biological Science, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
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41
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Functional relevance of SATB1 in immune regulation and tumorigenesis. Biomed Pharmacother 2018; 104:87-93. [DOI: 10.1016/j.biopha.2018.05.045] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 05/05/2018] [Accepted: 05/08/2018] [Indexed: 02/07/2023] Open
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42
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The transcription factor Zfp90 regulates the self-renewal and differentiation of hematopoietic stem cells. Cell Death Dis 2018; 9:677. [PMID: 29880802 PMCID: PMC5992204 DOI: 10.1038/s41419-018-0721-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Revised: 05/09/2018] [Accepted: 05/16/2018] [Indexed: 12/21/2022]
Abstract
Hematopoietic stem cells (HSCs) can give rise to all blood cells that are essential to defend against pathogen invasion. The defective capability of HSC self-renewal is linked to many serious diseases, such as anemia. However, the potential mechanism regulating HSC self-renewal has not been thoroughly elucidated to date. In this study, we showed that Zfp90 was highly expressed in HSCs. Zfp90 deficiency in the hematopoietic system caused impaired HSPC pools and led to HSC dysfunction. We showed that Zfp90 deletion inhibited HSC proliferation, while HSC apoptosis was not affected. Regarding the mechanism of this effect on HSC proliferation, we found that Zfp90 interacted with Snf2l, a subunit of the NURF complex, to regulate Hoxa9 expression. Ectopic expression of Hoxa9 rescued the HSC repopulation capacity in Zfp90-deficient mice, which indicates that Hoxa9 is the downstream effector of Zfp90. In summary, our findings identify Zfp90 as a key transcription factor in determining the fate of HSCs.
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43
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Abstract
Purpose of Review Functional decline of hematopoiesis that occurs in the elderly, or in patients who receive therapies that trigger cellular senescence effects, results in a progressive reduction in the immune response and an increased incidence of myeloid malignancy. Intracellular signals in hematopoietic stem cells and progenitors (HSC/P) mediate systemic, microenvironment, and cell-intrinsic effector aging signals that induce their decline. This review intends to summarize and critically review our advances in the understanding of the intracellular signaling pathways responsible for HSC decline during aging and opportunities for intervention. Recent Findings For a long time, aging of HSC has been thought to be an irreversible process imprinted in stem cells due to the cell intrinsic nature of aging. However, recent murine models and human correlative studies provide evidence that aging is associated with molecular signaling pathways, including oxidative stress, metabolic dysfunction, loss of polarity and an altered epigenome. These signaling pathways provide potential targets for prevention or reversal of age-related changes. Summary Here we review our current understanding of the signalling pathways that are differentially activated or repressed during HSC/P aging, focusing on the oxidative, metabolic, biochemical and structural consequences downstream, and cell-intrinsic, systemic, and environmental influences.
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44
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Akiba Y, Kuwabara T, Mukozu T, Mikami T, Kondo M. Special AT-rich sequence binding protein 1 is required for maintenance of T cell receptor responsiveness and development of experimental autoimmune encephalomyelitis. Microbiol Immunol 2018; 62:255-268. [PMID: 29388727 PMCID: PMC5947310 DOI: 10.1111/1348-0421.12579] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Revised: 01/29/2018] [Accepted: 01/30/2018] [Indexed: 01/19/2023]
Abstract
The genome organizer special AT‐rich sequence binding protein 1 (SATB1) regulates specific functions through chromatin remodeling in T helper cells. It was recently reported by our team that T cells from SATB1 conditional knockout (SATB1cKO) mice, in which the Satb1 gene is deleted from hematopoietic cells, impair phosphorylation of signaling molecules in response to T cell receptor (TCR) crosslinking. However, in vivo T cell responses upon antigen presentation in the absence of SATB1 remain unclear. In the current study, it was shown that SATB1 modulates T cell antigen responses during the induction and effector phases. Expression of SATB1 was upregulated in response to TCR stimulation, suggesting that SATB1 is important for this antigen response. The role of SATB1 in TCR responses and induced experimental autoimmune encephalomyelitis (EAE) was therefore examined using the myelin oligodendrocyte glycoprotein peptide 35‐55 (MOG35‐55) and pertussis toxin. SATB1cKO mice were found to be resistant to EAE and had defects in IL‐17‐ and IFN‐γ‐producing pathogenic T cells. Thus, SATB1 expression appears necessary for T cell function in the induction phase. To examine SATB1 function during the effector phase, a tamoxifen‐inducible SATB1 deletion system, SATB1cKO‐ER‐Cre mice, was used. Encephalitogenic T cells from MOG35‐55‐immunized SATB1cKO‐ER‐Cre mice were transferred into healthy mice. Mice that received tamoxifen before the onset of paralysis were resistant to EAE. Furthermore, no disease progression occurred in recipient mice treated with tamoxifen after the onset of EAE. Thus, SATB1 is essential for maintaining TCR responsiveness during the induction and effector phases and may provide a novel therapeutic target for T cell‐mediated autoimmune diseases.
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Affiliation(s)
- Yasushi Akiba
- Department of Molecular Immunology, Toho University School of Medicine, Tokyo 143-8540, Japan.,Toho University Graduate School of Medicine, Tokyo 143-8540, Japan
| | - Taku Kuwabara
- Department of Molecular Immunology, Toho University School of Medicine, Tokyo 143-8540, Japan
| | - Takanori Mukozu
- Department of Molecular Immunology, Toho University School of Medicine, Tokyo 143-8540, Japan.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, Toho University Omori Medical Center, Tokyo 143-8541, Japan
| | - Tetuo Mikami
- Department of Pathology, Toho University, Faculty of Medicine, Tokyo 143-8540, Japan
| | - Motonari Kondo
- Department of Molecular Immunology, Toho University School of Medicine, Tokyo 143-8540, Japan
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45
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The Special AT-rich Sequence Binding Protein 1 (SATB1) and its role in solid tumors. Cancer Lett 2018; 417:96-111. [DOI: 10.1016/j.canlet.2017.12.031] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 12/19/2017] [Accepted: 12/21/2017] [Indexed: 02/07/2023]
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46
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Reconstruction of complex single-cell trajectories using CellRouter. Nat Commun 2018; 9:892. [PMID: 29497036 PMCID: PMC5832860 DOI: 10.1038/s41467-018-03214-y] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Accepted: 01/25/2018] [Indexed: 12/11/2022] Open
Abstract
A better understanding of the cell-fate transitions that occur in complex cellular ecosystems in normal development and disease could inform cell engineering efforts and lead to improved therapies. However, a major challenge is to simultaneously identify new cell states, and their transitions, to elucidate the gene expression dynamics governing cell-type diversification. Here, we present CellRouter, a multifaceted single-cell analysis platform that identifies complex cell-state transition trajectories by using flow networks to explore the subpopulation structure of multi-dimensional, single-cell omics data. We demonstrate its versatility by applying CellRouter to single-cell RNA sequencing data sets to reconstruct cell-state transition trajectories during hematopoietic stem and progenitor cell (HSPC) differentiation to the erythroid, myeloid and lymphoid lineages, as well as during re-specification of cell identity by cellular reprogramming of monocytes and B-cells to HSPCs. CellRouter opens previously undescribed paths for in-depth characterization of complex cellular ecosystems and establishment of enhanced cell engineering approaches. Single cell analysis provides insight into cell states and transitions, but to interpret the data, improved algorithms are needed. Here, the authors present CellRouter as a method to analyse single-cell trajectories from RNA-sequencing data, and provide insight into erythroid, myeloid and lymphoid differentiation.
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47
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Identification of MS4A3 as a reliable marker for early myeloid differentiation in human hematopoiesis. Biochem Biophys Res Commun 2018; 495:2338-2343. [DOI: 10.1016/j.bbrc.2017.12.117] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2017] [Accepted: 12/20/2017] [Indexed: 12/12/2022]
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48
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Lim JE, Son Y. Endogenous Stem Cells in Homeostasis and Aging. Tissue Eng Regen Med 2017; 14:679-698. [PMID: 30603520 PMCID: PMC6171667 DOI: 10.1007/s13770-017-0097-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 11/06/2017] [Accepted: 11/07/2017] [Indexed: 12/22/2022] Open
Abstract
In almost all human tissues and organs, adult stem cells or tissue stem cells are present in a unique location, the so-called stem cell niche or its equivalent, continuously replenishing functional differentiated cells. Those endogenous stem cells can be expanded for cell therapeutics using ex vivo cell culture or recalled for tissue repair in situ through cell trafficking and homing. In the aging process, inefficiency in the endogenous stem cell-mediated healing mechanism can emerge from a variety of impairments that accumulate in the processes of stem cell self-renewal, function, differentiation capacity, and trafficking through cell autonomous intrinsic pathways (such as epigenetic alterations) or systemic extrinsic pathways. This review examines the homeostasis of endogenous stem cells, particularly bone marrow stem cells, and their dysregulation in disease and aging and discusses possible intervention strategies. Several systemic pro-aging and rejuvenating factors, recognized in heterochronic parabiosis or premature aging progeroid animal models, are reviewed as possible anti-aging pharmaceutical targets from the perspective of a healthy environment for endogenous stem cells. A variety of epigenetic modifications and chromosome architectures are reviewed as an intrinsic cellular pathway for aging and senescence. A gradual increase in inflammatory burden during aging is also reviewed. Finally, the tissue repair and anti-aging effects of Substance-P, a peptide stimulating stem cell trafficking from the bone marrow and modifying the inflammatory response, are discussed as a future anti-aging target.
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Affiliation(s)
- Ji Eun Lim
- Department of Genetic Engineering, College of Life Science and Graduate School of Biotechnology, Kyung Hee University, 1732 Deogyeong-daero, Giheung-gu, Yongin-si, Gyeonggi-do 17104 Republic of Korea
| | - Youngsook Son
- Department of Genetic Engineering, College of Life Science and Graduate School of Biotechnology, Kyung Hee University, 1732 Deogyeong-daero, Giheung-gu, Yongin-si, Gyeonggi-do 17104 Republic of Korea
- Kyung Hee Institute of Regenerative Medicine, Kyung Hee University Hospital, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02453 Republic of Korea
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49
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Suppression of SRCAP chromatin remodelling complex and restriction of lymphoid lineage commitment by Pcid2. Nat Commun 2017; 8:1518. [PMID: 29138493 PMCID: PMC5686073 DOI: 10.1038/s41467-017-01788-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2016] [Accepted: 10/16/2017] [Indexed: 12/31/2022] Open
Abstract
Lymphoid lineage commitment is an important process in haematopoiesis, which forms the immune system to protect the host from pathogen invasion. However, how multipotent progenitors (MPP) switch into common lymphoid progenitors (CLP) or common myeloid progenitors (CMP) during this process remains elusive. Here we show that PCI domain-containing protein 2 (Pcid2) is highly expressed in MPPs. Pcid2 deletion in the haematopoietic system causes skewed lymphoid lineage specification. In MPPs, Pcid2 interacts with the Zinc finger HIT-type containing 1 (ZNHIT1) to block Snf2-related CREBBP activator protein (SRCAP) activity and prevents the deposition of histone variant H2A.Z and transcription factor PU.1 to key lymphoid fate regulator genes. Furthermore, Znhit1 deletion also abrogates H2A/H2A.Z exchange in MPPs. Thus Pcid2 controls lymphoid lineage commitment through the regulation of SRCAP remodelling activity.
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50
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Tanaka Y, Sotome T, Inoue A, Mukozu T, Kuwabara T, Mikami T, Kowhi-Shigematsu T, Kondo M. SATB1 Conditional Knockout Results in Sjögren's Syndrome in Mice. THE JOURNAL OF IMMUNOLOGY 2017; 199:4016-4022. [PMID: 29127143 DOI: 10.4049/jimmunol.1700550] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Accepted: 10/16/2017] [Indexed: 12/20/2022]
Abstract
Sjögren's syndrome (SS) is an autoimmune disease in which exocrine tissues are affected by cellular and humoral immunity. As a result, the salivary and lacrimal glands of patients with SS are damaged, leading to xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes). Because experimental approaches to investigate SS pathogenesis in human patients are limited, development of a mouse model is indispensable for understanding the disease. In this study, we show that special AT-rich sequence binding protein-1 conditional knockout (SATB1cKO) mice, in which the SATB1 gene is specifically deleted from hematopoietic cells, develop SS by 4 wk of age, soon after weaning. Female mice presented an earlier onset of the disease than males, suggesting that female SATB1cKO mice are more susceptible to SS. T cell-dominant immune cell infiltration was observed in the salivary glands of 4 wk old SATB1cKO mice, and the frequency of B cells gradually increased as the mice aged. Consistently, levels of anti-SSA and anti-SSB Abs were increased around 8 wk of age, after salivary production reached its lowest level in SATB1cKO mice. These results suggest that SATB1cKO mice can be a novel SS model, in which the progression and characteristics of the disease resemble those of human SS.
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Affiliation(s)
- Yuriko Tanaka
- Department of Molecular Immunology, Toho University School of Medicine, Tokyo 143-8540, Japan
| | - Takehiko Sotome
- Department of Pediatrics, Toho University Omori Medical Center, Tokyo 143-8541, Japan
| | - Akiko Inoue
- Department of Otorhinolaryngology, Toho University Omori Medical Center, Tokyo 143-8541, Japan.,Toho University Graduate School of Medicine, Tokyo 143-8540, Japan
| | - Takanori Mukozu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Toho University Omori Medical Center, Tokyo 143-8541, Japan
| | - Taku Kuwabara
- Department of Molecular Immunology, Toho University School of Medicine, Tokyo 143-8540, Japan
| | - Tetuo Mikami
- Department of Pathology, Toho University School of Medicine, Tokyo 143-8540, Japan; and
| | - Terumi Kowhi-Shigematsu
- Department of Orofacial Sciences, University of California San Francisco School of Dentistry, San Francisco, CA 94143
| | - Motonari Kondo
- Department of Molecular Immunology, Toho University School of Medicine, Tokyo 143-8540, Japan;
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