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Iida R, Ishida S, Wang J, Hattori K, Yoshimi K, Yamazaki S, Mashimo T. A novel Kit mutant rat enables hematopoietic stem cell engraftment without irradiation. Exp Hematol 2024; 132:104174. [PMID: 38331018 DOI: 10.1016/j.exphem.2024.104174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 01/10/2024] [Accepted: 01/13/2024] [Indexed: 02/10/2024]
Abstract
Hematopoietic stem cell (HSC) transplantation is extensively studied in mouse models, but their limited scale presents challenges for effective engraftment and comprehensive evaluations. Rats, owing to their larger size and anatomical similarity to humans, offer a promising alternative. In this study, we establish a rat model with the KitV834M mutation, mirroring KitW41 mice often used in KIT signaling and HSC research. KitV834M rats are viable and fertile, displaying anemia and mast cell depletion similar to KitW41 mice. The colony-forming unit assay revealed that the KitV834M mutation leads to reduced proliferation and loss of or decreased pluripotency of hematopoietic stem and progenitor cells (HSPCs), resulting in diminished competitive repopulating capacity of KitV834M HSPCs in competitive transplantation assays. Importantly, KitV834M rats support donor rat-HSC engraftment without irradiation. Leveraging the larger scale of this rat model enhances our understanding of HSC biology and transplantation dynamics, potentially advancing our knowledge in this field.
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Affiliation(s)
- Ryuya Iida
- Division of Animal Genetics, Laboratory Animal Research Center, Institute of Medical Science, the University of Tokyo, Tokyo, Japan
| | - Saeko Ishida
- Division of Animal Genetics, Laboratory Animal Research Center, Institute of Medical Science, the University of Tokyo, Tokyo, Japan.
| | - Jinxi Wang
- Division of Animal Genetics, Laboratory Animal Research Center, Institute of Medical Science, the University of Tokyo, Tokyo, Japan
| | - Kosuke Hattori
- Division of Animal Genetics, Laboratory Animal Research Center, Institute of Medical Science, the University of Tokyo, Tokyo, Japan
| | - Kazuto Yoshimi
- Division of Animal Genetics, Laboratory Animal Research Center, Institute of Medical Science, the University of Tokyo, Tokyo, Japan; Division of Genome Engineering, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Satoshi Yamazaki
- Division of Cell Regulation, Center of Experimental Medicine and Systems Biology, the Institute of Medical Science, the University of Tokyo, Tokyo, Japan; Laboratory of Stem Cell Therapy, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Tomoji Mashimo
- Division of Animal Genetics, Laboratory Animal Research Center, Institute of Medical Science, the University of Tokyo, Tokyo, Japan; Division of Genome Engineering, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
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2
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Barisas DAG, Choi K. Extramedullary hematopoiesis in cancer. Exp Mol Med 2024; 56:549-558. [PMID: 38443597 PMCID: PMC10985111 DOI: 10.1038/s12276-024-01192-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 12/21/2023] [Accepted: 12/26/2023] [Indexed: 03/07/2024] Open
Abstract
Hematopoiesis can occur outside of the bone marrow during inflammatory stress to increase the production of primarily myeloid cells at extramedullary sites; this process is known as extramedullary hematopoiesis (EMH). As observed in a broad range of hematologic and nonhematologic diseases, EMH is now recognized for its important contributions to solid tumor pathology and prognosis. To initiate EMH, hematopoietic stem cells (HSCs) are mobilized from the bone marrow into the circulation and to extramedullary sites such as the spleen and liver. At these sites, HSCs primarily produce a pathological subset of myeloid cells that contributes to tumor pathology. The EMH HSC niche, which is distinct from the bone marrow HSC niche, is beginning to be characterized. The important cytokines that likely contribute to initiating and maintaining the EMH niche are KIT ligands, CXCL12, G-CSF, IL-1 family members, LIF, TNFα, and CXCR2. Further study of the role of EMH may offer valuable insights into emergency hematopoiesis and therapeutic approaches against cancer. Exciting future directions for the study of EMH include identifying common and distinct EMH mechanisms in cancer, infectious diseases, and chronic autoimmune diseases to control these conditions.
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Affiliation(s)
- Derek A G Barisas
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | - Kyunghee Choi
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
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3
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Matsuoka S, Facchini R, Luis TC, Carrelha J, Woll PS, Mizukami T, Wu B, Boukarabila H, Buono M, Norfo R, Arai F, Suda T, Mead AJ, Nerlov C, Jacobsen SEW. Loss of endothelial membrane KIT ligand affects systemic KIT ligand levels but not bone marrow hematopoietic stem cells. Blood 2023; 142:1622-1632. [PMID: 37562000 PMCID: PMC10733828 DOI: 10.1182/blood.2022019018] [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: 11/10/2022] [Revised: 07/24/2023] [Accepted: 07/25/2023] [Indexed: 08/12/2023] Open
Abstract
A critical regulatory role of hematopoietic stem cell (HSC) vascular niches in the bone marrow has been implicated to occur through endothelial niche cell expression of KIT ligand. However, endothelial-derived KIT ligand is expressed in both a soluble and membrane-bound form and not unique to bone marrow niches, and it is also systemically distributed through the circulatory system. Here, we confirm that upon deletion of both the soluble and membrane-bound forms of endothelial-derived KIT ligand, HSCs are reduced in mouse bone marrow. However, the deletion of endothelial-derived KIT ligand was also accompanied by reduced soluble KIT ligand levels in the blood, precluding any conclusion as to whether the reduction in HSC numbers reflects reduced endothelial expression of KIT ligand within HSC niches, elsewhere in the bone marrow, and/or systemic soluble KIT ligand produced by endothelial cells outside of the bone marrow. Notably, endothelial deletion, specifically of the membrane-bound form of KIT ligand, also reduced systemic levels of soluble KIT ligand, although with no effect on stem cell numbers, implicating an HSC regulatory role primarily of soluble rather than membrane KIT ligand expression in endothelial cells. In support of a role of systemic rather than local niche expression of soluble KIT ligand, HSCs were unaffected in KIT ligand deleted bones implanted into mice with normal systemic levels of soluble KIT ligand. Our findings highlight the need for more specific tools to unravel niche-specific roles of regulatory cues expressed in hematopoietic niche cells in the bone marrow.
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Affiliation(s)
- Sahoko Matsuoka
- Haematopoietic Stem Cell Biology Laboratory, Medical Research Council Molecular Haematology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
| | - Raffaella Facchini
- Haematopoietic Stem Cell Biology Laboratory, Medical Research Council Molecular Haematology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
| | - Tiago C. Luis
- Haematopoietic Stem Cell Biology Laboratory, Medical Research Council Molecular Haematology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
- Department of Immunology and Inflammation, Centre for Inflammatory Disease, Imperial College London, London, United Kingdom
| | - Joana Carrelha
- Haematopoietic Stem Cell Biology Laboratory, Medical Research Council Molecular Haematology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
| | - Petter S. Woll
- Department of Medicine Huddinge, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Takuo Mizukami
- Haematopoietic Stem Cell Biology Laboratory, Medical Research Council Molecular Haematology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
| | - Bishan Wu
- Haematopoietic Stem Cell Biology Laboratory, Medical Research Council Molecular Haematology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
| | - Hanane Boukarabila
- Haematopoietic Stem Cell Biology Laboratory, Medical Research Council Molecular Haematology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
| | - Mario Buono
- Medical Research Council Molecular Haematology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
| | - Ruggiero Norfo
- Haematopoietic Stem Cell Biology Laboratory, Medical Research Council Molecular Haematology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
| | - Fumio Arai
- Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Toshio Suda
- Cancer Science Institute, National University of Singapore, Singapore, Singapore
| | - Adam J. Mead
- Haematopoietic Stem Cell Biology Laboratory, Medical Research Council Molecular Haematology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
- Medical Research Council Molecular Haematology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
| | - Claus Nerlov
- Medical Research Council Molecular Haematology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
| | - Sten Eirik W. Jacobsen
- Haematopoietic Stem Cell Biology Laboratory, Medical Research Council Molecular Haematology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
- Department of Medicine Huddinge, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
- Medical Research Council Molecular Haematology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
- Karolinska University Hospital Huddinge, Stockholm, Sweden
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4
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Blacher P, De Gasperin O, Grasso G, Sarton-Lohéac S, Allemann R, Chapuisat M. Cryptic recessive lethality of a supergene controlling social organization in ants. Mol Ecol 2023; 32:1062-1072. [PMID: 36504171 DOI: 10.1111/mec.16821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 11/23/2022] [Accepted: 12/05/2022] [Indexed: 12/14/2022]
Abstract
Supergenes are clusters of linked loci that control complex phenotypes, such as alternative forms of social organization in ants. Explaining the long-term maintenance of supergenes is challenging, particularly when the derived haplotype lacks homozygous lethality and causes gene drive. In the Alpine silver ant, Formica selysi, a large and ancient social supergene with two haplotypes, M and P, controls colony social organization. Single-queen colonies only contain MM females, while multiqueen colonies contain MP and PP females. The derived P haplotype, found only in multiqueen colonies, selfishly enhances its transmission through maternal effect killing, which could have led to its fixation. A population genetic model showed that a stable social polymorphism can only be maintained under a narrow set of conditions, which includes partial assortative mating by social form (which is known to occur in the wild), and low fitness of PP queens. With a combination of field and laboratory experiments, we show that the P haplotype has deleterious effects on female fitness. The survival rate of PP queens and workers was around half that of other genotypes. Moreover, P-carrying queens had lower fertility and fecundity compared to other queens. We discuss how cryptic lethal effects of the P haplotype help stabilize this ancient polymorphism.
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Affiliation(s)
- Pierre Blacher
- Department of Ecology and Evolution, University of Lausanne, Lausanne, Switzerland
| | - Ornela De Gasperin
- Department of Ecology and Evolution, University of Lausanne, Lausanne, Switzerland.,Red de Ecoetología, Instituto de Ecología A. C., Veracruz, Mexico
| | - Guglielmo Grasso
- Department of Ecology and Evolution, University of Lausanne, Lausanne, Switzerland.,University of Manchester, Manchester, UK
| | - Solenn Sarton-Lohéac
- Department of Ecology and Evolution, University of Lausanne, Lausanne, Switzerland
| | - Roxane Allemann
- Department of Ecology and Evolution, University of Lausanne, Lausanne, Switzerland
| | - Michel Chapuisat
- Department of Ecology and Evolution, University of Lausanne, Lausanne, Switzerland
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Shah M, Kumar H, Qiu S, Li H, Harris M, He J, Abraham A, Crossman DK, Paterson A, Welner RS, Bhatia R. Low c-Kit expression identifies primitive, therapy-resistant CML stem cells. JCI Insight 2023; 8:e157421. [PMID: 36413413 PMCID: PMC9870079 DOI: 10.1172/jci.insight.157421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 11/17/2022] [Indexed: 11/23/2022] Open
Abstract
Despite the efficacy of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML), malignant long-term hematopoietic stem cells (LT-HSCs) persist as a source of relapse. However, LT-HSCs are heterogenous and the most primitive, drug-resistant LT-HSC subpopulations are not well characterized. In normal hematopoiesis, self-renewal and long-term reconstitution capacity are enriched within LT-HSCs with low c-Kit expression (c-KITlo). Here, using a transgenic CML mouse model, we found that long-term engraftment and leukemogenic capacity were restricted to c-KITlo CML LT-HSCs. CML LT-HSCs demonstrated enhanced differentiation with expansion of mature progeny following exposure to the c-KIT ligand, stem cell factor (SCF). Conversely, SCF deletion led to depletion of normal LT-HSCs but increase in c-KITlo and total CML LT-HSCs with reduced generation of mature myeloid cells. CML c-KITlo LT-HSCs showed reduced cell cycling and expressed enhanced quiescence and inflammatory gene signatures. SCF administration led to enhanced depletion of CML primitive progenitors but not LT-HSCs after TKI treatment. Human CML LT-HSCs with low or absent c-KIT expression were markedly enriched after TKI treatment. We conclude that CML LT-HSCs expressing low c-KIT levels are enriched for primitive, quiescent, drug-resistant leukemia-initiating cells and represent a critical target for eliminating disease persistence.
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Affiliation(s)
- Mansi Shah
- Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Harish Kumar
- Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Shaowei Qiu
- Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Hui Li
- Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Mason Harris
- Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Jianbo He
- Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Ajay Abraham
- Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | | | - Andrew Paterson
- Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Robert S. Welner
- Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Ravi Bhatia
- Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA
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6
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Abstract
The bone marrow (BM) is home to numerous cell types arising from hematopoietic stem cells (HSCs) and nonhematopoietic mesenchymal stem cells, as well as stromal cell components. Together they form the BM microenvironment or HSC niche. HSCs critically depend on signaling from these niches to function and survive in the long term. Significant advances in imaging technologies over the past decade have permitted the study of the BM microenvironment in mice, particularly with the development of intravital microscopy (IVM), which provides a powerful method to study these cells in vivo and in real time. Still, there is a lot to be learnt about the interactions of individual HSCs with their environment - at steady state and under various stresses - and whether specific niches exist for distinct developing hematopoietic lineages. Here, we describe our protocol and techniques used to visualize transplanted HSCs in the mouse calvarium, using combined confocal and two-photon IVM.
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Affiliation(s)
- Myriam L R Haltalli
- Imperial College London, London, UK
- The Francis Crick Institute, London, UK
- Wellcome - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Cristina Lo Celso
- Imperial College London, London, UK.
- The Francis Crick Institute, London, UK.
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7
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Liang X, Lan J, Xu M, Qin K, Liu H, Sun G, Liu X, Chen Y, He Z. Impact of KIT Editing on Coat Pigmentation and Fresh Meat Color in Yorkshire Pigs. CRISPR J 2022; 5:825-842. [PMID: 36315201 DOI: 10.1089/crispr.2022.0039] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The white coat color of Yorkshire pigs is caused by the dominant white I allele, which has been associated with at least one copy of the 450-kb duplication encompassing the entire KIT gene and a splice mutation (G > A) at the first base of intron 17. The splice mutation in KIT has an adverse effect on pigmentation in mice. Therefore, removing the 450 kb duplications harboring the KIT copy with splice mutations is expected to affect Yorkshire pig pigmentation. In this study, we describe the use of a Yorkshire pig kidney cell strain with the I?/IBe-ed genotype, previously created by CRISPR-Cas9, as donor cells for somatic cell nuclear transfer to generate gene-edited Yorkshire pigs. The removal of the 450 kb duplications harboring the KIT copy with splice mutation did not alter the white coat color of Yorkshire pigs, which was confirmed by the absence of fully mature melanocytes and melanin accumulation in the hair follicles. Except for the improved transcription of tyrosinase, and slight increase in microphthalmia transcription factor and tyrosinase-related protein 1 protein expression, there was no significant impact of the removal of splice mutations on genes and signaling pathways (PI3K/AKT) involved in melanogenesis. However, the removal of the 450 kb duplications harboring the KIT copy with splice mutation substantially improved fresh meat color accompanied by significantly increased red blood cell number, which merits further investigation. Our study provides new insights into the role of structural mutations of the KIT gene in the formation of white coat color and erythropoiesis in Yorkshire pigs.
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Affiliation(s)
- Xinyu Liang
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Jin Lan
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Meina Xu
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Ke Qin
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Hongbo Liu
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Guanjie Sun
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Xiaohong Liu
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Yaosheng Chen
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Zuyong He
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
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Klein-Rodewald T, Micklich K, Sanz-Moreno A, Tost M, Calzada-Wack J, Adler T, Klaften M, Sabrautzki S, Aigner B, Kraiger M, Gailus-Durner V, Fuchs H, Gründer A, Pahl H, Wolf E, Hrabe de Angelis M, Rathkolb B, Rozman J, Puk O, Schrewe A, Schulz H, Adamski J, Busch DH, Esposito I, Wurst W, Stoeger C, Gründer A, Pahl H, Wolf E, Hrabe de Angelis M, Rathkolb B. New C3H Kit N824K/WT cancer mouse model develops late-onset malignant mammary tumors with high penetrance. Sci Rep 2022; 12:19793. [PMID: 36396684 PMCID: PMC9671887 DOI: 10.1038/s41598-022-23218-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 10/26/2022] [Indexed: 11/18/2022] Open
Abstract
Gastro-intestinal stromal tumors and acute myeloid leukemia induced by activating stem cell factor receptor tyrosine kinase (KIT) mutations are highly malignant. Less clear is the role of KIT mutations in the context of breast cancer. Treatment success of KIT-induced cancers is still unsatisfactory because of primary or secondary resistance to therapy. Mouse models offer essential platforms for studies on molecular disease mechanisms in basic cancer research. In the course of the Munich N-ethyl-N-nitrosourea (ENU) mutagenesis program a mouse line with inherited polycythemia was established. It carries a base-pair exchange in the Kit gene leading to an amino acid exchange at position 824 in the activation loop of KIT. This KIT variant corresponds to the N822K mutation found in human cancers, which is associated with imatinib-resistance. C3H KitN824K/WT mice develop hyperplasia of interstitial cells of Cajal and retention of ingesta in the cecum. In contrast to previous Kit-mutant models, we observe a benign course of gastrointestinal pathology associated with prolonged survival. Female mutants develop mammary carcinomas at late onset and subsequent lung metastasis. The disease model complements existing oncology research platforms. It allows for addressing the role of KIT mutations in breast cancer and identifying genetic and environmental modifiers of disease progression.
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Affiliation(s)
- Tanja Klein-Rodewald
- grid.4567.00000 0004 0483 2525Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Kateryna Micklich
- grid.4567.00000 0004 0483 2525Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Adrián Sanz-Moreno
- grid.4567.00000 0004 0483 2525Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Monica Tost
- grid.4567.00000 0004 0483 2525Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Julia Calzada-Wack
- grid.4567.00000 0004 0483 2525Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Thure Adler
- grid.4567.00000 0004 0483 2525Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Matthias Klaften
- grid.4567.00000 0004 0483 2525Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany ,Present Address: amcure GmbH, Herrman-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
| | - Sibylle Sabrautzki
- grid.4567.00000 0004 0483 2525Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany ,grid.4567.00000 0004 0483 2525Research Unit Comparative Medicine, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Bernhard Aigner
- grid.5252.00000 0004 1936 973XInstitute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Markus Kraiger
- grid.4567.00000 0004 0483 2525Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Valerie Gailus-Durner
- grid.4567.00000 0004 0483 2525Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Helmut Fuchs
- grid.4567.00000 0004 0483 2525Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | | | - Albert Gründer
- grid.7708.80000 0000 9428 7911Section of Molecular Hematology, Department of Hematology/Oncology, Universitäts Klinikum Freiburg, Freiburg, Germany
| | - Heike Pahl
- grid.7708.80000 0000 9428 7911Section of Molecular Hematology, Department of Hematology/Oncology, Universitäts Klinikum Freiburg, Freiburg, Germany
| | - Eckhard Wolf
- grid.5252.00000 0004 1936 973XInstitute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Martin Hrabe de Angelis
- grid.4567.00000 0004 0483 2525Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany ,grid.452622.5German Center for Diabetes Research (DZD), Neuherberg, Germany ,grid.6936.a0000000123222966Chair of Experimental Genetics, TUM School of Life Sciences, Technische Universität München, Freising, Germany
| | - Birgit Rathkolb
- grid.4567.00000 0004 0483 2525Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany ,grid.5252.00000 0004 1936 973XInstitute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany ,grid.452622.5German Center for Diabetes Research (DZD), Neuherberg, Germany
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Tátrai P, Gergely F. Centrosome function is critical during terminal erythroid differentiation. EMBO J 2022; 41:e108739. [PMID: 35678476 PMCID: PMC9289712 DOI: 10.15252/embj.2021108739] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 05/03/2022] [Accepted: 05/25/2022] [Indexed: 11/26/2022] Open
Abstract
Red blood cells are produced by terminal erythroid differentiation, which involves the dramatic morphological transformation of erythroblasts into enucleated reticulocytes. Microtubules are important for enucleation, but it is not known if the centrosome, a key microtubule-organizing center, is required as well. Mice lacking the conserved centrosome component, CDK5RAP2, are likely to have defective erythroid differentiation because they develop macrocytic anemia. Here, we show that fetal liver-derived, CDK5RAP2-deficient erythroid progenitors generate fewer and larger reticulocytes, hence recapitulating features of macrocytic anemia. In erythroblasts, but not in embryonic fibroblasts, loss of CDK5RAP2 or pharmacological depletion of centrosomes leads to highly aberrant spindle morphologies. Consistent with such cells exiting mitosis without chromosome segregation, tetraploidy is frequent in late-stage erythroblasts, thereby giving rise to fewer but larger reticulocytes than normal. Our results define a critical role for CDK5RAP2 and centrosomes in spindle formation specifically during blood production. We propose that disruption of centrosome and spindle function could contribute to the emergence of macrocytic anemias, for instance, due to nutritional deficiency or exposure to chemotherapy.
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Affiliation(s)
- Péter Tátrai
- Cancer Research UK Cambridge InstituteLi Ka Shing CentreUniversity of CambridgeCambridgeUK
- Present address:
Solvo BiotechnologyBudapestHungary
| | - Fanni Gergely
- Cancer Research UK Cambridge InstituteLi Ka Shing CentreUniversity of CambridgeCambridgeUK
- Department of BiochemistryUniversity of OxfordOxfordUK
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10
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Tsai M, Valent P, Galli SJ. KIT as a master regulator of the mast cell lineage. J Allergy Clin Immunol 2022; 149:1845-1854. [PMID: 35469840 PMCID: PMC9177781 DOI: 10.1016/j.jaci.2022.04.012] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/14/2022] [Accepted: 04/15/2022] [Indexed: 10/18/2022]
Abstract
The discovery in 1987/1988 and 1990 of the cell surface receptor KIT and its ligand, stem cell factor (SCF), was a critical achievement in efforts to understand the development and function of multiple distinct cell lineages. These include hematopoietic progenitors, melanocytes, germ cells, and mast cells, which all are significantly affected by loss-of-function mutations of KIT or SCF. Such mutations also influence the development and/or function of additional cells, including those in parts of the central nervous system and the interstitial cells of Cajal (which control gut motility). Many other cells can express KIT constitutively or during immune responses, including dendritic cells, eosinophils, type 2 innate lymphoid cells, and taste cells. Yet the biological importance of KIT in many of these cell types largely remains to be determined. We here review the history of work investigating mice with mutations affecting the white spotting locus (which encodes KIT) or the steel locus (which encodes SCF), focusing especially on the influence of such mutations on mast cells. We also briefly review efforts to target the KIT/SCF pathway with anti-SCF or anti-Kit antibodies in mouse models of allergic disorders, parasite immunity, or fibrosis in which mast cells are thought to play significant roles.
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Affiliation(s)
- Mindy Tsai
- Department of Pathology and the Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, Calif
| | - Peter Valent
- Department of Internal Medicine I, Division of Hematology, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
| | - Stephen J Galli
- Department of Pathology and the Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, Calif; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, Calif.
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11
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Differentiation of fetal hematopoietic stem cells requires ARID4B to restrict autocrine KITLG/KIT-Src signaling. Cell Rep 2021; 37:110036. [PMID: 34818550 PMCID: PMC8722094 DOI: 10.1016/j.celrep.2021.110036] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 07/15/2021] [Accepted: 11/01/2021] [Indexed: 11/26/2022] Open
Abstract
Balance between the hematopoietic stem cell (HSC) duality to either possess self-renewal capacity or differentiate into multipotency progenitors (MPPs) is crucial for maintaining homeostasis of the hematopoietic stem/progenitor cell (HSPC) compartment. To retain the HSC self-renewal activity, KIT, a receptor tyrosine kinase, in HSCs is activated by its cognate ligand KITLG originating from niche cells. Here, we show that AT-rich interaction domain 4B (ARID4B) interferes with KITLG/KIT signaling, consequently allowing HSC differentiation. Conditional Arid4b knockout in mouse hematopoietic cells blocks fetal HSC differentiation, preventing hematopoiesis. Mechanistically, ARID4B-deficient HSCs self-express KITLG and overexpress KIT. As to downstream pathways of KITLG/KIT signaling, inhibition of Src family kinases rescues the HSC differentiation defect elicited by ARID4B loss. In summary, the intrinsic ARID4B-KITLG/KIT-Src axis is an HSPC regulatory program that enables the differentiation state, while KIT stimulation by KITLG from niche cells preserves the HSPC undifferentiated pool. Hematopoietic stem cells (HSCs) at the top of the hematopoietic hierarchy are able to self-renew and differentiate to mature blood cells. Young et al. report that an HSC self-control mechanism established by ARID4B ensures HSC differentiation. ARID4B-deficient HSCs produce KITLG to stimulate KIT, leading to blockage of HSC differentiation and eventual hematopoietic failure.
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12
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Runner's niche: multipurpose stromal cells maintained by exercise. Trends Immunol 2021; 42:841-843. [PMID: 34479798 DOI: 10.1016/j.it.2021.08.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/17/2021] [Accepted: 08/17/2021] [Indexed: 11/21/2022]
Abstract
Using newly developed reporter and lineage-tracing mice, Shen et al. found perivascular stromal cells coexpressing osteolectin and leptin receptor in the bone marrow that specifically supported lymphoid progenitors, served as osteoblast progenitors, and were maintained by mechanical stimulation. Exercise may thus have joint positive influences on lymphopoiesis and bone formation.
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13
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Russkamp NF, Myburgh R, Kiefer JD, Neri D, Manz MG. Anti-CD117 immunotherapy to eliminate hematopoietic and leukemia stem cells. Exp Hematol 2021; 95:31-45. [PMID: 33484750 DOI: 10.1016/j.exphem.2021.01.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 01/18/2021] [Accepted: 01/18/2021] [Indexed: 12/11/2022]
Abstract
Precise replacement of diseased or dysfunctional organs is the goal of regenerative medicine and has appeared to be a distant goal for a long time. In the field of hematopoietic stem cell transplantation, this goal is now becoming tangible as gene-editing technologies and novel conditioning agents are entering the clinical arena. Targeted immunologic depletion of hematopoietic stem cells (HSCs), which are at the very root of the hematopoietic system, will enable more selective and potentially more effective hematopoietic stem cell transplantation in patients with hematological diseases. In contrast to current conditioning regimes based on ionizing radiation and chemotherapy, immunologic conditioning will spare mature hematopoietic cells and cause substantially less inflammation and unspecific collateral damage to other organs. Biological agents that target the stem cell antigen CD117 are the frontrunners for this purpose and have exhibited preclinical activity in depletion of healthy HSCs. The value of anti-CD117 antibodies as conditioning agents is currently being evaluated in early clinical trials. Whereas mild, antibody-based immunologic conditioning concepts might be appropriate for benign hematological disorders in which incomplete replacement of diseased cells is sufficient, higher efficacy will be required for treatment and elimination of hematologic stem cell malignancies such as acute myeloid leukemia and myelodysplastic syndrome. Antibody-drug conjugates, bispecific T-cell engaging and activating antibodies (TEAs), or chimeric antigen receptor (CAR) T cells might offer increased efficacy compared with naked antibodies and yet higher tolerability and safety compared with current genotoxic conditioning approaches. Here, we summarize the current state regarding immunologic conditioning concepts for the treatment of HSC disorders and outline potential future developments.
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Affiliation(s)
- Norman F Russkamp
- Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Comprehensive Cancer Center Zurich (CCCZ), Zurich, Switzerland
| | - Renier Myburgh
- Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Comprehensive Cancer Center Zurich (CCCZ), Zurich, Switzerland
| | - Jonathan D Kiefer
- Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Comprehensive Cancer Center Zurich (CCCZ), Zurich, Switzerland; Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), Zurich, Switzerland
| | - Dario Neri
- Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), Zurich, Switzerland
| | - Markus G Manz
- Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Comprehensive Cancer Center Zurich (CCCZ), Zurich, Switzerland.
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14
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Dlec1 is required for spermatogenesis and male fertility in mice. Sci Rep 2020; 10:18883. [PMID: 33144677 PMCID: PMC7642295 DOI: 10.1038/s41598-020-75957-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 10/22/2020] [Indexed: 12/14/2022] Open
Abstract
Deleted in lung and esophageal cancer 1 (DLEC1) is a tumour suppressor gene that is downregulated in various cancers in humans; however, the physiological and molecular functions of DLEC1 are still unclear. This study investigated the critical role of Dlec1 in spermatogenesis and male fertility in mice. Dlec1 was significantly expressed in testes, with dominant expression in germ cells. We disrupted Dlec1 in mice and analysed its function in spermatogenesis and male fertility. Dlec1 deletion caused male infertility due to impaired spermatogenesis. Spermatogenesis progressed normally to step 8 spermatids in Dlec1−/− mice, but in elongating spermatids, we observed head deformation, a shortened tail, and abnormal manchette organization. These phenotypes were similar to those of various intraflagellar transport (IFT)-associated gene-deficient sperm. In addition, DLEC1 interacted with tailless complex polypeptide 1 ring complex (TRiC) and Bardet–Biedl Syndrome (BBS) protein complex subunits, as well as α- and β-tubulin. DLEC1 expression also enhanced primary cilia formation and cilia length in A549 lung adenocarcinoma cells. These findings suggest that DLEC1 is a possible regulator of IFT and plays an essential role in sperm head and tail formation in mice.
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15
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Paulson RF, Hariharan S, Little JA. Stress erythropoiesis: definitions and models for its study. Exp Hematol 2020; 89:43-54.e2. [PMID: 32750404 DOI: 10.1016/j.exphem.2020.07.011] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 07/28/2020] [Accepted: 07/30/2020] [Indexed: 12/12/2022]
Abstract
Steady-state erythropoiesis generates new erythrocytes at a constant rate, and it has enormous productive capacity. This production is balanced by the removal of senescent erythrocytes by macrophages in the spleen and liver. Erythroid homeostasis is highly regulated to maintain sufficient erythrocytes for efficient oxygen delivery to the tissues, while avoiding viscosity problems associated with overproduction. However, there are times when this constant production of erythrocytes is inhibited or is inadequate; at these times, erythroid output is increased to compensate for the loss of production. In some cases, increased steady-state erythropoiesis can offset the loss of erythrocytes but, in response to inflammation caused by infection or tissue damage, steady-state erythropoiesis is inhibited. To maintain homeostasis under these conditions, an alternative stress erythropoiesis pathway is activated. Emerging data suggest that the bone morphogenetic protein 4 (BMP4)-dependent stress erythropoiesis pathway is integrated into the inflammatory response and generates a bolus of new erythrocytes that maintain homeostasis until steady-state erythropoiesis can resume. In this perspective, we define the mechanisms that generate new erythrocytes when steady-state erythropoiesis is impaired and discuss experimental models to study human stress erythropoiesis.
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Affiliation(s)
- Robert F Paulson
- Center for Molecular Immunology and Infectious Disease and the Department of Veterinary and Biomedical Sciences, Penn State University, University Park, PA; Intercollege Graduate Program in Genetics, Penn State University, University Park, PA.
| | - Sneha Hariharan
- Intercollege Graduate Program in Genetics, Penn State University, University Park, PA
| | - Jane A Little
- Department of Medicine, University of North Carolina Comprehensive Sickle Cell Disease Program, Chapel Hill, NC
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16
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Wang YB, de Lartigue G, Page AJ. Dissecting the Role of Subtypes of Gastrointestinal Vagal Afferents. Front Physiol 2020; 11:643. [PMID: 32595525 PMCID: PMC7300233 DOI: 10.3389/fphys.2020.00643] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 05/20/2020] [Indexed: 12/22/2022] Open
Abstract
Gastrointestinal (GI) vagal afferents convey sensory signals from the GI tract to the brain. Numerous subtypes of GI vagal afferent have been identified but their individual roles in gut function and feeding regulation are unclear. In the past decade, technical approaches to selectively target vagal afferent subtypes and to assess their function has significantly progressed. This review examines the classification of GI vagal afferent subtypes and discusses the current available techniques to study vagal afferents. Investigating the distribution of GI vagal afferent subtypes and understanding how to access and modulate individual populations are essential to dissect their fundamental roles in the gut-brain axis.
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Affiliation(s)
- Yoko B Wang
- Vagal Afferent Research Group, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
| | - Guillaume de Lartigue
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, United States.,Center for Integrative Cardiovascular and Metabolic Disease, University of Florida, Gainesville, FL, United States
| | - Amanda J Page
- Vagal Afferent Research Group, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.,Nutrition, Diabetes and Gut Health, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
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17
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Abstract
A central feature of atherosclerosis, the most prevalent chronic vascular disease and root cause of myocardial infarction and stroke, is leukocyte accumulation in the arterial wall. These crucial immune cells are produced in specialized niches in the bone marrow, where a complex cell network orchestrates their production and release. A growing body of clinical studies has documented a correlation between leukocyte numbers and cardiovascular disease risk. Understanding how leukocytes are produced and how they contribute to atherosclerosis and its complications is, therefore, critical to understanding and treating the disease. In this review, we focus on the key cells and products that regulate hematopoiesis under homeostatic conditions, during atherosclerosis and after myocardial infarction.
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Affiliation(s)
- Wolfram C Poller
- From the Center for Systems Biology (W.C.P., M.N., F.K.S.), Massachusetts General Hospital and Harvard Medical School, Boston
| | - Matthias Nahrendorf
- From the Center for Systems Biology (W.C.P., M.N., F.K.S.), Massachusetts General Hospital and Harvard Medical School, Boston
- Department of Radiology (M.N., F.K.S.), Massachusetts General Hospital and Harvard Medical School, Boston
| | - Filip K Swirski
- From the Center for Systems Biology (W.C.P., M.N., F.K.S.), Massachusetts General Hospital and Harvard Medical School, Boston
- Department of Radiology (M.N., F.K.S.), Massachusetts General Hospital and Harvard Medical School, Boston
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18
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Galli SJ, Metz M, Starkl P, Marichal T, Tsai M. Mast cells and IgE in defense against lethality of venoms: Possible "benefit" of allergy[]. ALLERGO JOURNAL INTERNATIONAL 2020; 29:46-62. [PMID: 33224714 PMCID: PMC7673288 DOI: 10.1007/s40629-020-00118-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 10/20/2019] [Indexed: 01/15/2023]
Abstract
Physicians think of mast cells and IgE primarily in the context of allergic disorders, including fatal anaphylaxis. This 'bad side' of mast cells and IgE is so well accepted that it can be difficult to think of them in other contexts, particularly those in which they may have beneficial functions. However, there is evidence that mast cells and IgE, as well as basophils (circulating granulocytes whose functions partially overlap with those of mast cells), can contribute to host defense as components of adaptive type 2 immune responses to helminths, ticks and certain other parasites. Accordingly, allergies often are conceptualized as "misdirected" type 2 immune responses, in which IgE antibodies are produced against any of a diverse group of apparently harmless antigens, and against components of animal venoms. Indeed, certain unfortunate patients who have become sensitized to venoms develop severe IgE-associated allergic reactions, including fatal anaphylaxis, upon subsequent venom exposure. In this review, we will describe evidence that mast cells can enhance innate resistance, and survival, to challenge with reptile or arthropod venoms during a first exposure to such venoms. We also will discuss findings indicating that, in mice surviving an initial encounter with venom, acquired type 2 immune responses, IgE antibodies, the high affinity IgE receptor (FcεRI), and mast cells can contribute to acquired resistance to the lethal effects of both honeybee venom and Russell's viper venom. These findings support the hypothesis that mast cells and IgE can help protect the host against venoms and perhaps other noxious substances.
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Affiliation(s)
- Stephen J. Galli
- Department of Pathology and the Sean N. Parker Center for Allergy Research, Stanford University School of Medicine, Stanford, California, 94305; USA
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, 94305; USA
| | - Martin Metz
- Department of Dermatology and Allergy, Charité – Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Philipp Starkl
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria
- Department of Medicine 1, Laboratory of Infection Biology, Medical University of Vienna, 1090 Vienna, Austria
| | - Thomas Marichal
- GIGA-Research and Faculty of Veterinary Medicine, University of Liege, 4000 Liege, Belgium
| | - Mindy Tsai
- Department of Pathology and the Sean N. Parker Center for Allergy Research, Stanford University School of Medicine, Stanford, California, 94305; USA
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19
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Kondaiah P, Sharp PA, Pullakhandam R. Zinc induces iron egress from intestinal Caco-2 cells via induction of Hephaestin: A role for PI3K in intestinal iron absorption. Biochem Biophys Res Commun 2020; 523:987-992. [DOI: 10.1016/j.bbrc.2020.01.023] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Accepted: 01/03/2020] [Indexed: 01/23/2023]
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20
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Galli SJ, Metz M, Starkl P, Marichal T, Tsai M. Mast cells and IgE in defense against lethality of venoms: Possible "benefit" of allergy*. ALLERGO JOURNAL 2020. [DOI: 10.1007/s15007-020-0746-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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21
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Parsons SP, Huizinga JD. A myogenic motor pattern in mice lacking myenteric interstitial cells of Cajal explained by a second coupled oscillator network. Am J Physiol Gastrointest Liver Physiol 2020; 318:G225-G243. [PMID: 31813235 PMCID: PMC7052571 DOI: 10.1152/ajpgi.00311.2019] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The interstitial cells of Cajal associated with the myenteric plexus (ICC-MP) are a network of coupled oscillators in the small intestine that generate rhythmic electrical phase waves leading to corresponding waves of contraction, yet rhythmic action potentials and intercellular calcium waves have been recorded from c-kit-mutant mice that lack the ICC-MP, suggesting that there may be a second pacemaker network. The gap junction blocker carbenoxolone induced a "pinstripe" motor pattern consisting of rhythmic "stripes" of contraction that appeared simultaneously across the intestine with a period of ~4 s. The infinite velocity of these stripes suggested they were generated by a coupled oscillator network, which we call X. In c-kit mutants rhythmic contraction waves with the period of X traveled the length of the intestine, before the induction of the pinstripe pattern by carbenoxolone. Thus X is not the ICC-MP and appears to operate under physiological conditions, a fact that could explain the viability of these mice. Individual stripes consisted of a complex pattern of bands of contraction and distension, and between stripes there could be slide waves and v waves of contraction. We hypothesized that these phenomena result from an interaction between X and the circular muscle that acts as a damped oscillator. A mathematical model of two chains of coupled Fitzhugh-Nagumo systems, representing X and circular muscle, supported this hypothesis. The presence of a second coupled oscillator network in the small intestine underlines the complexity of motor pattern generation in the gut.NEW & NOTEWORTHY Physiological experiments and a mathematical model indicate a coupled oscillator network in the small intestine in addition to the c-kit-expressing myenteric interstitial cells of Cajal. This network interacts with the circular muscle, which itself acts as a system of damped oscillators, to generate physiological contraction waves in c-kit (W) mutant mice.
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Affiliation(s)
- Sean P. Parsons
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Jan D. Huizinga
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
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22
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Federici G, Varricchio L, Martelli F, Falchi M, Picconi O, Francescangeli F, Contavalli P, Girelli G, Tafuri A, Petricoin EF, Mazzarini M, Zeuner A, Migliaccio AR. Phosphoproteomic Landscaping Identifies Non-canonical cKIT Signaling in Polycythemia Vera Erythroid Progenitors. Front Oncol 2019; 9:1245. [PMID: 31824842 PMCID: PMC6883719 DOI: 10.3389/fonc.2019.01245] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 10/29/2019] [Indexed: 01/08/2023] Open
Abstract
Although stem cell factor (SCF)/cKIT interaction plays key functions in erythropoiesis, cKIT signaling in human erythroid cells is still poorly defined. To provide new insights into cKIT-mediated erythroid expansion in development and disease, we performed phosphoproteomic profiling of primary erythroid progenitors from adult blood (AB), cord blood (CB), and Polycythemia Vera (PV) at steady-state and upon SCF stimulation. While AB and CB, respectively, activated transient or sustained canonical cKIT-signaling, PV showed a non-canonical signaling including increased mTOR and ERK1 and decreased DEPTOR. Accordingly, screening of FDA-approved compounds showed increased PV sensitivity to JAK, cKIT, and MEK inhibitors. Moreover, differently from AB and CB, in PV the mature 145kDa-cKIT constitutively associated with the tetraspanin CD63 and was not endocytosed upon SCF stimulation, contributing to unrestrained cKIT signaling. These results identify a clinically exploitable variegation of cKIT signaling/metabolism that may contribute to the great erythroid output occurring during development and in PV.
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Affiliation(s)
| | - Lilian Varricchio
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Fabrizio Martelli
- National Center for Preclinical and Clinical Research and Evaluation of Pharmaceutical Drugs, Istituto Superiore di Sanità, Rome, Italy
| | - Mario Falchi
- National HIV/AIDS Center, Istituto Superiore di Sanità, Rome, Italy
| | - Orietta Picconi
- National HIV/AIDS Center, Istituto Superiore di Sanità, Rome, Italy
| | | | - Paola Contavalli
- Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Gabriella Girelli
- Immunohematology and Transfusion Medicine Unit, "La Sapienza" University of Rome, Rome, Italy
| | - Agostino Tafuri
- Sant'Andrea Hospital-La Sapienza, Department of Clinic and Molecular Medicine "La Sapienza" University of Rome, Rome, Italy
| | - Emanuel F Petricoin
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, United States
| | - Maria Mazzarini
- Department of Biomedical and Neuromotorial Sciences, Alma Mater University, Bologna, Italy
| | - Ann Zeuner
- Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Anna Rita Migliaccio
- Myeloproliferative Neoplasm Research Consortium, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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23
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Iino S, Horiguchi K, Horiguchi S. c-Kit-stem cell factor signal-independent development of interstitial cells of Cajal in murine small intestine. Cell Tissue Res 2019; 379:121-129. [PMID: 31741038 DOI: 10.1007/s00441-019-03120-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2019] [Accepted: 10/06/2019] [Indexed: 01/08/2023]
Abstract
c-Kit receptor tyrosine kinase and its ligand stem cell factor (SCF) play critical roles in regulating the development and proliferation of various cells, including the interstitial cells of Cajal (ICC) in the gastrointestinal tract. Many subtypes of ICC are known to be lacking in c-Kit-SCF-insufficient mice, such as W/Wv and Sl/Sld, whereas ICC-deep muscular plexus (DMP) in small intestine are not lacking. In this study, we examine ICC-DMP development in normal and c-Kit-SCF signal-insufficient mice. In normal mice, numerous ICC-DMP labeled with c-Kit and neurokinin 1 receptor (NK1R) antibodies were observed only in the duodenum on the day of birth, in the duodenum and the jejunum on postnatal day 4 and throughout the small intestine after postnatal day 6. In W mutant mice (W/Wv, Wv/Wv, W/W), ICC-DMP investigated using c-Kit and NK1R immunoreactivities were similar to that in normal mice. c-Kit ligand SCF-deficient mice (Sl/Sl) also showed almost identical ICC-DMP development and proliferation as normal mice. These results show that the development and proliferation of ICC-DMP occur in the postnatal period independent of c-Kit-SCF signaling.
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Affiliation(s)
- Satoshi Iino
- Department of Anatomy, University of Fukui Faculty of Medical Sciences, Eiheiji, Fukui, 910-1193, Japan.
| | - Kazuhide Horiguchi
- Department of Anatomy, University of Fukui Faculty of Medical Sciences, Eiheiji, Fukui, 910-1193, Japan
| | - Satomi Horiguchi
- Department of Anatomy, University of Fukui Faculty of Medical Sciences, Eiheiji, Fukui, 910-1193, Japan
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24
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Meng D, Carvajal RD. KIT as an Oncogenic Driver in Melanoma: An Update on Clinical Development. Am J Clin Dermatol 2019; 20:315-323. [PMID: 30707374 DOI: 10.1007/s40257-018-0414-1] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Metastatic melanoma is a heterogenous disease that has served as a model for the development of both targeted therapy and immunotherapy. KIT-mutated melanoma represents a rare subset, most commonly arising from acral, mucosal, and chronically sun-damaged skin. Additionally, KIT alterations are enriched in the triple wild-type subtype of cutaneous melanoma. Activating alterations of KIT-a transmembrane receptor tyrosine kinase important for cell development, growth, and differentiation-have been shown to be critical to oncogenesis across many tumor subtypes. Following the successes of BRAF-targeted therapy in melanoma and KIT-targeted therapy in gastrointestinal stromal tumors, small-molecule tyrosine kinase inhibitors targeting KIT have been examined in KIT-mutated melanoma. KIT inhibitors that have been investigated in relevant clinical trials in advanced melanoma include imatinib, sunitinib, dasatinib, and nilotinib. In these studies, selected patients with KIT-mutated melanoma were shown to be responsive to therapy with KIT inhibition, especially patients with L576P and K642E mutations. This has led to the incorporation of KIT-targeted therapy in the National Comprehensive Cancer Network guidelines for systemic therapy for metastatic or unresectable melanoma. Current research and development efforts include novel KIT-targeted therapies and testing KIT inhibitors in combination with immunotherapy.
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25
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Frumento G, Zuo J, Verma K, Croft W, Ramagiri P, Chen FE, Moss P. CD117 (c-Kit) Is Expressed During CD8 + T Cell Priming and Stratifies Sensitivity to Apoptosis According to Strength of TCR Engagement. Front Immunol 2019; 10:468. [PMID: 30930902 PMCID: PMC6428734 DOI: 10.3389/fimmu.2019.00468] [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: 05/31/2018] [Accepted: 02/21/2019] [Indexed: 01/04/2023] Open
Abstract
CD117 (cKit) is the receptor for stem cell factor (SCF) and plays an important role in early haemopoiesis. We show that CD117 is also expressed following priming of mature human CD8+ T cells in vitro and is detectable following primary infection in vivo. CD117 expression is mediated through an intrinsic pathway and is suppressed by IL-12. Importantly, the extent of CD117 expression is inversely related to the strength of the activating stimulus and subsequent engagement with cell-bound SCF markedly increases susceptibility to apoptosis. CD117 is therefore likely to shape the pattern of CD8+ T cell immunodominance during a primary immune response by rendering cells with low avidity for antigen more prone to apoptosis. Furthermore, CD117+ T cells are highly sensitive to apoptosis mediated by galectin-1, a molecule commonly expressed within the tumor microenvironment, and CD117 expression may therefore represent a novel and potentially targetable mechanism of tumor immune evasion.
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Affiliation(s)
- Guido Frumento
- Institute of Immunology and Immunotherapy, University of Birmingham Birmingham, United Kingdom.,NHS Blood and Transplant, Birmingham, United Kingdom
| | - Jianmin Zuo
- Institute of Immunology and Immunotherapy, University of Birmingham Birmingham, United Kingdom
| | - Kriti Verma
- Institute of Immunology and Immunotherapy, University of Birmingham Birmingham, United Kingdom
| | - Wayne Croft
- Institute of Immunology and Immunotherapy, University of Birmingham Birmingham, United Kingdom.,Centre for Computational Biology, University of Birmingham Birmingham, United Kingdom
| | - Pradeep Ramagiri
- Institute of Immunology and Immunotherapy, University of Birmingham Birmingham, United Kingdom
| | - Frederick E Chen
- Institute of Immunology and Immunotherapy, University of Birmingham Birmingham, United Kingdom.,NHS Blood and Transplant, Birmingham, United Kingdom.,Centre for Clinical Haematology, University Hospitals Birmingham NHS Foundation Trust Birmingham, United Kingdom.,Royal London Hospital, Barts Health NHS Trust London, United Kingdom
| | - Paul Moss
- Institute of Immunology and Immunotherapy, University of Birmingham Birmingham, United Kingdom.,Centre for Clinical Haematology, University Hospitals Birmingham NHS Foundation Trust Birmingham, United Kingdom
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27
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Targeting the niche: depleting haemopoietic stem cells with targeted therapy. Bone Marrow Transplant 2019; 54:961-968. [PMID: 30664721 DOI: 10.1038/s41409-019-0445-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Revised: 12/04/2018] [Accepted: 12/30/2018] [Indexed: 12/11/2022]
Abstract
Haemopoietic stem cell transplantation is an expanding procedure worldwide but is associated with significant morbidity and mortality. Depletion of resident haemopoietic stem and progenitor cells (HSPC) is required for both autologous and allogeneic haemopoietic stem cell transplantation. Current conditioning protocols utilise chemotherapy or radiation to effectively reduce HSPC but are toxic in both the short and long term. The initial trials to use monoclonal antibodies to target HSPC were limited with marginal efficacy but platforms including antibody drug conjugates and chimeric antigen receptor T cells have made targeted conditioning strategies achievable. In this review we summarise the work developing targeted conditioning that may replace or reduce alkylating agents and total body irradiation. The prospect of conditioning with significantly reduced toxicity will improve outcomes and open transplantation to patients unable to tolerate current conditioning protocols.
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Comazzetto S, Murphy MM, Berto S, Jeffery E, Zhao Z, Morrison SJ. Restricted Hematopoietic Progenitors and Erythropoiesis Require SCF from Leptin Receptor+ Niche Cells in the Bone Marrow. Cell Stem Cell 2019; 24:477-486.e6. [PMID: 30661958 DOI: 10.1016/j.stem.2018.11.022] [Citation(s) in RCA: 134] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 10/18/2018] [Accepted: 11/21/2018] [Indexed: 12/20/2022]
Abstract
Hematopoietic stem cells (HSCs) are maintained in a perivascular niche in bone marrow, in which leptin receptor+ (LepR) stromal cells and endothelial cells synthesize factors required for HSC maintenance, including stem cell factor (SCF). An important question is why LepR+ cells are one hundred times more frequent than HSCs. Here, we show that SCF from LepR+ cells is also necessary to maintain many c-kit+-restricted hematopoietic progenitors. Conditional deletion of Scf from LepR+ cells depleted common myeloid progenitors (CMPs), common lymphoid progenitors (CLPs), granulocyte-macrophage progenitors (GMPs), megakaryocyte-erythrocyte progenitors (MEPs), pre-megakaryocyte-erythrocyte progenitors (PreMegEs), and colony-forming units-erythroid (CFU-Es), as well as myeloid and erythroid blood cells. This was not caused by HSC depletion, as many other restricted progenitors were unaffected. Moreover, Scf deletion from endothelial cells depleted HSCs, but not progenitors. Early erythroid progenitors were closely associated with perisinusoidal LepR+ cells. This reveals cellular specialization within the niche: SCF from LepR+ cells is broadly required by HSCs and restricted progenitors while SCF from endothelial cells is required mainly by HSCs.
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Affiliation(s)
- Stefano Comazzetto
- Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Malea M Murphy
- Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Stefano Berto
- Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Elise Jeffery
- Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Zhiyu Zhao
- Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Sean J Morrison
- Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
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29
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Sanders KM, Ward SM. Nitric oxide and its role as a non-adrenergic, non-cholinergic inhibitory neurotransmitter in the gastrointestinal tract. Br J Pharmacol 2019; 176:212-227. [PMID: 30063800 PMCID: PMC6295421 DOI: 10.1111/bph.14459] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Revised: 07/06/2018] [Accepted: 07/12/2018] [Indexed: 12/19/2022] Open
Abstract
NO is a neurotransmitter released from enteric inhibitory neurons and responsible for modulating gastrointestinal (GI) motor behaviour. Enteric neurons express nNOS (NOS1) that associates with membranes of nerve varicosities. NO released from neurons binds to soluble guanylate cyclase in post-junctional cells to generate cGMP. cGMP-dependent protein kinase type 1 (PKG1) is a major mediator but perhaps not the only pathway involved in cGMP-mediated effects in GI muscles based on gene deletion studies. NOS1+ neurons form close contacts with smooth muscle cells (SMCs), interstitial cells of Cajal (ICC) and PDGFRα+ cells, and these cells are electrically coupled (SIP syncytium). Cell-specific gene deletion studies have shown that nitrergic responses are due to mechanisms in SMCs and ICC. Controversy exists about the ion channels and other post-junctional mechanisms that mediate nitrergic responses in GI muscles. Reduced nNOS expression in enteric inhibitory motor neurons and/or reduced connectivity between nNOS+ neurons and the SIP syncytium appear to be responsible for motor defects that develop in diabetes. An overproduction of NO in some inflammatory conditions also impairs normal GI motor activity. This review summarizes recent findings regarding the role of NO as an enteric inhibitory neurotransmitter. LINKED ARTICLES: This article is part of a themed section on Nitric Oxide 20 Years from the 1998 Nobel Prize. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.2/issuetoc.
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Affiliation(s)
- Kenton M Sanders
- Department of Physiology and Cell BiologyUniversity of Nevada, Reno, School of MedicineRenoNVUSA
| | - Sean M Ward
- Department of Physiology and Cell BiologyUniversity of Nevada, Reno, School of MedicineRenoNVUSA
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Abstract
KIT is a receptor tyrosine kinase that after binding to its ligand stem cell factor activates signaling cascades linked to biological processes such as proliferation, differentiation, migration and cell survival. Based on studies performed on SCF and/or KIT mutant animals that presented anemia, sterility, and/or pigmentation disorders, KIT signaling was mainly considered to be involved in the regulation of hematopoiesis, gametogenesis, and melanogenesis. More recently, novel animal models and ameliorated cellular and molecular techniques have led to the discovery of a widen repertoire of tissue compartments and functions that are being modulated by KIT. This is the case for the lung, heart, nervous system, gastrointestinal tract, pancreas, kidney, liver, and bone. For this reason, the tyrosine kinase inhibitors that were originally developed for the treatment of hemato-oncological diseases are being currently investigated for the treatment of non-oncological disorders such as asthma, rheumatoid arthritis, and alzheimer's disease, among others. The beneficial effects of some of these tyrosine kinase inhibitors have been proven to depend on KIT inhibition. This review will focus on KIT expression and regulation in healthy and pathologic conditions other than cancer. Moreover, advances in the development of anti-KIT therapies, including tyrosine kinase inhibitors, and their application will be discussed.
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Abstract
Humoral regulation by ligand/receptor interactions is a fundamental feature of vertebrate hematopoiesis. Zebrafish are an established vertebrate animal model of hematopoiesis, sharing with mammals conserved genetic, molecular and cell biological regulatory mechanisms. This comprehensive review considers zebrafish hematopoiesis from the perspective of the hematopoietic growth factors (HGFs), their receptors and their actions. Zebrafish possess multiple HGFs: CSF1 (M-CSF) and CSF3 (G-CSF), kit ligand (KL, SCF), erythropoietin (EPO), thrombopoietin (THPO/TPO), and the interleukins IL6, IL11, and IL34. Some ligands and/or receptor components have been duplicated by various mechanisms including the teleost whole genome duplication, adding complexity to the ligand/receptor interactions possible, but also providing examples of several different outcomes of ligand and receptor subfunctionalization or neofunctionalization. CSF2 (GM-CSF), IL3 and IL5 and their receptors are absent from zebrafish. Overall the humoral regulation of hematopoiesis in zebrafish displays considerable similarity with mammals, which can be applied in biological and disease modelling research.
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Affiliation(s)
- Vahid Pazhakh
- a Australian Regenerative Medicine Institute, Monash University , Clayton , Australia
| | - Graham J Lieschke
- a Australian Regenerative Medicine Institute, Monash University , Clayton , Australia
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32
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Neo WH, Booth CAG, Azzoni E, Chi L, Delgado-Olguín P, de Bruijn MF, Jacobsen SEW, Mead AJ. Cell-extrinsic hematopoietic impact of Ezh2 inactivation in fetal liver endothelial cells. Blood 2018; 131:2223-2234. [PMID: 29555646 PMCID: PMC5960588 DOI: 10.1182/blood-2017-10-811455] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 03/01/2018] [Indexed: 12/15/2022] Open
Abstract
Despite the well-established cell-intrinsic role of epigenetic factors in normal and malignant hematopoiesis, their cell-extrinsic role remains largely unexplored. Herein we investigated the hematopoietic impact of inactivating Ezh2, a key component of polycomb repressive complex 2 (PRC2), in the fetal liver (FL) vascular niche. Hematopoietic specific (Vav-iCre) Ezh2 inactivation enhanced FL hematopoietic stem cell (HSC) expansion with normal FL erythropoiesis. In contrast, endothelium (Tie2-Cre) targeted Ezh2 inactivation resulted in embryonic lethality with severe anemia at embryonic day 13.5 despite normal emergence of functional HSCs. Ezh2-deficient FL endothelium overexpressed Mmp9, which cell-extrinsically depleted the membrane-bound form of Kit ligand (mKitL), an essential hematopoietic cytokine, in FL. Furthermore, Mmp9 inhibition in vitro restored mKitL expression along with the erythropoiesis supporting capacity of FL endothelial cells. These data establish that Ezh2 is intrinsically dispensable for FL HSCs and provides proof of principle that modulation of epigenetic regulators in niche components can exert a marked cell-extrinsic impact.
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Affiliation(s)
- Wen Hao Neo
- Haematopoietic Stem Cell Biology Laboratory, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom
- MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom
| | - Christopher A. G. Booth
- Haematopoietic Stem Cell Biology Laboratory, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom
- MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom
| | - Emanuele Azzoni
- MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom
| | - Lijun Chi
- Translational Medicine, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, and Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Paul Delgado-Olguín
- Translational Medicine, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, and Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Marella F.T.R. de Bruijn
- MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom
| | - Sten Eirik W. Jacobsen
- Haematopoietic Stem Cell Biology Laboratory, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom
- MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom
- Department of Cell and Molecular Biology and Department of Medicine Huddinge, Karolinska Institutet, and Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge Stockholm, Sweden
| | - Adam J. Mead
- Haematopoietic Stem Cell Biology Laboratory, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom
- MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom
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Hamer G, de Rooij DG. Mutations causing specific arrests in the development of mouse primordial germ cells and gonocytes. Biol Reprod 2018; 99:75-86. [DOI: 10.1093/biolre/ioy075] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2018] [Accepted: 03/22/2018] [Indexed: 11/13/2022] Open
Affiliation(s)
- Geert Hamer
- Center for Reproductive Medicine, Amsterdam Research Institute Reproduction and Development, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Dirk G de Rooij
- Center for Reproductive Medicine, Amsterdam Research Institute Reproduction and Development, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Reproductive Biology Group, Division of Developmental Biology, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands
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Direct engagement of the PI3K pathway by mutant KIT dominates oncogenic signaling in gastrointestinal stromal tumor. Proc Natl Acad Sci U S A 2017; 114:E8448-E8457. [PMID: 28923937 DOI: 10.1073/pnas.1711449114] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) predominantly harbor activating mutations in the receptor tyrosine kinase KIT. To genetically dissect in vivo the requirement of different signal transduction pathways emanating from KIT for tumorigenesis, the oncogenic KitV558Δ mutation was combined with point mutations abrogating specific phosphorylation sites on KIT. Compared with single-mutant KitV558Δ/+ mice, double-mutant KitV558Δ;Y567F/Y567F knock-in mice lacking the SRC family kinase-binding site on KIT (pY567) exhibited attenuated MAPK signaling and tumor growth. Surprisingly, abrogation of the PI3K-binding site (pY719) in KitV558Δ;Y719F/Y719F mice prevented GIST development, although the interstitial cells of Cajal (ICC), the cells of origin of GIST, were normal. Pharmacologic inhibition of the PI3K pathway in tumor-bearing KitV558Δ/+ mice with the dual PI3K/mTOR inhibitor voxtalisib, the pan-PI3K inhibitor pilaralisib, and the PI3K-alpha-restricted inhibitor alpelisib each diminished tumor proliferation. The addition of the MEK inhibitor PD-325901 or binimetinib further decreased downstream KIT signaling. Moreover, combining PI3K and MEK inhibition was effective against imatinib-resistant KitV558Δ;T669I/+ tumors.
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Otsuka A, Nomura T, Rerknimitr P, Seidel JA, Honda T, Kabashima K. The interplay between genetic and environmental factors in the pathogenesis of atopic dermatitis. Immunol Rev 2017; 278:246-262. [DOI: 10.1111/imr.12545] [Citation(s) in RCA: 83] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Atsushi Otsuka
- Department of Dermatology; Kyoto University Graduate School of Medicine; Kyoto Japan
| | - Takashi Nomura
- Department of Dermatology; Kyoto University Graduate School of Medicine; Kyoto Japan
| | - Pawinee Rerknimitr
- Department of Dermatology; Kyoto University Graduate School of Medicine; Kyoto Japan
- Division of Dermatology; Department of Medicine; Faculty of Medicine, Allergy and Clinical Immunology Research Group; Chulalongkorn University; Bangkok Thailand
| | - Judith A. Seidel
- Department of Dermatology; Kyoto University Graduate School of Medicine; Kyoto Japan
| | - Tetsuya Honda
- Department of Dermatology; Kyoto University Graduate School of Medicine; Kyoto Japan
| | - Kenji Kabashima
- Department of Dermatology; Kyoto University Graduate School of Medicine; Kyoto Japan
- Singapore Immunology Network (SIgN) and Institute of Medical Biology; Agency for Science, Technology and Research (A*STAR); Biopolis; Singapore
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37
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Kumfu S, Fucharoen S, Chattipakorn SC, Chattipakorn N. Cardiac complications in beta-thalassemia: From mice to men. Exp Biol Med (Maywood) 2017; 242:1126-1135. [PMID: 28485683 DOI: 10.1177/1535370217708977] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Beta-thalassemia is an inherited hemoglobin disorder caused by reduced or absent synthesis of the beta globin chains of hemoglobin. This results in variable outcomes ranging from clinically asymptomatic to severe anemia, which then typically requires regular blood transfusion. These regular blood transfusions can result in an iron overload condition. The iron overload condition can lead to iron accumulation in various organs, especially in the heart, leading to iron overload cardiomyopathy, which is the major cause of mortality in patients with thalassemia. In the past decades, there is no doubt that the use of β-thalassemic mice as a study model to investigate the pathophysiology of iron overload cardiomyopathy and the role of various pharmacological interventions, has shed some light in understanding this serious complication and in improving the associated cardiac dysfunction. In this review, the effects that iron overload has on the hearts of β-thalassemic mice under conditions of iron overload as well as the efficacy of pharmacological interventions to combat these adverse effects on the heart are reviewed and discussed. The in-depth understanding of biomolecular alterations in the heart of these iron overload thalassemic mice will help give guidance for more effective therapeutic approaches in the near future. Impact statement Iron overload cardiomyopathy is a major cause of morbidity and mortality in patients with thalassemia. Since investigation of iron overload cardiomyopathy in thalassemia patients has many limitations, a search for an animal model for this condition has been ongoing for decades. In the past decades, there is no doubt that the use of β-thalassemic mice as a study model to investigate the pathophysiology of iron overload cardiomyopathy and the role of various pharmacological interventions, has shed some light in understanding this serious complication and in improving the associated cardiac dysfunction. In this review, the effects of iron overload on the hearts of β-thalassemic mice under conditions of iron overload as well as the efficacy of pharmacological interventions to combat these adverse effects on the heart are reviewed and discussed.
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Affiliation(s)
- Sirinart Kumfu
- 1 Faculty of Medicine, Cardiac Electrophysiology Research and Training Center, Chiang Mai University, Chiang Mai 50200, Thailand.,2 Faculty of Medicine, Department of Physiology, Cardiac Electrophysiology Unit, Chiang Mai University, Chiang Mai 50200, Thailand.,3 Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Suthat Fucharoen
- 4 Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom 73170, Thailand
| | - Siriporn C Chattipakorn
- 1 Faculty of Medicine, Cardiac Electrophysiology Research and Training Center, Chiang Mai University, Chiang Mai 50200, Thailand.,3 Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand.,5 Faculty of Dentistry, Department of Oral Biology and Diagnostic Sciences, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Nipon Chattipakorn
- 1 Faculty of Medicine, Cardiac Electrophysiology Research and Training Center, Chiang Mai University, Chiang Mai 50200, Thailand.,2 Faculty of Medicine, Department of Physiology, Cardiac Electrophysiology Unit, Chiang Mai University, Chiang Mai 50200, Thailand.,3 Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand
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Barroeta Seijas AB, Simonetti S, Vitale S, Runci D, Quinci AC, Soriani A, Criscuoli M, Filippi I, Naldini A, Sacchetti FM, Tarantino U, Oliva F, Piccirilli E, Santoni A, Di Rosa F. GM-CSF Inhibits c-Kit and SCF Expression by Bone Marrow-Derived Dendritic Cells. Front Immunol 2017; 8:147. [PMID: 28261209 PMCID: PMC5311071 DOI: 10.3389/fimmu.2017.00147] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Accepted: 01/30/2017] [Indexed: 01/20/2023] Open
Abstract
Stem cell factor (SCF), the ligand of c-kit, is a key cytokine for hematopoiesis. Hematopoietic precursors express c-kit, whereas differentiated cells of hematopoietic lineage are negative for this receptor, with the exception of NK cells, mast cells, and a few others. While it has long been recognized that dendritic cells (DCs) can express c-kit, several questions remain concerning the SCF/c-kit axis in DCs. This is particularly relevant for DCs found in those organs wherein SCF is highly expressed, including the bone marrow (BM). We characterized c-kit expression by conventional DCs (cDCs) from BM and demonstrated a higher proportion of c-kit+ cells among type 1 cDC subsets (cDC1s) than type 2 cDC subsets (cDC2s) in both humans and mice, whereas similar levels of c-kit expression were observed in cDC1s and cDC2s from mouse spleen. To further study c-kit regulation, DCs were generated with granulocyte-macrophage colony-stimulating factor (GM-CSF) from mouse BM, a widely used protocol. CD11c+ cells were purified from pooled non-adherent and slightly adherent cells collected after 7 days of culture, thus obtaining highly purified BM-derived DCs (BMdDCs). BMdDCs contained a small fraction of c-kit+ cells, and by replating them for 2 days with GM-CSF, we obtained a homogeneous population of c-kit+ CD40hi MHCIIhi cells. Not only did BMdDCs express c-kit but they also produced SCF, and both were striking upregulated if GM-CSF was omitted after replating. Furthermore, a small but significant reduction in BMdDC survival was observed upon SCF silencing. Incubation of BMdDCs with SCF did not modulate antigen presentation ability of these cells, nor it did regulate their membrane expression of the chemokine receptor CXCR4. We conclude that the SCF/c-kit-mediated prosurvival circuit may have been overlooked because of the prominent use of GM-CSF in DC cultures in vitro, including those human DC cultures destined for the clinics. We speculate that DCs more prominently rely on SCF in vivo in some microenvironments, with potential implications for graft-versus-host disease and antitumor immunity.
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Affiliation(s)
- Amairelys Belen Barroeta Seijas
- Institute of Molecular Biology and Pathology, National Research Council (CNR), c/o Department of Molecular Medicine, University of Rome "Sapienza", Rome, Italy; Department of Molecular Medicine, University of Rome "Sapienza", Rome, Italy
| | - Sonia Simonetti
- Department of Molecular Medicine, University of Rome "Sapienza" , Rome , Italy
| | - Sara Vitale
- Institute of Molecular Biology and Pathology, National Research Council (CNR), c/o Department of Molecular Medicine, University of Rome "Sapienza" , Rome , Italy
| | - Daniele Runci
- Istituto Pasteur Italia - Fondazione Cenci Bolognetti , Rome , Italy
| | | | - Alessandra Soriani
- Department of Molecular Medicine, University of Rome "Sapienza" , Rome , Italy
| | - Mattia Criscuoli
- Department of Molecular and Developmental Medicine, University of Siena , Siena , Italy
| | - Irene Filippi
- Department of Molecular and Developmental Medicine, University of Siena , Siena , Italy
| | - Antonella Naldini
- Department of Molecular and Developmental Medicine, University of Siena , Siena , Italy
| | | | - Umberto Tarantino
- Department of Orthopaedics and Traumatology, University of Rome "Tor Vergata" , Rome , Italy
| | - Francesco Oliva
- Department of Orthopaedics and Traumatology, University of Rome "Tor Vergata" , Rome , Italy
| | - Eleonora Piccirilli
- Department of Orthopaedics and Traumatology, University of Rome "Tor Vergata" , Rome , Italy
| | - Angela Santoni
- Department of Molecular Medicine, University of Rome "Sapienza", Rome, Italy; Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Rome, Italy
| | - Francesca Di Rosa
- Institute of Molecular Biology and Pathology, National Research Council (CNR), c/o Department of Molecular Medicine, University of Rome "Sapienza" , Rome , Italy
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Galli SJ. The Mast Cell-IgE Paradox: From Homeostasis to Anaphylaxis. THE AMERICAN JOURNAL OF PATHOLOGY 2016; 186:212-24. [PMID: 26776074 DOI: 10.1016/j.ajpath.2015.07.025] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/10/2015] [Revised: 07/23/2015] [Accepted: 07/30/2015] [Indexed: 12/20/2022]
Abstract
Mast cells and IgE are so inextricably linked to the pathology of allergic disorders, including fatal anaphylaxis, that it can be difficult to think of them in other contexts. Surely, we do not have mast cells and IgE so that we can eat a peanut and die! It is thought that mast cells and IgE and basophils (circulating granulocytes, whose functions partially overlap with those of mast cells) can contribute to host defense as components of adaptive T helper cell type 2 immune responses to helminths, ticks, and certain other parasites. Accordingly, it was suggested that allergies are misdirected type 2 immune responses in which IgE antibodies are produced against any of a broad variety of apparently harmless antigens. However, components of animal venoms also can sensitize individuals to develop severe IgE-associated allergic reactions, including fatal anaphylaxis, on subsequent venom exposure. Here, I describe evidence that mast cells can enhance innate host resistance to reptile or arthropod venoms during responses to an initial exposure to such venoms and that acquired type 2 immune responses, IgE antibodies, the high-affinity IgE receptor FcεRI, and mast cells can contribute toward acquired resistance in mice to the lethal effects of honeybee or Russell's viper venom. These findings support the hypothesis that mast cells and IgE can help protect the host against noxious substances.
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Affiliation(s)
- Stephen J Galli
- Department of Pathology, Stanford University School of Medicine, Stanford, California; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California; Sean N. Parker Center for Allergy Research, Stanford University School of Medicine, Stanford, California.
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40
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Roles of basophils and mast cells in cutaneous inflammation. Semin Immunopathol 2016; 38:563-70. [PMID: 27170045 DOI: 10.1007/s00281-016-0570-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Accepted: 05/02/2016] [Indexed: 10/21/2022]
Abstract
Mast cells and basophils are associated with T helper 2 (Th2) immune responses. Newly developed mast cell-deficient mice have provided evidence that mast cells initiate contact hypersensitivity via activating dendritic cells. Studies using basophil-deficient mice have also revealed that basophils are responsible for cutaneous Th2 skewing to haptens and peptide antigens but not to protein antigens. Recently, several studies reported the existence of innate lymphoid cells (ILCs), which differ from classic T cells in that they lack the T cell receptor. Mast cells and basophils can interact with ILCs and play some roles in the pathogenesis of Th2 responses. Basophil-derived interleukin (IL)-4 enhances the expression of the chemokine CCL11, as well as IL-5, IL-9, and IL-13 in ILC2s, leading to the accumulation of eosinophils in allergic reactions. IL-33-stimulated mast cells can play a regulatory role in the development of ILC2-mediated non-antigen-specific protease-induced acute inflammation. In this review, we discuss the recent advances in our understanding of mast cells and basophils in immunity and inflammation.
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41
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Buono M, Facchini R, Matsuoka S, Thongjuea S, Waithe D, Luis TC, Giustacchini A, Besmer P, Mead AJ, Jacobsen SEW, Nerlov C. A dynamic niche provides Kit ligand in a stage-specific manner to the earliest thymocyte progenitors. Nat Cell Biol 2016; 18:157-67. [PMID: 26780297 PMCID: PMC4972409 DOI: 10.1038/ncb3299] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Accepted: 12/08/2015] [Indexed: 12/17/2022]
Abstract
Thymic T cell development is initiated from bone-marrow-derived multi potent thymus-seeding progenitors. During the early stages of thymocyte differentiation, progenitors become T cell restricted. However, the cellular environments supporting these critical initial stages of T cell development within the thymic cortex are not known. Here we use the dependence of early, c-Kit-expressing thymic progenitors on Kit ligand (KitL) to show that CD4(-)CD8(-)c-Kit(+)CD25(-) DN1-stage progenitors associate with, and depend on, the membrane-bound form of KitL (mKitL) provided by a cortex-specific KitL-expressing vascular endothelial cell (VEC) population. In contrast, the subsequent CD4(-)CD8(-)c-Kit(+)CD25(+) DN2-stage progenitors associate selectively with cortical thymic epithelial cells (cTECs) and depend on cTEC-presented mKitL. These results show that the dynamic process of early thymic progenitor differentiation is paralleled by migration-dependent change to the supporting niche, and identify VECs as a thymic niche cell, with mKitL as a critical ligand.
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Affiliation(s)
- Mario Buono
- MRC Molecular Hematology Unit, University of Oxford, Oxford OX3 9DS, United Kingdom
| | - Raffaella Facchini
- MRC Molecular Hematology Unit, University of Oxford, Oxford OX3 9DS, United Kingdom
- Haematopoietic Stem Cell Biology Laboratory and University of Oxford, Oxford OX3 9DS, United Kingdom
| | - Sahoko Matsuoka
- MRC Molecular Hematology Unit, University of Oxford, Oxford OX3 9DS, United Kingdom
- Haematopoietic Stem Cell Biology Laboratory and University of Oxford, Oxford OX3 9DS, United Kingdom
| | - Supat Thongjuea
- MRC Molecular Hematology Unit, University of Oxford, Oxford OX3 9DS, United Kingdom
| | - Dominique Waithe
- Wolfson Imaging Center, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom
| | - Tiago C. Luis
- MRC Molecular Hematology Unit, University of Oxford, Oxford OX3 9DS, United Kingdom
- Haematopoietic Stem Cell Biology Laboratory and University of Oxford, Oxford OX3 9DS, United Kingdom
| | - Alice Giustacchini
- MRC Molecular Hematology Unit, University of Oxford, Oxford OX3 9DS, United Kingdom
- Haematopoietic Stem Cell Biology Laboratory and University of Oxford, Oxford OX3 9DS, United Kingdom
| | - Peter Besmer
- Sloan-Kettering Institute, New York, NY 10065, United States
| | - Adam J. Mead
- MRC Molecular Hematology Unit, University of Oxford, Oxford OX3 9DS, United Kingdom
- Haematopoietic Stem Cell Biology Laboratory and University of Oxford, Oxford OX3 9DS, United Kingdom
| | - Sten Eirik W. Jacobsen
- MRC Molecular Hematology Unit, University of Oxford, Oxford OX3 9DS, United Kingdom
- Haematopoietic Stem Cell Biology Laboratory and University of Oxford, Oxford OX3 9DS, United Kingdom
| | - Claus Nerlov
- MRC Molecular Hematology Unit, University of Oxford, Oxford OX3 9DS, United Kingdom
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McCracken MN, George BM, Kao KS, Marjon KD, Raveh T, Weissman IL. Normal and Neoplastic Stem Cells. COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY 2016; 81:1-9. [PMID: 28416577 PMCID: PMC5766001 DOI: 10.1101/sqb.2016.81.030965] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
A stem cell is broadly defined as a cell that retains the capacity to self-renew, a feature that confers the ability to continuously make identical daughter cells or additional cells that will differentiate into downstream progeny. This highly regulated genetic program to retain "stemness" is under active investigation. Research in our laboratory has explored similarities and differences in embryonic, tissue-specific, and neoplastic stem cells and their terminally differentiated counterparts. In this review, we will focus on the contributions of our laboratory, in particular on the studies that identified the mouse hematopoietic stem cell (HSC) and the human leukemic stem cell. These studies have led to significant improvements in both preclinical and clinical research, including improved clinical bone marrow transplantation protocols, isolation of nonleukemic HSCs, a cancer immunotherapy currently in clinical trials, and development of a HSC reporter mouse. These studies and the current follow-up research by us and others will continue to identify the properties, function, and regulation of both normal and neoplastic stem cells.
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Affiliation(s)
- Melissa N McCracken
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305
- Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, California 94305
- Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California 94305
| | - Benson M George
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305
- Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, California 94305
- Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California 94305
| | - Kevin S Kao
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305
- Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, California 94305
| | - Kristopher D Marjon
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305
- Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, California 94305
- Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California 94305
| | - Tal Raveh
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305
| | - Irving L Weissman
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305
- Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, California 94305
- Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California 94305
- Department of Pathology, Stanford University Medical Center, Stanford, California 94305
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Galli SJ, Starkl P, Marichal T, Tsai M. Mast cells and IgE in defense against venoms: Possible "good side" of allergy? Allergol Int 2016; 65:3-15. [PMID: 26666482 DOI: 10.1016/j.alit.2015.09.002] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Accepted: 09/03/2015] [Indexed: 01/05/2023] Open
Abstract
Physicians think of mast cells and IgE primarily in the context of allergic disorders, including fatal anaphylaxis. This 'bad side' of mast cells and IgE is so well accepted that it can be difficult to think of them in other contexts, particularly those in which they may have beneficial functions. However, there is evidence that mast cells and IgE, as well as basophils (circulating granulocytes whose functions partially overlap with those of mast cells), can contribute to host defense as components of adaptive type 2 immune responses to helminths, ticks and certain other parasites. Accordingly, allergies often are conceptualized as "misdirected" type 2 immune responses, in which IgE antibodies are produced against any of a diverse group of apparently harmless antigens, as well as against components of animal venoms. Indeed, certain unfortunate patients who have become sensitized to venoms develop severe IgE-associated allergic reactions, including fatal anaphylaxis, upon subsequent venom exposure. In this review, we will describe evidence that mast cells can enhance innate resistance to reptile or arthropod venoms during a first exposure to such venoms. We also will discuss findings indicating that, in mice which survive an initial encounter with venom, acquired type 2 immune responses, IgE antibodies, the high affinity IgE receptor (FcɛRI), and mast cells can contribute to acquired resistance to the lethal effects of both honeybee venom and Russell's viper venom. These findings support the hypothesis that mast cells and IgE can help protect the host against venoms and perhaps other noxious substances.
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Affiliation(s)
- Stephen J Galli
- Department of Pathology and the Sean N. Parker Center for Allergy Research, Stanford University School of Medicine, Stanford, CA, USA; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
| | - Philipp Starkl
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Department of Medicine 1, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria
| | - Thomas Marichal
- GIGA-Research and Faculty of Veterinary Medicine, University of Liege, Liege, Belgium
| | - Mindy Tsai
- Department of Pathology and the Sean N. Parker Center for Allergy Research, Stanford University School of Medicine, Stanford, CA, USA
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Abstract
Current knowledge on gonadal development and sex determination is the product of many decades of research involving a variety of scientific methods from different biological disciplines such as histology, genetics, biochemistry, and molecular biology. The earliest embryological investigations, followed by the invention of microscopy and staining methods, were based on histological examinations. The most robust development of histological staining techniques occurred in the second half of the nineteenth century and resulted in structural descriptions of gonadogenesis. These first studies on gonadal development were conducted on domesticated animals; however, currently the mouse is the most extensively studied species. The next key point in the study of gonadogenesis was the advancement of methods allowing for the in vitro culture of fetal gonads. For instance, this led to the description of the origin of cell lines forming the gonads. Protein detection using antibodies and immunolabeling methods and the use of reporter genes were also invaluable for developmental studies, enabling the visualization of the formation of gonadal structure. Recently, genetic and molecular biology techniques, especially gene expression analysis, have revolutionized studies on gonadogenesis and have provided insight into the molecular mechanisms that govern this process. The successive invention of new methods is reflected in the progress of research on gonadal development.
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Affiliation(s)
- Rafal P Piprek
- Department of Comparative Anatomy, Institute of Zoology, Jagiellonian University, Gronostajowa 9, 30-387, Kraków, Poland.
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45
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Hematopoietic Kit Deficiency, rather than Lack of Mast Cells, Protects Mice from Obesity and Insulin Resistance. Cell Metab 2015; 21:678-91. [PMID: 25955205 DOI: 10.1016/j.cmet.2015.04.013] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Revised: 02/20/2015] [Accepted: 04/07/2015] [Indexed: 12/12/2022]
Abstract
Obesity, insulin resistance, and related pathologies are associated with immune-mediated chronic inflammation. Kit mutant mice are protected from diet-induced obesity and associated co-morbidities, and this phenotype has previously been attributed to their lack of mast cells. We performed a comprehensive metabolic analysis of Kit-dependent Kit(W/Wv) and Kit-independent Cpa3(Cre/+) mast-cell-deficient mouse strains, employing diet-induced or genetic (Lep(Ob/Ob) background) models of obesity. Our results show that mast cell deficiency, in the absence of Kit mutations, plays no role in the regulation of weight gain or insulin resistance. Moreover, we provide evidence that the metabolic phenotype observed in Kit mutant mice, while independent of mast cells, is immune regulated. Our data underscore the value of definitive mast cell deficiency models to conclusively test the involvement of this enigmatic cell in immune-mediated pathologies and identify Kit as a key hematopoietic factor in the pathogenesis of metabolic syndrome.
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46
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Otsuka A, Kabashima K. Mast cells and basophils in cutaneous immune responses. Allergy 2015; 70:131-40. [PMID: 25250718 DOI: 10.1111/all.12526] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/17/2014] [Indexed: 12/19/2022]
Abstract
Mast cells and basophils share some functions in common and are generally associated with T helper 2 (Th2) immune responses, but taking basophils as surrogate cells for mast cell research or vice versa for several decades is problematic. Thus far, their in vitro functions have been well studied, but their in vivo functions remained poorly understood. New research tools for their functional analysis in vivo have revealed previously unrecognized roles for mast cells and basophils in several skin disorders. Newly developed mast cell-deficient mice provided evidence that mast cells initiate contact hypersensitivity via activating dendritic cells. In addition, studies using basophil-deficient mice have revealed that basophils were responsible for cutaneous Th2 skewing to haptens and peptide antigens but not to protein antigens. Moreover, human basophils infiltrate different skin lesions and have been implicated in the pathogenesis of skin diseases ranging from atopic dermatitis to autoimmune diseases. In this review, we will discuss the recent advances related to mast cells and basophils in human and murine cutaneous immune responses.
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Affiliation(s)
- A. Otsuka
- Department of Dermatology; Kyoto University Graduate School of Medicine; Kyoto Japan
| | - K. Kabashima
- Department of Dermatology; Kyoto University Graduate School of Medicine; Kyoto Japan
- PRESTO; Japan Science and Technology Agency; Kawaguchi Saitama Japan
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47
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McIntosh BE, Brown ME, Duffin BM, Maufort JP, Vereide DT, Slukvin II, Thomson JA. Nonirradiated NOD,B6.SCID Il2rγ-/- Kit(W41/W41) (NBSGW) mice support multilineage engraftment of human hematopoietic cells. Stem Cell Reports 2015; 4:171-80. [PMID: 25601207 PMCID: PMC4325197 DOI: 10.1016/j.stemcr.2014.12.005] [Citation(s) in RCA: 169] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2014] [Revised: 12/06/2014] [Accepted: 12/08/2014] [Indexed: 12/22/2022] Open
Abstract
In this study, we demonstrate a newly derived mouse model that supports engraftment of human hematopoietic stem cells (HSCs) in the absence of irradiation. We cross the NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) strain with the C57BL/6J-KitW-41J/J (C57BL/6.KitW41) strain and engraft, without irradiation, the resulting NBSGW strain with human cord blood CD34+ cells. At 12-weeks postengraftment in NBSGW mice, we observe human cell chimerism in marrow (97% ± 0.4%), peripheral blood (61% ± 2%), and spleen (94% ± 2%) at levels observed with irradiation in NSG mice. We also detected a significant number of glycophorin-A-positive expressing cells in the developing NBSGW marrow. Further, the observed levels of human hematopoietic chimerism mimic those reported for both irradiated NSG and NSG-transgenic strains. This mouse model permits HSC engraftment while avoiding the complicating hematopoietic, gastrointestinal, and neurological side effects associated with irradiation and allows investigators without access to radiation to pursue engraftment studies with human HSCs.
In engraftment experiments, nonirradiated NBSGW mice show enhanced humanization Similar levels of human chimerism are observed between both irNSG and NBSGW mice NBSGW mice are conducive to serial transplantation without irradiation NBSGW mice harbor a mutant KitW41 allele, aiding Gly-A+ development in the marrow
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Affiliation(s)
| | - Matthew E Brown
- Department of Surgery, University of Wisconsin, Madison, WI 53715, USA
| | - Bret M Duffin
- Morgridge Institute for Research, Madison, WI 53715, USA
| | - John P Maufort
- Morgridge Institute for Research, Madison, WI 53715, USA
| | - David T Vereide
- Morgridge Institute for Research, Madison, WI 53715, USA; Biotechnology Center, University of Wisconsin, Madison, WI 53706, USA
| | - Igor I Slukvin
- Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI 53715, USA; Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI 53715, USA
| | - James A Thomson
- Morgridge Institute for Research, Madison, WI 53715, USA; Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA; Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.
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48
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da Silva EZM, Jamur MC, Oliver C. Mast cell function: a new vision of an old cell. J Histochem Cytochem 2014; 62:698-738. [PMID: 25062998 PMCID: PMC4230976 DOI: 10.1369/0022155414545334] [Citation(s) in RCA: 416] [Impact Index Per Article: 37.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Accepted: 07/07/2014] [Indexed: 02/06/2023] Open
Abstract
Since first described by Paul Ehrlich in 1878, mast cells have been mostly viewed as effectors of allergy. It has been only in the past two decades that mast cells have gained recognition for their involvement in other physiological and pathological processes. Mast cells have a widespread distribution and are found predominantly at the interface between the host and the external environment. Mast cell maturation, phenotype and function are a direct consequence of the local microenvironment and have a marked influence on their ability to specifically recognize and respond to various stimuli through the release of an array of biologically active mediators. These features enable mast cells to act as both first responders in harmful situations as well as to respond to changes in their environment by communicating with a variety of other cells implicated in physiological and immunological responses. Therefore, the critical role of mast cells in both innate and adaptive immunity, including immune tolerance, has gained increased prominence. Conversely, mast cell dysfunction has pointed to these cells as the main offenders in several chronic allergic/inflammatory disorders, cancer and autoimmune diseases. This review summarizes the current knowledge of mast cell function in both normal and pathological conditions with regards to their regulation, phenotype and role.
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Affiliation(s)
- Elaine Zayas Marcelino da Silva
- Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil (EZMDS, MCJ, CO)
| | - Maria Célia Jamur
- Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil (EZMDS, MCJ, CO)
| | - Constance Oliver
- Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil (EZMDS, MCJ, CO)
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Dendritic cell c-kit signaling and adaptive immunity: implications for the upper airways. Curr Opin Allergy Clin Immunol 2014; 14:7-12. [PMID: 24300419 DOI: 10.1097/aci.0000000000000019] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
PURPOSE OF REVIEW Binding of the receptor tyrosine kinase, c-kit, to its ligand, stem cell factor (SCF), mediates numerous biological functions. Important roles for c-kit in hematopoiesis, melanogenesis, erythropoiesis, spermatogenesis, and carcinogenesis are well documented. Similarly, activation of mast cells and eosinophils by c-kit ligation has long been known to result in degranulation with concomitant release of pro-inflammatory mediators including cytokines. This review will highlight a recently discovered function of c-kit in regulating the adaptive immune responses with relevance to allergic diseases. RECENT FINDINGS Recent studies in a number of laboratories including our own highlight the previously unappreciated functions for c-kit in immunological processes. Increased expression of c-kit and its ligand, SCF, on dendritic cells by Th2/Th17-inducing stimuli leads to c-kit activation and immune skewing toward these subsets and away from Th1 responses. Treatment of dendritic cells with inhibitors of c-kit activation such as imatinib mesylate (Gleevec) induces breach of T-cell tolerance, skewing of responses toward Th1, and activation of natural killer cells. SUMMARY Taken together, these observations suggest that the c-kit/SCF axis may be a useful target for redirecting deleterious immune responses in various disease settings, including allergic diseases that are often associated with Th2 and Th17 responses.
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50
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Carvajal RD, Hamid O, Antonescu CR. Selecting patients for KIT inhibition in melanoma. Methods Mol Biol 2014; 1102:137-62. [PMID: 24258978 DOI: 10.1007/978-1-62703-727-3_9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
For many years, melanoma has been regarded as a single disease in terms of therapeutic considerations. The more recent identification of multiple molecular mechanisms underlying the development, progression, and prognosis of melanoma has led to a new paradigm for the management of this disease, has created new therapeutic opportunities, and has led to improved clinical outcomes. Such advances, however, are dependent upon methods that can reproducibly identify key molecular alterations within an individual tumor, define clinically relevant genetic subgroups of disease, and permit improved patient selection for targeted therapies.Melanomas harboring genetic alterations of KIT have been demonstrated to constitute one such molecular subgroup of disease. In this chapter, we will discuss the biology of KIT in melanoma, review the rationale for and clinical data regarding KIT inhibition in melanomas harboring activating alterations of KIT, propose guidelines for the selection of patients for KIT inhibitor therapy, and, finally, present laboratory methods for KIT assessment in melanoma.
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Affiliation(s)
- Richard D Carvajal
- Melanoma/Sarcoma Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
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