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Li J, Xiao C, Li C, He J. Tissue-resident immune cells: from defining characteristics to roles in diseases. Signal Transduct Target Ther 2025; 10:12. [PMID: 39820040 PMCID: PMC11755756 DOI: 10.1038/s41392-024-02050-5] [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: 06/04/2024] [Revised: 09/28/2024] [Accepted: 11/04/2024] [Indexed: 01/19/2025] Open
Abstract
Tissue-resident immune cells (TRICs) are a highly heterogeneous and plastic subpopulation of immune cells that reside in lymphoid or peripheral tissues without recirculation. These cells are endowed with notably distinct capabilities, setting them apart from their circulating leukocyte counterparts. Many studies demonstrate their complex roles in both health and disease, involving the regulation of homeostasis, protection, and destruction. The advancement of tissue-resolution technologies, such as single-cell sequencing and spatiotemporal omics, provides deeper insights into the cell morphology, characteristic markers, and dynamic transcriptional profiles of TRICs. Currently, the reported TRIC population includes tissue-resident T cells, tissue-resident memory B (BRM) cells, tissue-resident innate lymphocytes, tissue-resident macrophages, tissue-resident neutrophils (TRNs), and tissue-resident mast cells, but unignorably the existence of TRNs is controversial. Previous studies focus on one of them in specific tissues or diseases, however, the origins, developmental trajectories, and intercellular cross-talks of every TRIC type are not fully summarized. In addition, a systemic overview of TRICs in disease progression and the development of parallel therapeutic strategies is lacking. Here, we describe the development and function characteristics of all TRIC types and their major roles in health and diseases. We shed light on how to harness TRICs to offer new therapeutic targets and present burning questions in this field.
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Affiliation(s)
- Jia Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chu Xiao
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chunxiang Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Jie He
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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2
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Abdul BA, Isa HI, Shittu M, Oladele SB. Insight into didecyl dimethyl ammonium bromide toxicity following acute exposure in pullets (Gallus gallusdomesticus). Vet Res Commun 2024; 48:3909-3919. [PMID: 39365554 DOI: 10.1007/s11259-024-10564-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 09/29/2024] [Indexed: 10/05/2024]
Abstract
Didecyl dimethyl ammonium bromide (DDAB) is a quaternary ammonium compound used for the sanitation of drinking water of poultry and water pipelines in farms. There is scarcity of information on the toxicology of DDAB in poultry. This study set out to profile the acute toxicity of DDAB in poultry. Issa brown pullets (n = 34) as experimental birds were orally administered varying doses of DDAB, using a syringe, after 12 h fasting, and observed for toxicity over 14 days. Control birds (n = 10) were similarly given normal saline orally. Toxic signs in the experimental birds were depression, anorexia, adipsia, vocalization with foamy salivation, later emaciation and death. The LD50 was calculated as 458.00 mg/kg. Birds given 2151 mg/kg DDAB died within 24 h, while those treated with 516 mg/kg succumbed on Day 14. At necropsy, grossly, there were necrosis and sloughing of the oesophagus and intestines, pale and friable liver, congested and necrotic lungs, friable popped out kidneys and emaciated carcasses. Microscopically, desquamation and necrosis of the oesophagus, crop, proventriculus and intestines and disruption of the koilin membrane of the gizzard were observed. The lungs, liver and kidneys were congested with mononuclear cellular infiltration plus loss of architecture in the lungs and liver. In conclusion, at high doses, DDAB caused significant toxicity in chickens and these findings provide new information which could serve as a guide in the diagnosis of quaternary ammonium toxicity in chicken. The results could be extrapolated to other quaternary ammonium toxicities in related avian species.
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Affiliation(s)
- Bello Ayema Abdul
- Department of Veterinary Pharmacology and Toxicology, Ahmadu Bello University, Zaria, Nigeria
- Department of Veterinary Pharmacology and Toxicology, Bayero University, Kano, Nigeria
| | - Hamza Ibrahim Isa
- Department of Veterinary Pharmacology and Toxicology, Ahmadu Bello University, Zaria, Nigeria.
| | - Muftau Shittu
- Department of Veterinary Pharmacology and Toxicology, Ahmadu Bello University, Zaria, Nigeria
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Mahmoudi A, Meidany P, Almahmeed W, Jamialahmadi T, Sahebkar A. Stem Cell Therapy as a Potential Treatment of Non-Alcoholic Steatohepatitis-Related End-Stage Liver Disease: A Narrative Review. CURRENT STEM CELL REPORTS 2024; 10:85-107. [DOI: 10.1007/s40778-024-00241-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/17/2024] [Indexed: 01/04/2025]
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4
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Rieux M, Alpaugh M, Salem S, Siddu A, Saint-Pierre M, Denis HL, Rohweder H, Herrmann F, Bazenet C, Lacroix S, Cicchetti F. Understanding the role of the hematopoietic niche in Huntington's disease's phenotypic expression: in vivo evidence using a parabiosis model. Neurobiol Dis 2023; 180:106091. [PMID: 36967065 DOI: 10.1016/j.nbd.2023.106091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 03/06/2023] [Accepted: 03/16/2023] [Indexed: 03/31/2023] Open
Abstract
In a previous study, we have shown that parabiotic coupling of a knock-in mouse model (zQ175) of Huntington's disease (HD) to wild-type (WT) littermates resulted in a worsening of the normal phenotype as seen by detection of mutant huntingtin protein (mHTT) aggregates within peripheral organs and the cerebral cortex as well as vascular abnormalities in WT mice. In contrast, parabiosis improved disease features in the zQ175 mice such as reduction of mHTT aggregate number in the liver and cortex, decrease in blood-brain barrier (BBB) permeability and attenuation of mitochondrial impairments. While the shared circulation mediated these effects, no specific factor was identified. To better understand which blood elements were involved in the aforementioned changes, WT and zQ175 mice underwent parabiotic surgery prior to exposing one of the paired animals to irradiation. The irradiation procedure successfully eliminated the hematopoietic niche followed by repopulation with cells originating from the non-irradiated parabiont, as measured by the quantification of mHTT levels in peripheral blood mononuclear cells. Although irradiation of the WT parabiont, causing the loss of healthy hematopoietic cells, did lead to a few alterations in mitochondrial function in the muscle (TOM40 levels), and increased neuroinflammation in the striatum (GFAP levels), most of the changes observed were likely attributable to the irradiation procedure itself (e.g. mHTT aggregates in cortex and liver; cellular stress in peripheral organs). However, factors such as mHTT aggregation in the brain and periphery, and BBB leakage, which were improved in zQ175 mice when paired to WT littermates in the previous parabiosis experiment, were unaffected by perturbation of the hematopoietic niche. It would therefore appear that cells of the hematopoietic stem cell niche are largely uninvolved in the beneficial effects of parabiosis.
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Affiliation(s)
- Marie Rieux
- Centre de recherche du CHU de Québec - Université Laval, Axe neurosciences, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada; Département de médecine moléculaire, Université Laval, 1050 avenue de la Médecine, Québec, QC G1V 0A6, Canada
| | - Melanie Alpaugh
- Centre de recherche du CHU de Québec - Université Laval, Axe neurosciences, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada; Département de psychiatrie & neurosciences, Université Laval, 1050 avenue de la Médecine, Québec, QC G1V 0A6, Canada
| | - Shireen Salem
- Centre de recherche du CHU de Québec - Université Laval, Axe neurosciences, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada; Département de médecine moléculaire, Université Laval, 1050 avenue de la Médecine, Québec, QC G1V 0A6, Canada
| | - Alberto Siddu
- Centre de recherche du CHU de Québec - Université Laval, Axe neurosciences, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada; Département de psychiatrie & neurosciences, Université Laval, 1050 avenue de la Médecine, Québec, QC G1V 0A6, Canada
| | - Martine Saint-Pierre
- Centre de recherche du CHU de Québec - Université Laval, Axe neurosciences, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada
| | - Hélèna L Denis
- Centre de recherche du CHU de Québec - Université Laval, Axe neurosciences, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada; Département de psychiatrie & neurosciences, Université Laval, 1050 avenue de la Médecine, Québec, QC G1V 0A6, Canada
| | | | | | | | - Steve Lacroix
- Centre de recherche du CHU de Québec - Université Laval, Axe neurosciences, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada; Département de médecine moléculaire, Université Laval, 1050 avenue de la Médecine, Québec, QC G1V 0A6, Canada
| | - Francesca Cicchetti
- Centre de recherche du CHU de Québec - Université Laval, Axe neurosciences, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada; Département de médecine moléculaire, Université Laval, 1050 avenue de la Médecine, Québec, QC G1V 0A6, Canada; Département de psychiatrie & neurosciences, Université Laval, 1050 avenue de la Médecine, Québec, QC G1V 0A6, Canada.
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Muench MO, Fomin ME, Gutierrez AG, López-Terrada D, Gilfanova R, Nosworthy C, Beyer AI, Ostolaza G, Kats D, Matlock KL, Cairo S, Keller C. CD203c is expressed by human fetal hepatoblasts and distinguishes subsets of hepatoblastoma. Front Oncol 2023; 13:927852. [PMID: 36845728 PMCID: PMC9947649 DOI: 10.3389/fonc.2023.927852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 01/19/2023] [Indexed: 02/11/2023] Open
Abstract
Background & Aims Hepatocytic cells found during prenatal development have unique features compared to their adult counterparts, and are believed to be the precursors of pediatric hepatoblastoma. The cell-surface phenotype of hepatoblasts and hepatoblastoma cell lines was evaluated to discover new markers of these cells and gain insight into the development of hepatocytic cells and the phenotypes and origins of hepatoblastoma. Methods Human midgestation livers and four pediatric hepatoblastoma cell lines were screened using flow cytometry. Expression of over 300 antigens was evaluated on hepatoblasts defined by their expression of CD326 (EpCAM) and CD14. Also analyzed were hematopoietic cells, expressing CD45, and liver sinusoidal-endothelial cells (LSECs), expressing CD14 but lacking CD45 expression. Select antigens were further examined by fluorescence immunomicroscopy of fetal liver sections. Antigen expression was also confirmed on cultured cells by both methods. Gene expression analysis by liver cells, 6 hepatoblastoma cell lines, and hepatoblastoma cells was performed. Immunohistochemistry was used to evaluate CD203c, CD326, and cytokeratin-19 expression on three hepatoblastoma tumors. Results Antibody screening identified many cell surface markers commonly or divergently expressed by hematopoietic cells, LSECs, and hepatoblasts. Thirteen novel markers expressed on fetal hepatoblasts were identified including ectonucleotide pyrophosphatase/phosphodiesterase family member 3 (ENPP-3/CD203c), which was found to be expressed by hepatoblasts with widespread expression in the parenchyma of the fetal liver. In culture CD203c+CD326++ cells resembled hepatocytic cells with coexpression of albumin and cytokeratin-19 confirming a hepatoblast phenotype. CD203c expression declined rapidly in culture whereas the loss of CD326 was not as pronounced. CD203c and CD326 were co-expressed on a subset of hepatoblastoma cell lines and hepatoblastomas with an embryonal pattern. Conclusions CD203c is expressed on hepatoblasts and may play a role in purinergic signaling in the developing liver. Hepatoblastoma cell lines were found to consist of two broad phenotypes consisting of a cholangiocyte-like phenotype that expressed CD203c and CD326 and a hepatocyte-like phenotype with diminished expression of these markers. CD203c was expressed by some hepatoblastoma tumors and may represent a marker of a less differentiated embryonal component.
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Affiliation(s)
- Marcus O. Muench
- Vitalant Research Institute, San Francisco, CA, United States,Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, United States,*Correspondence: Marcus O. Muench,
| | - Marina E. Fomin
- Vitalant Research Institute, San Francisco, CA, United States
| | | | - Dolores López-Terrada
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, United States,Texas Children’s Cancer Center, Texas Children’s Hospital, Houston, TX, United States
| | | | | | - Ashley I. Beyer
- Vitalant Research Institute, San Francisco, CA, United States
| | | | - Dina Kats
- Pediatric Cancer Biology, Children’s Cancer Therapy Development Institute, Beaverton, OR, United States
| | | | - Stefano Cairo
- Research and Development Unit, XenTech, Evry, France
| | - Charles Keller
- Pediatric Cancer Biology, Children’s Cancer Therapy Development Institute, Beaverton, OR, United States
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Zhang W, Wang Y, Zhong F, Wang X, Sucher R, Lin CH, Brandacher G, Solari MG, Gorantla VS, Zheng XX. Donor derived hematopoietic stem cell niche transplantation facilitates mixed chimerism mediated donor specific tolerance. Front Immunol 2023; 14:1093302. [PMID: 36875068 PMCID: PMC9978155 DOI: 10.3389/fimmu.2023.1093302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 02/08/2023] [Indexed: 02/18/2023] Open
Abstract
Compelling experimental evidence confirms that the robustness and longevity of mixed chimerism (MC) relies on the persistence and availability of donor-derived hematopoietic stem cell (HSC) niches in recipients. Based on our prior work in rodent vascularized composite allotransplantation (VCA) models, we hypothesize that the vascularized bone components in VCA bearing donor HSC niches, thus may provide a unique biologic opportunity to facilitate stable MC and transplant tolerance. In this study, by utilizing a series of rodent VCA models we demonstrated that donor HSC niches in the vascularized bone facilitate persistent multilineage hematopoietic chimerism in transplant recipients and promote donor-specific tolerance without harsh myeloablation. In addition, the transplanted donor HSC niches in VCA facilitated the donor HSC niches seeding to the recipient bone marrow compartment and contributed to the maintenance and homeostasis of stable MC. Moreover, this study provided evidences that chimeric thymus plays a role in MC-mediated transplant tolerance through a mechanism of thymic central deletion. Mechanistic insights from our study could lead to the use of vascularized donor bone with pre-engrafted HSC niches as a safe, complementary strategy to induce robust and stable MC-mediated tolerance in VCA or solid organ transplantation recipients.
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Affiliation(s)
- Wensheng Zhang
- Department of Plastic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.,Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Yong Wang
- Department of Plastic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.,Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Fushun Zhong
- Transplantation Medical Center, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Xinghuan Wang
- Transplantation Medical Center, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Robert Sucher
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital Leipzig, Leipzig, Germany
| | - Cheng-Hung Lin
- Center for Vascularized Composite Allotransplantation, Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Tao-Yuan, Taiwan
| | - Gerald Brandacher
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Mario G Solari
- Department of Plastic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.,Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Vijay S Gorantla
- Departments of Surgery, Ophthalmology and Bioengineering, Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Xin Xiao Zheng
- Department of Plastic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.,Transplantation Medical Center, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
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7
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Deng ZH, Zhong J, Jiang HL, Jeong HW, Chen JW, Shu YH, Tan M, Adams RH, Xie KP, Chen Q, Liu Y. Antipsychotic drugs induce vascular defects in hematopoietic organs. FASEB J 2022; 36:e22538. [PMID: 36065631 DOI: 10.1096/fj.202200862r] [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: 06/07/2022] [Revised: 08/21/2022] [Accepted: 08/24/2022] [Indexed: 11/11/2022]
Abstract
Antipsychotic agents are clinically utilized to treat schizophrenia and other mental disorders. These drugs induce neurological and metabolic side effects, but their influence on blood vessels remains largely unknown. Here, we show that haloperidol, one of the most frequently prescribed antipsychotic agents, induces vascular defects in bone marrow. Acute haloperidol treatment results in vascular dilation that is specific to hematopoietic organs. This vessel dilation is associated with disruption of hematopoiesis and hematopoietic stem/progenitor cells (HSPCs), both of which are reversible after haloperidol withdrawal. Mechanistically, haloperidol treatment blocked the secretion of vascular endothelial growth factor A (VEGF-A) from HSPCs. Genetic blockade of VEGF-A secretion from hematopoietic cells or inhibition of VEGFR2 in endothelial cells result in similar vessel dilation in bone marrow during regeneration after irradiation and transplantation. Conversely, VEGF-A gain of function rescues the bone marrow vascular defects induced by haloperidol treatment and irradiation. Our work reveals an unknown effect of antipsychotic agents on the vasculature and hematopoiesis with potential implications for drug application in clinic.
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Affiliation(s)
- Zhao-Hua Deng
- Center for cell lineage and development, CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre
- GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou, China
| | - Jing Zhong
- Center for cell lineage and development, CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre
- GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Hai-Lin Jiang
- Department of Pathology and Center for Pancreatic Cancer Research, School of Medicine, South China University of Technology, Guangzhou, China
| | - Hyun-Woo Jeong
- Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Faculty of Medicine, University of Münster, Münster, Germany
| | - Jian-Wei Chen
- Center for cell lineage and development, CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre
- GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou, China.,Institutes of Physical Science and Information Technology, Anhui University, Hefei, China
| | - Ya-Hai Shu
- Center for cell lineage and development, CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre
- GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou, China
| | - Ming Tan
- Center for cell lineage and development, CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre
- GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou, China
| | - Ralf H Adams
- Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Faculty of Medicine, University of Münster, Münster, Germany
| | - Ke-Ping Xie
- Department of Pathology and Center for Pancreatic Cancer Research, School of Medicine, South China University of Technology, Guangzhou, China
| | - Qi Chen
- Center for cell lineage and development, CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre
- GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou, China.,Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Faculty of Medicine, University of Münster, Münster, Germany.,Biomedical Sciences College & Shandong Medicinal Biotechnology Centre
- NHC Key Laboratory of biotechnology drugs
- Key Lab for Rare & Uncommon Diseases of Shandong Province, Shandong First Medical University, Shandong Academy of Medical Sciences, Ji'nan, China
| | - Yang Liu
- Department of Pathology and Center for Pancreatic Cancer Research, School of Medicine, South China University of Technology, Guangzhou, China.,Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Faculty of Medicine, University of Münster, Münster, Germany
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Saglam A, Singh K, Gollapudi S, Kumar J, Brar N, Butzmann A, Warnke R, Ohgami RS. Indolent T-lymphoblastic proliferation: A systematic review of the literature analyzing the epidemiologic, clinical, and pathologic features of 45 cases. Int J Lab Hematol 2022; 44:700-711. [PMID: 35577551 DOI: 10.1111/ijlh.13873] [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: 01/31/2022] [Accepted: 04/25/2022] [Indexed: 11/26/2022]
Abstract
An indolent T-lymphoblastic proliferation (iT-LBP) is a rare benign disorder characterized by an abnormal expansion of immature T-cells, which morphologically can mimic malignancy. Since the first case was described in 1999, dozens more have been reported in the literature. However, the epidemiologic, clinical, pathologic, and biologic features of this disease have not been well described. Here, we retrospectively reviewed all known cases reported in the literature to better understand this entity. A PubMed search up to January 2022 highlighted 25 papers describing cases/case series of iT-LBP, one of which was a case presentation in a slide workshop. Except for 9 of the cases in one of the papers, where it was evident that the number of CD3+/TdT+ cells were too few to conform with a diagnosis of iT-LBP, all papers and all the cases reported were included in the study amounting to a total of 45 cases. Clinicopathologic characteristics were analyzed using descriptive statistics and frequencies. Our analysis highlighted the previously known association with Castleman disease and Castleman-like features and underlined its association with dendritic cell proliferations in general, as well as uncovering high frequency of concurrence with hepatocellular carcinoma and autoimmune diseases, most notably myasthenia gravis, paraneoplastic pemphigus and paraneoplastic autoimmune multiorgan syndrome. Furthermore, the co-expression of CD4 and CD8 and high prevalence of extranodal disease and recurrences were other less well described features that were revealed.
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Affiliation(s)
- Arzu Saglam
- Department of Pathology, Hacettepe University, Ankara, Turkey
| | - Kunwar Singh
- Department of Pathology, University of California San Francisco, San Francisco, California, USA
| | - Sumanth Gollapudi
- Department of Pathology, University of California San Francisco, San Francisco, California, USA
| | - Jyoti Kumar
- Department of Pathology, Stanford University, Stanford, California, USA
| | - Nivaz Brar
- Department of Pathology, Stanford University, Stanford, California, USA
| | - Alexandra Butzmann
- Department of Pathology, University of California San Francisco, San Francisco, California, USA
| | - Roger Warnke
- Department of Pathology, Stanford University, Stanford, California, USA
| | - Robert S Ohgami
- Department of Pathology, University of California San Francisco, San Francisco, California, USA
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9
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Zbinden A, Canté-Barrett K, Pike-Overzet K, Staal FJT. Stem Cell-Based Disease Models for Inborn Errors of Immunity. Cells 2021; 11:cells11010108. [PMID: 35011669 PMCID: PMC8750661 DOI: 10.3390/cells11010108] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 12/23/2021] [Accepted: 12/29/2021] [Indexed: 11/24/2022] Open
Abstract
The intrinsic capacity of human hematopoietic stem cells (hHSCs) to reconstitute myeloid and lymphoid lineages combined with their self-renewal capacity hold enormous promises for gene therapy as a viable treatment option for a number of immune-mediated diseases, most prominently for inborn errors of immunity (IEI). The current development of such therapies relies on disease models, both in vitro and in vivo, which allow the study of human pathophysiology in great detail. Here, we discuss the current challenges with regards to developmental origin, heterogeneity and the subsequent implications for disease modeling. We review models based on induced pluripotent stem cell technology and those relaying on use of adult hHSCs. We critically review the advantages and limitations of current models for IEI both in vitro and in vivo. We conclude that existing and future stem cell-based models are necessary tools for developing next generation therapies for IEI.
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10
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Mende N, Laurenti E. Hematopoietic stem and progenitor cells outside the bone marrow: where, when, and why. Exp Hematol 2021; 104:9-16. [PMID: 34687807 DOI: 10.1016/j.exphem.2021.10.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 10/06/2021] [Accepted: 10/08/2021] [Indexed: 12/23/2022]
Abstract
Bone marrow (BM) is the primary site of adult blood production, hosting the majority of all hematopoietic stem and progenitor cells (HSPCs). Rare HSPCs are also found outside of the BM at steady state. In times of large hematopoietic demand or BM failure, substantial production of mature blood cells from HSPCs can occur in a number of tissues, in a process termed extramedullary hematopoiesis (EMH). Over the past decades, our understanding of BM hematopoiesis has advanced drastically. In contrast there has been very little focus on the study of extramedullary HSPC pools and their contributions to blood production. Here we summarize what is currently known about extramedullary HSPCs and EMH in mice and humans. We describe the evidence of existing extramedullary HSPC pools at steady state, then discuss their role in the hematopoietic stress response. We highlight that although EMH in humans is much less pronounced and likely physiologically distinct to that in mice, it can be informative about premalignant and malignant changes. Finally, we reflect on the open questions in the field and on whether a better understanding of EMH, particularly in humans, may have relevant clinical implications for hematological and nonhematological disorders.
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Affiliation(s)
- Nicole Mende
- Department of Haematology and Wellcome MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Elisa Laurenti
- Department of Haematology and Wellcome MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
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11
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Mehrabi M, Amini F, Mehrabi S. Kill and Clearance in HCC: An Approach Based on NK Cells and Macrophages. Front Oncol 2021; 11:693076. [PMID: 34557407 PMCID: PMC8453146 DOI: 10.3389/fonc.2021.693076] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 08/23/2021] [Indexed: 11/15/2022] Open
Affiliation(s)
| | | | - Shima Mehrabi
- Internal Medicine, Iran University of Medical Sciences, Tehran, Iran
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12
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Hwang JW, Desterke C, Loisel-Duwattez J, Griscelli F, Bennaceur-Griscelli A, Turhan AG. Detection of Hematopoietic Stem Cell Transcriptome in Human Fetal Kidneys and Kidney Organoids Derived From Human Induced Pluripotent Stem Cells. Front Cell Dev Biol 2021; 9:668833. [PMID: 34178994 PMCID: PMC8226023 DOI: 10.3389/fcell.2021.668833] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 05/12/2021] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND In mammalians, hematopoietic stem cells (HSCs) arise in the dorsal aorta from the hemogenic endothelium, followed by their migration to the fetal liver and to the bone marrow. In zebrafish, the kidney is the site of primary hematopoiesis. In humans, the presence of HSCs in the fetal or adult kidney has not been established. METHODS We analyzed the presence of HSC markers in the human fetal kidneys by analysis of single-cell datasets. We then analyzed in kidney organoids derived from induced pluripotent stem cells (iPSCs) the presence of hematopoietic markers using transcriptome analyses. RESULTS Twelve clusters were identified as stromal, endothelial, and nephron cell type-specific markers in the two fetal stage (17 weeks) kidney datasets. Among these, the expression of hematopoietic cells in cluster 9 showed an expression of primitive markers. Moreover, whole transcriptome analysis of our iPSC-derived kidney organoids revealed induction of the primitive hematopoietic transcription factor RUNX1 as found in the human fetal kidney cortex. CONCLUSION These finding support the presence of cells expressing HSC transcriptome in the human kidney. The mechanisms of the appearance of the cells with the same transcriptional features during iPSC-derived kidney organoid generation require further investigation.
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Affiliation(s)
- Jin Wook Hwang
- INSERM U935/UA09, Université Paris-Saclay, Villejuif, France
- ESTeam Paris Sud, Université Paris Sud, Villejuif, France
| | - Christophe Desterke
- INSERM U935/UA09, Université Paris-Saclay, Villejuif, France
- ESTeam Paris Sud, Université Paris Sud, Villejuif, France
| | - Julien Loisel-Duwattez
- INSERM U1195, AP-HP, Service de Neurologie, Faculté de Médecine, Hôpital Bicêtre, Université Paris-Saclay, Le Kremlin-Bicêtre, France
| | - Frank Griscelli
- INSERM U935/UA09, Université Paris-Saclay, Villejuif, France
- ESTeam Paris Sud, Université Paris Sud, Villejuif, France
- INGESTEM National IPSC Infrastructure, Villejuif, France
- Division of Hematology, AP-HP Paris Saclay, Le Kremlin-Bicêtre, France
| | - Annelise Bennaceur-Griscelli
- INSERM U935/UA09, Université Paris-Saclay, Villejuif, France
- ESTeam Paris Sud, Université Paris Sud, Villejuif, France
- INGESTEM National IPSC Infrastructure, Villejuif, France
- Division of Hematology, AP-HP Paris Saclay, Le Kremlin-Bicêtre, France
| | - Ali G. Turhan
- INSERM U935/UA09, Université Paris-Saclay, Villejuif, France
- ESTeam Paris Sud, Université Paris Sud, Villejuif, France
- INGESTEM National IPSC Infrastructure, Villejuif, France
- Division of Hematology, AP-HP Paris Saclay, Le Kremlin-Bicêtre, France
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13
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Nakano R, Yoshida O, Kimura S, Nakao T, Yokota S, Ono Y, Minervini MI, Geller DA, Thomson AW. Donor plasmacytoid dendritic cells modulate effector and regulatory T cell responses in mouse spontaneous liver transplant tolerance. Am J Transplant 2021; 21:2040-2055. [PMID: 33247989 PMCID: PMC8628164 DOI: 10.1111/ajt.16412] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 10/22/2020] [Accepted: 11/17/2020] [Indexed: 01/25/2023]
Abstract
We assessed the role of donor liver non-conventional plasmacytoid dendritic cells (pDCs) in spontaneous liver transplant tolerance in a fully MHC-mismatched (C57BL/6 (H2b ) to C3H (H2k )) mouse model. Compared with spleen pDCs, liver pDCs expressed higher levels of DNAX-activating protein of 12 kDa and its co-receptor, triggering receptor expressed by myeloid cells 2, and higher ratios of programed death ligand-1 (PD-L1):costimulatory CD80/CD86 in the steady state and after Toll-like receptor 9 ligation. Moreover, liver pDCs potently suppressed allogeneic CD4+ and CD8+ T cell proliferative responses. Survival of pDC-depleted livers was much poorer (median survival time: 25 days) than that of either untreated donor livers or pDC-depleted syngeneic donor livers that survived indefinitely. Numbers of forkhead box p3 (FoxP3)+ regulatory T cells in grafts and mesenteric lymph nodes of mice given pDC-depleted allogeneic livers were reduced significantly compared with those in recipients of untreated livers. Graft-infiltrating CD8+ T cells with an exhausted phenotype (programed cell death protein 1+ , T cell immunoglobulin and mucin domain-containing protein 3+ ) were also reduced in recipients of pDC-depleted livers. PD1-PD-L1 pathway blockade reversed the reduction in exhausted T cells. These novel observations link immunoregulatory functions of liver interstitial pDCs, alloreactive T cell exhaustion, and spontaneous liver transplant tolerance.
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Affiliation(s)
- Ryosuke Nakano
- Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Osamu Yoshida
- Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania,Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Shoko Kimura
- Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania,Transplant Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Toshimasa Nakao
- Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania,Department of Drug Discovery Medicine, Kyoto Prefectural University of Medicine, Kyoto City, Japan
| | - Shinichiro Yokota
- Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania,Department of Surgery, Allegheny General Hospital, Pittsburgh, Pennsylvania
| | - Yoshihiro Ono
- Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania,Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Marta I. Minervini
- Department of Pathology, Division of Transplantation Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - David A. Geller
- Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania,Liver Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Angus W. Thomson
- Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania,Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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14
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Ahmed O, Robinson MW, O'Farrelly C. Inflammatory processes in the liver: divergent roles in homeostasis and pathology. Cell Mol Immunol 2021; 18:1375-1386. [PMID: 33864004 PMCID: PMC8166849 DOI: 10.1038/s41423-021-00639-2] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 01/10/2021] [Indexed: 02/07/2023] Open
Abstract
The hepatic immune system is designed to tolerate diverse harmless foreign moieties to maintain homeostasis in the healthy liver. Constant priming and regulation ensure that appropriate immune activation occurs when challenged by pathogens and tissue damage. Failure to accurately discriminate, regulate, or effectively resolve inflammation offsets this balance, jeopardizing overall tissue health resulting from an either overly tolerant or an overactive inflammatory response. Compelling scientific and clinical evidence links dysregulated hepatic immune and inflammatory responses upon sterile injury to several pathological conditions in the liver, particularly nonalcoholic steatohepatitis and ischemia-reperfusion injury. Murine and human studies have described interactions between diverse immune repertoires and nonhematopoietic cell populations in both physiological and pathological activities in the liver, although the molecular mechanisms driving these associations are not clearly understood. Here, we review the dynamic roles of inflammatory mediators in responses to sterile injury in the context of homeostasis and disease, the clinical implications of dysregulated hepatic immune activity and therapeutic developments to regulate liver-specific immunity.
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Affiliation(s)
- Ola Ahmed
- School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Mark W Robinson
- Department of Biology, Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Ireland
| | - Cliona O'Farrelly
- School of Medicine, Trinity College Dublin, Dublin, Ireland.
- School of Biochemistry & Immunology, Trinity College Dublin, Dublin 2, Ireland.
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15
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Human megakaryocytic microparticles induce de novo platelet biogenesis in a wild-type murine model. Blood Adv 2021; 4:804-814. [PMID: 32119736 DOI: 10.1182/bloodadvances.2019000753] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 02/03/2020] [Indexed: 12/16/2022] Open
Abstract
Platelet transfusions are used to treat idiopathic or drug-induced thrombocytopenia. Platelets are an expensive product in limited supply, with limited storage and distribution capabilities because they cannot be frozen. We have demonstrated that, in vitro, human megakaryocytic microparticles (huMkMPs) target human CD34+ hematopoietic stem and progenitor cells (huHSPCs) and induce their Mk differentiation and platelet biogenesis in the absence of thrombopoietin. In this study, we showed that, in vitro, huMkMPs can also target murine HSPCs (muHSPCs) to induce them to differentiate into megakaryocytes in the absence of thrombopoietin. Based on that, using wild-type BALB/c mice, we demonstrated that intravenously administering 2 × 106 huMkMPs triggered de novo murine platelet biogenesis to increase platelet levels up to 49% 16 hours after administration. huMkMPs also largely rescued low platelet levels in mice with induced thrombocytopenia 16 hours after administration by increasing platelet counts by 51%, compared with platelet counts in thrombocytopenic mice. Normalized on a tissue-mass basis, biodistribution experiments show that MkMPs localized largely to the bone marrow, lungs, and liver 24 hours after huMkMP administration. Beyond the bone marrow, CD41+ (megakaryocytes and Mk-progenitor) cells were frequent in lungs, spleen, and especially, liver. In the liver, infused huMKMPs colocalized with Mk progenitors and muHSPCs, thus suggesting that huMkMPs interact with muHSPCs in vivo to induce platelet biogenesis. Our data demonstrate the potential of huMkMPs, which can be stored frozen, to treat thrombocytopenias and serve as effective carriers for in vivo, target-specific cargo delivery to HSPCs.
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16
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Umeshappa CS, Solé P, Surewaard BGJ, Yamanouchi J, Mohapatra S, Uddin MM, Clarke R, Ortega M, Singha S, Mondal D, Yang Y, Vignali DAA, Serra P, Kubes P, Santamaria P. Liver-specific T regulatory type-1 cells program local neutrophils to suppress hepatic autoimmunity via CRAMP. Cell Rep 2021; 34:108919. [PMID: 33789099 DOI: 10.1016/j.celrep.2021.108919] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 12/17/2020] [Accepted: 03/08/2021] [Indexed: 12/17/2022] Open
Abstract
Neutrophils with immunoregulatory properties, also referred to as type-2 neutrophils (N2), myeloid-derived suppressor cells (MDSCs), or tumor-associated neutrophils (TANs), comprise a heterogeneous subset of cells that arise from unknown precursors in response to poorly understood cues. Here, we find that, in several models of liver autoimmunity, pharmacologically induced, autoantigen-specific T regulatory type-1 (TR1) cells and TR1-cell-induced B regulatory (Breg) cells use five immunoregulatory cytokines to coordinately recruit neutrophils into the liver and program their transcriptome to generate regulatory neutrophils. The liver-associated neutrophils from the treated mice, unlike their circulating counterparts or the liver neutrophils of sick mice lacking antigen-specific TR1 cells, are proliferative, can transfer disease protection to immunocompromised hosts engrafted with pathogenic effectors, and blunt antigen-presentation and local autoimmune responses via cathelin-related anti-microbial peptide (CRAMP), a cathelicidin, in a CRAMP-receptor-dependent manner. These results, thus, identify antigen-specific regulatory T cells as drivers of tissue-restricted regulatory neutrophil formation and CRAMP as an effector of regulatory neutrophil-mediated immunoregulation.
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Affiliation(s)
- Channakeshava Sokke Umeshappa
- Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, AB T2N 4N1, Canada
| | - Patricia Solé
- Institut D'Investigacions Biomèdiques August Pi i Sunyer, Barcelona 08036, Spain
| | - Bas G J Surewaard
- Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, AB T2N 4N1, Canada
| | - Jun Yamanouchi
- Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, AB T2N 4N1, Canada
| | - Saswat Mohapatra
- Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, AB T2N 4N1, Canada
| | - Muhammad Myn Uddin
- Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, AB T2N 4N1, Canada
| | - Robert Clarke
- Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, AB T2N 4N1, Canada
| | - Mireia Ortega
- Institut D'Investigacions Biomèdiques August Pi i Sunyer, Barcelona 08036, Spain
| | - Santiswarup Singha
- Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, AB T2N 4N1, Canada
| | - Debajyoti Mondal
- Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, AB T2N 4N1, Canada
| | - Yang Yang
- Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, AB T2N 4N1, Canada; Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, AB T2N 4N1, Canada
| | - Dario A A Vignali
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Pau Serra
- Institut D'Investigacions Biomèdiques August Pi i Sunyer, Barcelona 08036, Spain
| | - Paul Kubes
- Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, AB T2N 4N1, Canada
| | - Pere Santamaria
- Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, AB T2N 4N1, Canada; Institut D'Investigacions Biomèdiques August Pi i Sunyer, Barcelona 08036, Spain.
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17
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Bai L, Vienne M, Tang L, Kerdiles Y, Etiennot M, Escalière B, Galluso J, Wei H, Sun R, Vivier E, Peng H, Tian Z. Liver type 1 innate lymphoid cells develop locally via an interferon-γ-dependent loop. Science 2021; 371:eaba4177. [PMID: 33766856 DOI: 10.1126/science.aba4177] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 05/10/2020] [Accepted: 02/02/2021] [Indexed: 12/11/2022]
Abstract
The pathways that lead to the development of tissue-resident lymphocytes, including liver type 1 innate lymphoid cells (ILC1s), remain unclear. We show here that the adult mouse liver contains Lin-Sca-1+Mac-1+ hematopoietic stem cells derived from the fetal liver. This population includes Lin-CD122+CD49a+ progenitors that can generate liver ILC1s but not conventional natural killer cells. Interferon-γ (IFN-γ) production by the liver ILC1s themselves promotes the development of these cells in situ, through effects on their IFN-γR+ liver progenitors. Thus, an IFN-γ-dependent loop drives liver ILC1 development in situ, highlighting the contribution of extramedullary hematopoiesis to regional immune composition within the liver.
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Affiliation(s)
- Lu Bai
- Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Margaux Vienne
- Aix Marseille Univ., CNRS, INSERM, CIML, Marseille, France
| | - Ling Tang
- Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Yann Kerdiles
- Aix Marseille Univ., CNRS, INSERM, CIML, Marseille, France
| | | | | | | | - Haiming Wei
- Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Institute of Immunology, University of Science and Technology of China, Hefei, China
- Research Unit for NK Cell Study, Chinese Academy of Medical Sciences, Beijing, China
| | - Rui Sun
- Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
- Institute of Immunology, University of Science and Technology of China, Hefei, China
- Research Unit for NK Cell Study, Chinese Academy of Medical Sciences, Beijing, China
| | - Eric Vivier
- Aix Marseille Univ., CNRS, INSERM, CIML, Marseille, France.
- APHM, Hôpital de la Timone, Marseille-Immunopole, Marseille, France
- Innate Pharma, Marseille, France
| | - Hui Peng
- Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
- Institute of Immunology, University of Science and Technology of China, Hefei, China
- Research Unit for NK Cell Study, Chinese Academy of Medical Sciences, Beijing, China
| | - Zhigang Tian
- Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
- Institute of Immunology, University of Science and Technology of China, Hefei, China
- Research Unit for NK Cell Study, Chinese Academy of Medical Sciences, Beijing, China
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18
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Barcia Durán JG, Lu T, Houghton S, Geng F, Schreiner R, Xiang J, Rafii S, Redmond D, Lis R. Endothelial Jak3 expression enhances pro-hematopoietic angiocrine function in mice. Commun Biol 2021; 4:406. [PMID: 33767339 PMCID: PMC7994450 DOI: 10.1038/s42003-021-01846-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 02/12/2021] [Indexed: 02/08/2023] Open
Abstract
Jak3 is the only non-promiscuous member of the Jak family of secondary messengers. Studies to date have focused on understanding and targeting the cell-autonomous role of Jak3 in immunity, while functional Jak3 expression outside the hematopoietic system remains largely unreported. We show that Jak3 is expressed in endothelial cells across hematopoietic and non-hematopoietic organs, with heightened expression in the bone marrow. The bone marrow niche is understood as a network of different cell types that regulate hematopoietic function. We show that the Jak3-/- bone marrow niche is deleterious for the maintenance of long-term repopulating hematopoietic stem cells (LT-HSCs) and that JAK3-overexpressing endothelial cells have increased potential to expand LT-HSCs in vitro. This work may serve to identify a novel function for a highly specific tyrosine kinase in the bone marrow vascular niche and to further characterize the LT-HSC function of sinusoidal endothelium.
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Affiliation(s)
- José Gabriel Barcia Durán
- Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Tyler Lu
- Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
- Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine and Infertility, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Sean Houghton
- Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Fuqiang Geng
- Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Ryan Schreiner
- Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
- Department of Ophthalmology, Margaret Dyson Vision Research Institute, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Jenny Xiang
- Genomics Resources Core Facility, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Shahin Rafii
- Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
- Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine and Infertility, Weill Cornell Medicine, New York, NY, 10065, USA
| | - David Redmond
- Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA.
| | - Raphaël Lis
- Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA.
- Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine and Infertility, Weill Cornell Medicine, New York, NY, 10065, USA.
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19
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Soares-da-Silva F, Peixoto M, Cumano A, Pinto-do-Ó P. Crosstalk Between the Hepatic and Hematopoietic Systems During Embryonic Development. Front Cell Dev Biol 2020; 8:612. [PMID: 32793589 PMCID: PMC7387668 DOI: 10.3389/fcell.2020.00612] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 06/19/2020] [Indexed: 12/14/2022] Open
Abstract
Hematopoietic stem cells (HSCs) generated during embryonic development are able to maintain hematopoiesis for the lifetime, producing all mature blood lineages. HSC transplantation is a widely used cell therapy intervention in the treatment of hematologic, autoimmune and genetic disorders. Its use, however, is hampered by the inability to expand HSCs ex vivo, urging for a better understanding of the mechanisms regulating their physiological expansion. In the adult, HSCs reside in the bone marrow, in specific microenvironments that support stem cell maintenance and differentiation. Conversely, while developing, HSCs are transiently present in the fetal liver, the major hematopoietic site in the embryo, where they expand. Deeper insights on the dynamics of fetal liver composition along development, and on how these different cell types impact hematopoiesis, are needed. Both, the hematopoietic and hepatic fetal systems have been extensively studied, albeit independently. This review aims to explore their concurrent establishment and evaluate to what degree they may cross modulate their respective development. As insights on the molecular networks that govern physiological HSC expansion accumulate, it is foreseeable that strategies to enhance HSC proliferation will be improved.
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Affiliation(s)
- Francisca Soares-da-Silva
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- Instituto Nacional de Engenharia Biomédica, Universidade do Porto, Porto, Portugal
- Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
- Lymphocytes and Immunity Unit, Immunology Department, Pasteur Institute, Paris, France
- INSERM U1223, Paris, France
- Université Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Márcia Peixoto
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- Instituto Nacional de Engenharia Biomédica, Universidade do Porto, Porto, Portugal
- Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
- Lymphocytes and Immunity Unit, Immunology Department, Pasteur Institute, Paris, France
- INSERM U1223, Paris, France
- Université Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Ana Cumano
- Lymphocytes and Immunity Unit, Immunology Department, Pasteur Institute, Paris, France
- INSERM U1223, Paris, France
- Université Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Perpetua Pinto-do-Ó
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- Instituto Nacional de Engenharia Biomédica, Universidade do Porto, Porto, Portugal
- Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
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20
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Gomes AC, Saraiva M, Gomes MS. The bone marrow hematopoietic niche and its adaptation to infection. Semin Cell Dev Biol 2020; 112:37-48. [PMID: 32553581 DOI: 10.1016/j.semcdb.2020.05.014] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Revised: 05/14/2020] [Accepted: 05/19/2020] [Indexed: 12/13/2022]
Abstract
Hematopoiesis is responsible for the formation of all blood cells from hematopoietic stem cells (HSC) in the bone marrow (BM). It is a highly regulated process, in order to adapt its cellular output to changing body requirements. Specific microenvironmental conditions within the BM must exist in order to maintain HSC pluripotency and self-renewal, as well as to ensure appropriate differentiation of progenitor cells towards each hematopoietic lineage. Those conditions were coined "the hematopoietic niche" and their identity in terms of cell types, location and soluble molecular components has been the subject of intense research in the last decades. Infections are one of the environmental challenges to which hematopoiesis must respond, to feed the immune system with functional cell components and compensate for cellular losses. However, how infections impact the bone marrow hematopoietic niche(s) remains elusive and most of the mechanisms involved are still largely unknown. Here, we review the most recent advances on our knowledge on the hematopoietic niche composition and regulation during homeostasis and also on how the niche responds to infectious stress.
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Affiliation(s)
- Ana Cordeiro Gomes
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal; IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal; Departamento de Biologia Molecular, Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal
| | - Margarida Saraiva
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal; IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal
| | - Maria Salomé Gomes
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal; IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal; Departamento de Biologia Molecular, Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal.
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Lee JY, Hong SH. Hematopoietic Stem Cells and Their Roles in Tissue Regeneration. Int J Stem Cells 2020; 13:1-12. [PMID: 31887851 PMCID: PMC7119209 DOI: 10.15283/ijsc19127] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Revised: 11/18/2019] [Accepted: 12/01/2019] [Indexed: 12/22/2022] Open
Abstract
Hematopoietic stem cells (HSCs) are regarded as one of essential cell sources for treating regenerative diseases. Among many stem cells, the feasibility of using adult-derived hematopoietic stem cells in therapeutic approaches is very diverse, and is unarguably regarded as an important cell source in stem cell biology. So far, many investigators are exploring HSCs and modified HSCs for use in clinical and basic science. In the present review, we briefly summarized HSCs and their application in pathophysiologic conditions, including non-hematopoietic tissue regeneration as well as blood disorders. HSCs and HSCs-derived progenitors are promising cell sources in regenerative medicine and their contributions can be properly applied to treat pathophysiologic conditions. Among many adult stem cells, HSCs are a powerful tool to treat patients with diseases such as hematologic malignancies and liver disease. Since HSCs can be differentiated into diverse progenitors including endothelial progenitors, they may be useful for constructing strategies for effective therapy.
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Affiliation(s)
- Ji Yoon Lee
- CHA Advanced Research Institute, CHA University, Seongnam, Korea
| | - Seok-Ho Hong
- Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon, Korea
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22
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Qin Y, Fang K, Lu N, Hu Y, Tian Z, Zhang C. Interferon gamma inhibits the differentiation of mouse adult liver and bone marrow hematopoietic stem cells by inhibiting the activation of notch signaling. Stem Cell Res Ther 2019; 10:210. [PMID: 31311586 PMCID: PMC6636148 DOI: 10.1186/s13287-019-1311-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 06/18/2019] [Accepted: 06/20/2019] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND The paradigm of hematopoietic stem and progenitor cells (HSPCs) has become accepted ever since the discovery of adult mouse liver hematopoietic stem cells and their multipotent characteristics that give rise to all blood cells. However, differences between bone marrow (BM) and liver hematopoietic stem cells and the hematopoietic microenvironment remain poorly understood. In addition, the regulation of the liver hematopoietic system remains unknown. METHODS Clone formation assays were used to confirm that the proliferation of adult mouse liver and bone marrow HSPCs. Model mice with different interferon gamma (IFN-γ) levels and a co-culture system were used to detect the differentiation of liver HSPCs. The γ-secretase inhibitor (GSI) and the JAK/STAT inhibitor ruxolitinib and cell culture assays were used to explore the molecular mechanism by which IFN-γ impairs HSPC proliferation and differentiation. RESULTS The colony-forming activity of liver and bone marrow HSPCs was inhibited by IFN-γ. Model mice with different IFN-γ levels showed that the differentiation of liver HSPCs was impaired by IFN-γ. Using a co-culture system comprising liver HSPCs, we found that IFN-γ inhibited the development of liver hematopoietic stem cells into γδT cells. We then demonstrated that IFN-γ might impair liver HSPC differentiation by inhibiting the activation of the notch signaling via the JAK/STAT signaling pathway. CONCLUSIONS IFN-γ inhibited the proliferation of liver-derived HSPCs. IFN-γ also impaired the differentiation of long-term hematopoietic stem cells (LT-HSCs) into short-term hematopoietic stem cells (ST-HSCs) and multipotent progenitors (MPPs) and the process from LSK (Lineage-Sca-1+c-Kit+) cells to γδT cells. Importantly, we proposed that IFN-γ might inhibit the activation of notch signaling through the JAK/STAT signaling pathway and thus impair the differentiation process of mouse adult liver and BM hematopoietic stem cells.
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Affiliation(s)
- Yuhong Qin
- Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, Shandong, China
| | - Keke Fang
- Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, Shandong, China
| | - Nan Lu
- Institute of Diagnostics, School of Medicine, Shandong University, Jinan, 250012, Shandong, China.
| | - Yuan Hu
- Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, Shandong, China
| | - Zhigang Tian
- Institute of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, 230026, Anhui, China
| | - Cai Zhang
- Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, Shandong, China.
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Abrol N, Jadlowiec CC, Taner T. Revisiting the liver's role in transplant alloimmunity. World J Gastroenterol 2019; 25:3123-3135. [PMID: 31333306 PMCID: PMC6626728 DOI: 10.3748/wjg.v25.i25.3123] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 04/25/2019] [Accepted: 05/18/2019] [Indexed: 02/06/2023] Open
Abstract
The transplanted liver can modulate the recipient immune system to induce tolerance after transplantation. This phenomenon was observed nearly five decades ago. Subsequently, the liver's role in multivisceral transplantation was recognized, as it has a protective role in preventing rejection of simultaneously transplanted solid organs such as kidney and heart. The liver has a unique architecture and is home to many cells involved in immunity and inflammation. After transplantation, these cells migrate from the liver into the recipient. Early studies identified chimerism as an important mechanism by which the liver modulates the human immune system. Recent studies on human T-cell subtypes, cytokine expression, and gene expression in the allograft have expanded our knowledge on the potential mechanisms underlying immunomodulation. In this article, we discuss the privileged state of liver transplantation compared to other solid organ transplantation, the liver allograft's role in multivisceral transplantation, various cells in the liver involved in immune responses, and the potential mechanisms underlying immunomodulation of host alloresponses.
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Affiliation(s)
- Nitin Abrol
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Massyo Clinic, Rochester, MN 55905, United States
| | | | - Timucin Taner
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Massyo Clinic, Rochester, MN 55905, United States
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Meng D, Qin Y, Lu N, Fang K, Hu Y, Tian Z, Zhang C. Kupffer Cells Promote the Differentiation of Adult Liver Hematopoietic Stem and Progenitor Cells into Lymphocytes via ICAM-1 and LFA-1 Interaction. Stem Cells Int 2019; 2019:4848279. [PMID: 31354839 PMCID: PMC6636495 DOI: 10.1155/2019/4848279] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 05/28/2019] [Accepted: 06/03/2019] [Indexed: 02/07/2023] Open
Abstract
It has been reported that the adult liver contains hematopoietic stem and progenitor cells (HSPCs), which are associated with long-term hematopoietic reconstitution activity. Hepatic hematopoiesis plays an important role in the generation of cells involved in liver diseases. However, how the progenitors differentiate into functional myeloid cells and lymphocytes in the liver microenvironment remains unknown. In the present study, HSPC transplantation experiments were used to confirm that adult murine liver HSPCs differentiate into both myeloid cells and lymphocytes (preferentially T cells) compared with bone marrow HSPCs. Using a coculture system comprised of kupffer cells and HSPCs, we found that kupffer cells promote adult liver HSPCs to primarily generate T cells and B cells. We then demonstrated that kupffer cells can also promote HSPC expansion. A blockade of intercellular cell adhesion molecule-1 (ICAM-1) in a liver HSPC and kupffer cell coculture system impaired the adhesion, expansion, and differentiation of HSPCs. These results suggest a critical role of kupffer cells in the maintenance and promotion of adult mouse liver hematopoiesis. These findings provide important insight into understanding liver extramedullary hematopoiesis and its significance, particularly under the state of some liver diseases, such as hepatitis, nonalcoholic fatty liver disease (NAFLD), and hepatocellular carcinoma (HCC).
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Affiliation(s)
- Deping Meng
- Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012 Shandong, China
| | - Yuhong Qin
- Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012 Shandong, China
| | - Nan Lu
- Institute of Diagnostics, School of Medicine, Shandong University, Jinan, 250012 Shandong, China
| | - Keke Fang
- Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012 Shandong, China
| | - Yuan Hu
- Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012 Shandong, China
| | - Zhigang Tian
- Institute of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, 230027 Anhui, China
| | - Cai Zhang
- Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012 Shandong, China
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Abstract
Innate lymphoid cells (ILCs), including natural killer (NK) cells, ILC1s, ILC2s, ILC3s, and lymphoid tissue inducer (LTi) cells, comprise the first line of innate immune defense against pathogens and tumors. Over the past decade, accumulating evidence has demonstrated immunological memory in ILC subsets: for example, NK cells recall haptens, viruses, and cytokines; ILC1s recall haptens; and ILC2s recall cytokines. Although the development and functions of ILCs mirror those of T-cell subsets, ILC and T-cell memory exhibit both common characteristics and specific properties. Encouragingly, ILC memory has been found to confer benefits in long-term tumor control and vaccination, providing insight for novel memory ILC-based tumor immunotherapy and vaccine-development strategies. In this review, we discuss the evidence supporting ILC memory and present a comprehensive framework of the ILC memory system.
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Martrus G, Kautz T, Lunemann S, Richert L, Glau L, Salzberger W, Goebels H, Langeneckert A, Hess L, Poch T, Schramm C, Oldhafer KJ, Koch M, Tolosa E, Nashan B, Altfeld M. Proliferative capacity exhibited by human liver-resident CD49a+CD25+ NK cells. PLoS One 2017; 12:e0182532. [PMID: 28792982 PMCID: PMC5549915 DOI: 10.1371/journal.pone.0182532] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Accepted: 07/19/2017] [Indexed: 12/30/2022] Open
Abstract
The recruitment and retention of Natural Killer (NK) cells in the liver are thought to play an important role during hepatotropic infections and liver cirrhosis. The aims of this study were to determine differences between liver-derived and peripheral blood-derived NK cells in the context of liver inflammation and cirrhosis. We conducted a prospective dual-center cross-sectional study in patients undergoing liver transplantation or tumor-free liver resections, in which both liver tissue and peripheral blood samples were obtained from each consenting study participants. Intrahepatic lymphocytes and PBMCs were stained, fixed and analyzed by flow cytometry. Our results showed that, within cirrhotic liver samples, intrahepatic NK cells were particularly enriched for CD49a+ NK cells when compared to tumor-free liver resection samples. CD49a+ liver-derived NK cells included populations of cells expressing CD25, CD34 and CXCR3. Moreover, CD49a+CD25+ liver-derived NK cells exhibited high proliferative capacity in vitro in response to low doses of IL-2. Our study identified a specific subset of CD49a+CD25+ NK cells in cirrhotic livers bearing functional features of proliferation.
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Affiliation(s)
- Glòria Martrus
- Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Tobias Kautz
- Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Sebastian Lunemann
- Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Laura Richert
- Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
- Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, team SISTM, UMR1219 and Inria, Bordeaux, France
| | - Laura Glau
- Department of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Wilhelm Salzberger
- Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Hanna Goebels
- Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Annika Langeneckert
- Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Leonard Hess
- Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Tobias Poch
- First Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Schramm
- First Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Karl J. Oldhafer
- Department of General & Abdominal Surgery, Asklepios Hospital Barmbek, Semmelweis University of Medicine, Asklepios Campus, Hamburg, Germany
| | - Martina Koch
- Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Eva Tolosa
- Department of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Björn Nashan
- Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Marcus Altfeld
- Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
- * E-mail:
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Suzuki A, Zheng YW, Fukao K, Nakauchi H, Taniguchi H. Clonal Expansion of Hepatic Stem/Progenitor Cells following Flow Cytometric Cell Sorting. Cell Transplant 2017. [PMID: 11549060 DOI: 10.3727/000000001783986602] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Although hepatic stem cells are believed to exist and play a critical role in developing and regenerating liver, little is known about their cell surface specificity or differentiation capabilities. To make prospective studies of hepatic stem cells possible, we established an in vitro culture system for identification and characterization of hepatic stem/progenitor cells. By combining this culture system with fluorescence activated cell sorting (FACS), a population of cells that were capable of forming large colonies and providing their descendants for relative longer period was isolated from fetal mouse livers. These data suggest that hepatic stem/progenitor cells with high proliferative potential are existent in the developing mouse liver, and that they are enriched by using flow cytometry.
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Affiliation(s)
- Atsushi Suzuki
- Department of Surgery, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
| | - Yun-Wen Zheng
- Department of Surgery, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
| | - Katashi Fukao
- Department of Surgery, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
| | - Hiromitsu Nakauchi
- Department of Immunology, Institute of Basic Medical Sciences, University of Tsukuba, and CREST (Japan Science and Technology Corporation), 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
| | - Hideki Taniguchi
- Department of Surgery, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
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King A, Houlihan DD, Kavanagh D, Haldar D, Luu N, Owen A, Suresh S, Than NN, Reynolds G, Penny J, Sumption H, Ramachandran P, Henderson NC, Kalia N, Frampton J, Adams DH, Newsome PN. Sphingosine-1-Phosphate Prevents Egress of Hematopoietic Stem Cells From Liver to Reduce Fibrosis. Gastroenterology 2017; 153:233-248.e16. [PMID: 28363640 PMCID: PMC5511862 DOI: 10.1053/j.gastro.2017.03.022] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 02/27/2017] [Accepted: 03/18/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS There is growing interest in the use of bone marrow cells to treat liver fibrosis, however, little is known about their antifibrotic efficacy or the identity of their effector cell(s). Sphingosine-1-phosphate (S1P) mediates egress of immune cells from the lymphoid organs into the lymphatic vessels; we investigated its role in the response of hematopoietic stem cells (HSCs) to liver fibrosis in mice. METHODS Purified (c-kit+/sca1+/lin-) HSCs were infused repeatedly into mice undergoing fibrotic liver injury. Chronic liver injury was induced in BoyJ mice by injection of carbon tetrachloride (CCl4) or placement on a methionine-choline-deficient diet. Some mice were irradiated and given transplants of bone marrow cells from C57BL6 mice, with or without the S1P antagonist FTY720; we then studied HSC mobilization and localization. Migration of HSC lines was quantified in Transwell assays. Levels of S1P in liver, bone marrow, and lymph fluid were measured using an enzyme-linked immunosorbent assay. Liver tissues were collected and analyzed by immunohistochemical quantitative polymerase chain reaction and sphingosine kinase activity assays. We performed quantitative polymerase chain reaction analyses of the expression of sphingosine kinase 1 and 2, sphingosine-1-phosphate lyase 1, and sphingosine-1-phosphate phosphatase 1 in normal human liver and cirrhotic liver from patients with alcohol-related liver disease (n = 6). RESULTS Infusions of HSCs into mice with liver injury reduced liver scarring based on picrosirius red staining (49.7% reduction in mice given HSCs vs control mice; P < .001), and hepatic hydroxyproline content (328 mg/g in mice given HSCs vs 428 mg/g in control mice; P < .01). HSC infusion also reduced hepatic expression of α-smooth muscle actin (0.19 ± 0.007-fold compared with controls; P < .0001) and collagen type I α 1 chain (0.29 ± 0.17-fold compared with controls; P < .0001). These antifibrotic effects were maintained with infusion of lymphoid progenitors that lack myeloid potential and were associated with increased numbers of recipient neutrophils and macrophages in liver. In studies of HSC cell lines, we found HSCs to recruit monocytes, and this process to require C-C motif chemokine receptor 2. In fibrotic liver tissue from mice and patients, hepatic S1P levels increased owing to increased hepatic sphingosine kinase-1 expression, which contributed to a reduced liver:lymph S1P gradient and limited HSC egress from the liver. Mice given the S1P antagonist (FTY720) with HSCs had increased hepatic retention of HSCs (1697 ± 247 cells in mice given FTY720 vs 982 ± 110 cells in controls; P < .05), and further reductions in fibrosis. CONCLUSIONS In studies of mice with chronic liver injury, we showed the antifibrotic effects of repeated infusions of purified HSCs. We found that HSCs promote recruitment of endogenous macrophages and neutrophils. Strategies to reduce SIP signaling and increase retention of HSCs in the liver could increase their antifibrotic activities and be developed for treatment of patients with liver fibrosis.
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Affiliation(s)
- Andrew King
- Birmingham Liver Biomedical Research Unit, National Institute for Health Research, Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom.
| | - Diarmaid D. Houlihan
- Birmingham Liver Biomedical Research Unit, National Institute for Health Research, Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom
| | - Dean Kavanagh
- Centre for Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Debashis Haldar
- Birmingham Liver Biomedical Research Unit, National Institute for Health Research, Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom
| | - Nguyet Luu
- Birmingham Liver Biomedical Research Unit, National Institute for Health Research, Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom
| | - Andrew Owen
- Birmingham Liver Biomedical Research Unit, National Institute for Health Research, Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom
| | - Shankar Suresh
- Birmingham Liver Biomedical Research Unit, National Institute for Health Research, Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom
| | - Nwe Ni Than
- Birmingham Liver Biomedical Research Unit, National Institute for Health Research, Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom
| | - Gary Reynolds
- Birmingham Liver Biomedical Research Unit, National Institute for Health Research, Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom
| | - Jasmine Penny
- Birmingham Liver Biomedical Research Unit, National Institute for Health Research, Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom
| | - Henry Sumption
- Birmingham Liver Biomedical Research Unit, National Institute for Health Research, Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom
| | - Prakash Ramachandran
- Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
| | - Neil C. Henderson
- Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
| | - Neena Kalia
- Centre for Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Jon Frampton
- School Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - David H. Adams
- Birmingham Liver Biomedical Research Unit, National Institute for Health Research, Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom
| | - Philip N. Newsome
- Birmingham Liver Biomedical Research Unit, National Institute for Health Research, Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom,Reprint requests Address requests for reprints to: Philip Newsome, MD, PhD, or Andrew King, MD, PhD, Birmingham Liver Biomedical Research Unit, National Institute for Health Research, Centre for Liver Research, Institute of Biomedical Research, 5th Floor, University of Birmingham, Birmingham, B15 2TT United Kingdom. fax: (44) 121-415-8701.Birmingham Liver Biomedical Research UnitNational Institute for Health ResearchCentre for Liver ResearchInstitute of Biomedical Research5th Floor, University of BirminghamBirminghamB15 2TT United Kingdom
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Cellular Mechanisms of Liver Regeneration and Cell-Based Therapies of Liver Diseases. BIOMED RESEARCH INTERNATIONAL 2017; 2017:8910821. [PMID: 28210629 PMCID: PMC5292184 DOI: 10.1155/2017/8910821] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Revised: 11/29/2016] [Accepted: 12/27/2016] [Indexed: 12/14/2022]
Abstract
The emerging field of regenerative medicine offers innovative methods of cell therapy and tissue/organ engineering as a novel approach to liver disease treatment. The ultimate scientific foundation of both cell therapy of liver diseases and liver tissue and organ engineering is delivered by the in-depth studies of the cellular and molecular mechanisms of liver regeneration. The cellular mechanisms of the homeostatic and injury-induced liver regeneration are unique. Restoration of the mass of liver parenchyma is achieved by compensatory hypertrophy and hyperplasia of the differentiated parenchymal cells, hepatocytes, while expansion and differentiation of the resident stem/progenitor cells play a minor or negligible role. Participation of blood-borne cells of the bone marrow origin in liver parenchyma regeneration has been proven but does not exceed 1-2% of newly formed hepatocytes. Liver regeneration is activated spontaneously after injury and can be further stimulated by cell therapy with hepatocytes, hematopoietic stem cells, or mesenchymal stem cells. Further studies aimed at improving the outcomes of cell therapy of liver diseases are underway. In case of liver failure, transplantation of engineered liver can become the best option in the foreseeable future. Engineering of a transplantable liver or its major part is an enormous challenge, but rapid progress in induced pluripotency, tissue engineering, and bioprinting research shows that it may be doable.
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31
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Brown DL. Immunopathology of the Hepatobiliary System. MOLECULAR AND INTEGRATIVE TOXICOLOGY 2017:329-417. [DOI: 10.1007/978-3-319-47385-7_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Tissue-resident natural killer cells in the livers. SCIENCE CHINA-LIFE SCIENCES 2016; 59:1218-1223. [DOI: 10.1007/s11427-016-0334-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Accepted: 11/15/2016] [Indexed: 01/08/2023]
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Sasine JP, Yeo KT, Chute JP. Concise Review: Paracrine Functions of Vascular Niche Cells in Regulating Hematopoietic Stem Cell Fate. Stem Cells Transl Med 2016; 6:482-489. [PMID: 28191767 PMCID: PMC5442811 DOI: 10.5966/sctm.2016-0254] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Accepted: 08/04/2016] [Indexed: 01/09/2023] Open
Abstract
The functions of endothelial cells (ECs) in regulating oxygen delivery, nutrient exchange, coagulation, and transit of inflammatory cells throughout the body are well‐‐established. ECs have also been shown to regulate the maintenance and regeneration of organ‐specific stem cells in mammals. In the hematopoietic system, hematopoietic stem cells (HSCs) are dependent on signals from the bone marrow (BM) vascular niche for their maintenance and regeneration after myelosuppressive injury. Recent studies have demonstrated the essential functions of BM ECs and perivascular stromal cells in regulating these processes. In the present study, we summarize the current understanding of the role of BM ECs and perivascular cells in regulating HSC maintenance and regeneration and highlight the contribution of newly discovered EC‐derived paracrine factors that regulate HSC fate. Stem Cells Translational Medicine2017;6:482–489
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Affiliation(s)
- Joshua P. Sasine
- Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - Kelly T. Yeo
- Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - John P. Chute
- Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California, USA
- Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, California, USA
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34
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Affiliation(s)
- Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD 20892, USA
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35
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Robinson MW, Harmon C, O'Farrelly C. Liver immunology and its role in inflammation and homeostasis. Cell Mol Immunol 2016; 13:267-76. [PMID: 27063467 PMCID: PMC4856809 DOI: 10.1038/cmi.2016.3] [Citation(s) in RCA: 743] [Impact Index Per Article: 82.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Revised: 01/08/2016] [Accepted: 01/09/2016] [Indexed: 12/12/2022] Open
Abstract
The human liver is usually perceived as a non-immunological organ engaged primarily in metabolic, nutrient storage and detoxification activities. However, we now know that the healthy liver is also a site of complex immunological activity mediated by a diverse immune cell repertoire as well as non-hematopoietic cell populations. In the non-diseased liver, metabolic and tissue remodeling functions require elements of inflammation. This inflammation, in combination with regular exposure to dietary and microbial products, creates the potential for excessive immune activation. In this complex microenvironment, the hepatic immune system tolerates harmless molecules while at the same time remaining alert to possible infectious agents, malignant cells or tissue damage. Upon appropriate immune activation to challenge by pathogens or tissue damage, mechanisms to resolve inflammation are essential to maintain liver homeostasis. Failure to clear 'dangerous' stimuli or regulate appropriately activated immune mechanisms leads to pathological inflammation and disrupted tissue homeostasis characterized by the progressive development of fibrosis, cirrhosis and eventual liver failure. Hepatic inflammatory mechanisms therefore have a spectrum of roles in the healthy adult liver; they are essential to maintain tissue and organ homeostasis and, when dysregulated, are key drivers of the liver pathology associated with chronic infection, autoimmunity and malignancy. In this review, we explore the changing perception of inflammation and inflammatory mediators in normal liver homeostasis and propose targeting of liver-specific immune regulation pathways as a therapeutic approach to treat liver disease.
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Affiliation(s)
- Mark W Robinson
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin D2, Ireland
| | - Cathal Harmon
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin D2, Ireland
| | - Cliona O'Farrelly
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin D2, Ireland
- School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin D2, Ireland
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36
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Thiruchelvam U, Wingfield M, O'Farrelly C. Increased uNK Progenitor Cells in Women With Endometriosis and Infertility are Associated With Low Levels of Endometrial Stem Cell Factor. Am J Reprod Immunol 2016; 75:493-502. [PMID: 26791471 DOI: 10.1111/aji.12486] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Accepted: 12/17/2015] [Indexed: 12/30/2022] Open
Abstract
PROBLEM Uterine natural killer (uNK) cells play a significant role in successful human pregnancy. Having previously demonstrated uNK cell progenitors in human endometrium, we hypothesized that abnormal uNK cell maturation contributes to infertility in women with endometriosis. We aimed to characterize uNK cells at different developmental stages in women with and without endometriosis and to investigate possible mechanisms to explain any differences. METHOD OF STUDY We characterized uNK cell development in women with and without endometriosis using flow cytometry, protein array and in vitro experiments. RESULTS We found increased proportions of uNK cells at developmental stages 1 and 2 in endometrium from women with endometriosis (n = 36; mean = 21.2%) when compared with healthy fertile women (n = 9; mean = 7.0%). Protein array analysis revealed significantly lower levels of stem cell factor (SCF) in the eutopic endometrium of women with endometriosis when compared to healthy women. Addition of SCF to endometrial progenitor cells in vitro restored uNK cell maturation. CONCLUSION We have shown that women with endometriosis have low levels of endometrial SCF, which we hypothesize contributes to abnormal maturation of local uNK cell populations. This defect may also compromise embryo implantation and hence contribute to endometriosis-associated infertility. SCF replacement may be a new therapeutic approach.
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Affiliation(s)
- Uma Thiruchelvam
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
| | - Mary Wingfield
- Merrion Fertility Clinic, National Maternity Hospital, Dublin 2, Ireland.,UCD School of Medicine and Medical Science, Dublin 2, Ireland
| | - Cliona O'Farrelly
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.,School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
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Zuber J, Rosen S, Shonts B, Sprangers B, Savage TM, Richman S, Yang S, Lau SP, DeWolf S, Farber D, Vlad G, Zorn E, Wong W, Emond J, Levin B, Martinez M, Kato T, Sykes M. Macrochimerism in Intestinal Transplantation: Association With Lower Rejection Rates and Multivisceral Transplants, Without GVHD. Am J Transplant 2015; 15:2691-703. [PMID: 25988811 PMCID: PMC4575629 DOI: 10.1111/ajt.13325] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Revised: 03/01/2015] [Accepted: 03/25/2015] [Indexed: 01/25/2023]
Abstract
Blood chimerism has been reported sporadically among visceral transplant recipients, mostly in association with graft-vs-host disease (GVHD). We hypothesized that a higher degree of mixed chimerism would be observed in multivisceral (MVTx) than in isolated intestinal (iITx) and isolated liver transplant (iLTx) recipients, regardless of GVHD. We performed a longitudinal prospective study investigating multilineage blood chimerism with flow cytometry in 5 iITx and 4 MVTx recipients up to one year posttransplant. Although only one iITx patient experienced GVHD, T cell mixed chimerism was detected in 8 out of 9 iITx/MVTx recipients. Chimerism was significantly lower in the four subjects who displayed early moderate to severe rejection. Pre-formed high-titer donor-specific antibodies, bound in vivo to the circulating donor cells, were associated with an accelerated decline in chimerism. Blood chimerism was also studied in 10 iLTx controls. Among nonsensitized patients, MVTx recipients exhibited greater T and B cell chimerism than either iITx or iLTx recipients. Myeloid lineage chimerism was present exclusively among iLTx and MVTx (6/13) recipients, suggesting that its presence required the hepatic allograft. Our study demonstrates, for the first time, frequent T cell chimerism without GVHD following visceral transplantation and a possible relationship with reduced rejection rate in MVTx recipients.
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Affiliation(s)
- Julien Zuber
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, USA
| | - Sarah Rosen
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, USA
| | - Brittany Shonts
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, USA
| | - Ben Sprangers
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, USA
| | - Thomas M. Savage
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, USA
| | - Sarah Richman
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, USA
| | - Suxiao Yang
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, USA
| | - Sai Ping Lau
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, USA
| | - Susan DeWolf
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, USA
| | - Donna Farber
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, USA
| | - George Vlad
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, USA
| | - Emmanuel Zorn
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, USA
| | - Waichi Wong
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, USA
| | - Jean Emond
- Department of Surgery, Columbia University Medical Center, New York
| | - Bruce Levin
- Department of Biostatistics, Columbia University Medical Center, New York
| | - Mercedes Martinez
- Departments of Pediatrics, Columbia University Medical Center, New York, USA
| | - Tomoaki Kato
- Department of Surgery, Columbia University Medical Center, New York
| | - Megan Sykes
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, USA,Department of Surgery, Columbia University Medical Center, New York,Department of Microbiology & Immunology, Columbia University Medical Center, New York, USA,Department of Medicine, Columbia University Medical Center, New York, USA
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Saiman Y, Sugiyama T, Simchoni N, Spirli C, Bansal MB. Biliary Epithelial Cells Are Not the Predominant Source of Hepatic CXCL12. THE AMERICAN JOURNAL OF PATHOLOGY 2015; 185:1859-66. [PMID: 25934614 DOI: 10.1016/j.ajpath.2015.03.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Revised: 03/09/2015] [Accepted: 03/17/2015] [Indexed: 11/29/2022]
Abstract
Hepatic expression levels of CXCL12, a chemokine important in inflammatory and stem cell recruitment, and its receptor, C-X-C chemokine receptor 4, are increased during all forms of liver injury. CXCL12 is expressed by both parenchymal and nonparenchymal hepatic cells, and on the basis of immunohistochemistry, biliary epithelial cells (BECs) are thought to be a predominant source of hepatic CXCL12, thereby promoting periportal recruitment of C-X-C chemokine receptor 4-expressing lymphocytes. Our study aims to show that BECs may, in fact, not be the predominant source of hepatic CXCL12. We measured CXCL12 secretion and expression from human and murine BECs using enzyme-linked immunosorbent assay and Western blot analysis from cell culture supernatants and whole cell lysates, respectively, whereas CXCL12 expression in murine livers was analyzed in a Cxcl12-Gfp reporter mouse. Cell culture supernatants and whole cell lysates from BECs failed to demonstrate their expression of CXCL12. Furthermore, we confirmed these results with a Cxcl12-Gfp reporter mouse in which green fluorescent protein expression is notably absent from BECs. Interestingly, on the basis of green fluorescent protein expression, we demonstrate a population of CXCL12-expressing cells within the portal tract that are distinct, yet intimately associated with BECs. These findings indicate that BECs are not a predominant source of CXCL12.
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Affiliation(s)
- Yedidya Saiman
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Tatsuki Sugiyama
- Department of Immunobiology and Hematology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
| | - Noa Simchoni
- Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Carlo Spirli
- Liver Center and Digestive Diseases Section, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut
| | - Meena B Bansal
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
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Lysakova-Devine T, O'Farrelly C. Tissue-specific NK cell populations and their origin. J Leukoc Biol 2014; 96:981-90. [DOI: 10.1189/jlb.1ru0514-241r] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
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40
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Muench MO, Beyer AI, Fomin ME, Thakker R, Mulvaney US, Nakamura M, Suemizu H, Bárcena A. The adult livers of immunodeficient mice support human hematopoiesis: evidence for a hepatic mast cell population that develops early in human ontogeny. PLoS One 2014; 9:e97312. [PMID: 24819392 PMCID: PMC4018295 DOI: 10.1371/journal.pone.0097312] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Accepted: 04/18/2014] [Indexed: 11/19/2022] Open
Abstract
The liver plays a vital role in hematopoiesis during mammalian prenatal development but its hematopoietic output declines during the perinatal period. Nonetheless, hepatic hematopoiesis is believed to persist into adulthood. We sought to model human adult-liver hematopoiesis by transplantation of fetal and neonatal hematopoietic stem cells (HSCs) into adult immunodeficient mice. Livers were found to be engrafted with human cells consisting primarily of monocytes and B-cells with lesser contributions by erythrocytes, T-cells, NK-cells and mast-cells. A resident population of CD117(++)CD203c(+) mast cells was also documented in human midgestation liver, indicating that these cells comprise part of the liver's resident immune cell repertoire throughout human ontogeny. The murine liver was shown to support human multilineage hematopoiesis up to 321 days after transplant. Evidence of murine hepatic hematopoiesis was also found in common mouse strains as old as 2 years. Human HSC engraftment of the murine liver was demonstrated by detection of high proliferative-potential colony-forming cells in clonal cultures, observation of CD38-CD34(++) and CD133(+)CD34(++) cells by flow cytometry, and hematopoietic reconstitution of secondary transplant recipients of chimeric liver cells. Additionally, chimeric mice with both hematopoietic and endothelial reconstitution were generated by intrasplenic injection of immunodeficient mice with liver specific expression of the urokinase-type plasminogen activator (uPA) transgene. In conclusion, the murine liver is shown to be a hematopoietic organ throughout adult life that can also support human hematopoiesis in severely immunodeficient strains. Further humanization of the murine liver can be achieved in mice harboring an uPA transgene, which support engraftment of non-hematopoietic cells types. Thus, offering a model system to study the interaction of diverse human liver cell types that regulate hematopoiesis and immune function in the liver.
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Affiliation(s)
- Marcus O. Muench
- Blood Systems Research Institute, San Francisco, California, United States of America
- Laboratory Medicine, University of California San Francisco, San Francisco, California, United States of America
- Liver Center, University of California San Francisco, San Francisco, California, United States of America
- * E-mail:
| | - Ashley I. Beyer
- Blood Systems Research Institute, San Francisco, California, United States of America
| | - Marina E. Fomin
- Blood Systems Research Institute, San Francisco, California, United States of America
- Laboratory Medicine, University of California San Francisco, San Francisco, California, United States of America
| | - Rahul Thakker
- Blood Systems Research Institute, San Francisco, California, United States of America
| | - Usha S. Mulvaney
- Blood Systems Research Institute, San Francisco, California, United States of America
| | - Masato Nakamura
- Biomedical Research Department, Central Institute for Experimental Animals, Kawasaki, Japan
| | - Hiroshi Suemizu
- Biomedical Research Department, Central Institute for Experimental Animals, Kawasaki, Japan
| | - Alicia Bárcena
- Blood Systems Research Institute, San Francisco, California, United States of America
- Department of Obstetrics, Gynecology and Reproductive Sciences, Institute for Regeneration Medicine, University of California San Francisco, San Francisco, California, United States of America
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Banerjee ER. Looking for the elusive lung stem cell niche. TRANSLATIONAL RESPIRATORY MEDICINE 2014; 2:7. [PMID: 25932380 PMCID: PMC4406986 DOI: 10.1186/2213-0802-2-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2013] [Accepted: 02/04/2014] [Indexed: 01/24/2023]
Abstract
This discourse contains three perspectives on various aspects of Stem Cell Biology and tools available to study and translate into Regenerative Medicine. The lung incessantly faces onslaught of the environment, constantly undergoes oxidative stress, and is an important organ of detoxification. In degenerative diseases and inflammation, the lung undergoes irreversible remodeling that is difficult to therapeutically address and/or transplant a dying tissue. The other difficulty is to study its development and regenerative aspects to best address the aforementioned problems. This perspective therefore addresses- firstly, review of types of stem cells, their pathway of action and models in invertebrate organisms vis-a-vis microenvironment and its dynamics; secondly, stem cells in higher organisms and niche; and lastly data and inference on a novel approach to study stem cell destruction patterns in an injury model and information on putative lung stem cell niche. Stem cells are cryptic cells known to retain certain primitive characteristics making them akin to ancient cells of invertebrates, developmental stages in invertebrates and vertebrates and pliant cells of complex creatures like mammals that demonstrate stimulus-specific behavious, whether to clonally propagate or to remain well protected and hidden within specialized niches, or mobilize and differentiate into mature functionally operative cells to house-keep, repair injury or make new tissues. In lung fibrosis, alveolar epithelium degenerates progressively. In keeping with the goal of regenerative medicine, various models and assays to evaluate long and short term identity of stem cells and their niches is the subject of this perspective. We also report identification and characterization of functional lung stem cells to clarify how stem cell niches counteract this degenerative process. Inferences drawn from this injury model of lung degeneration using a short term assay by tracking side population cells and a long term assay tracking label retaining cells have been presented.
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Affiliation(s)
- Ena Ray Banerjee
- Department of Zoology, Immunology and Regenerative Medicine Research Laboratory, University of Calcutta, 35, Ballygunge Circular Road, Kolkata, 700019 West Bengal India
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Termini CM, Cotter ML, Marjon KD, Buranda T, Lidke KA, Gillette JM. The membrane scaffold CD82 regulates cell adhesion by altering α4 integrin stability and molecular density. Mol Biol Cell 2014; 25:1560-73. [PMID: 24623721 PMCID: PMC4019488 DOI: 10.1091/mbc.e13-11-0660] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Hematopoietic stem/progenitor cell (HSPC) interactions with the bone marrow microenvironment are important for maintaining HSPC self-renewal and differentiation. In recent work, we identified the tetraspanin protein, CD82, as a regulator of HPSC adhesion and homing to the bone marrow, although the mechanism by which CD82 mediated adhesion was unclear. In the present study, we determine that CD82 expression alters cell-matrix adhesion, as well as integrin surface expression. By combining the superresolution microscopy imaging technique, direct stochastic optical reconstruction microscopy, with protein clustering algorithms, we identify a critical role for CD82 in regulating the membrane organization of α4 integrin subunits. Our data demonstrate that CD82 overexpression increases the molecular density of α4 within membrane clusters, thereby increasing cellular adhesion. Furthermore, we find that the tight packing of α4 into membrane clusters depend on CD82 palmitoylation and the presence of α4 integrin ligands. In combination, these results provide unique quantifiable evidence of CD82's contribution to the spatial arrangement of integrins within the plasma membrane and suggest that regulation of integrin density by tetraspanins is a critical component of cell adhesion.
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Affiliation(s)
- Christina M Termini
- Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131
| | - Maura L Cotter
- Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131
| | - Kristopher D Marjon
- Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131
| | - Tione Buranda
- Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131
| | - Keith A Lidke
- Department of Physics and Astronomy, University of New Mexico, Albuquerque, NM 87131
| | - Jennifer M Gillette
- Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131
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Jiang X, Chen Y, Wei H, Sun R, Tian Z. Characterizing the lymphopoietic kinetics and features of hematopoietic progenitors contained in the adult murine liver in vivo. PLoS One 2013; 8:e76762. [PMID: 24130788 PMCID: PMC3793923 DOI: 10.1371/journal.pone.0076762] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2013] [Accepted: 09/01/2013] [Indexed: 01/26/2023] Open
Abstract
The appearance of donor-derived lymphocytes in liver transplant patients suggests that adult livers may contain cells capable of lymphopoiesis. However, only a few published studies have addressed the lymphopoietic capacity of adult liver cells, and its kinetics and features remain unclear. Herein, we investigated the lymphopoietic capacity of adult liver mononuclear cells (MNCs) and purified liver hematopoietic progenitor cells (HPCs) in vivo. Similar to bone-marrow transplantation (BMT), transplantation of liver MNCs alone was able to rescue survival of lethally irradiated mice. In terms of kinetics, liver MNC-derived myeloid lineage cells reconstituted more slowly than those from BMT. Liver MNC-derived lymphocyte lineage cells in the blood, spleen and BM also reconstituted more slowly than BMT, but lymphocytes in the liver recovered at a similar rate. Interestingly, liver MNCs predominantly gave rise to CD3+CD19− T cells in both irradiated WT and non-irradiated lymphocyte-deficient Rag-1−/−Il2rg−/− recipients. To define the lymphopoietic potential of various cell populations within liver MNCs, we transplanted purified lineage-negative (Lin−) liver HPCs into recipient mice. Unlike total liver MNCs, liver HPCs reconstituted T and B cells in similar frequencies to BMT. We further determined that the predominance of T cells observed after transplanting total liver MNCs likely originated from mature T cells, as purified donor liver T cells proliferated in the recipients and gave rise to CD8+ T cells. Thus, the capacity of donor adult liver cells to reconstitute lymphocytes in recipients derives from both HPCs and mature T cells contained in the liver MNC population.
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Affiliation(s)
- Xiaojun Jiang
- Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
| | - Yongyan Chen
- Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
| | - Haiming Wei
- Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
| | - Rui Sun
- Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
| | - Zhigang Tian
- Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
- Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, China
- * E-mail:
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Shin JW, Swift J, Ivanovska I, Spinler KR, Buxboim A, Discher DE. Mechanobiology of bone marrow stem cells: from myosin-II forces to compliance of matrix and nucleus in cell forms and fates. Differentiation 2013; 86:77-86. [PMID: 23790394 PMCID: PMC3964600 DOI: 10.1016/j.diff.2013.05.001] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2013] [Revised: 05/01/2013] [Accepted: 05/02/2013] [Indexed: 12/22/2022]
Abstract
Adult stem cells and progenitors are of great interest for their clinical application as well as their potential to reveal deep sensitivities to microenvironmental factors. The bone marrow is a niche for at least two types of stem cells, and the prototype is the hematopoietic stem cell/progenitors (HSC/Ps), which have saved many thousands of patients for several decades now. In bone marrow, HSC/Ps interact functionally with marrow stromal cells that are often referred to as mesenchymal stem cells (MSCs) or derivatives thereof. Myosin and matrix elasticity greatly affect MSC function, and these mechanobiological factors are now being explored with HSC/Ps both in vitro and in vivo. Also emerging is a role for the nucleus as a mechanically sensitive organelle that is semi-permeable to transcription factors which are modified for nuclear entry by cytoplasmic mechanobiological pathways. Since therapies envisioned with induced pluripotent stem cells and embryonic stem cells generally involve in vitro commitment to an adult stem cell or progenitor, a very deep understanding of stem cell mechanobiology is essential to progress with these multi-potent cells.
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Affiliation(s)
- Jae-Won Shin
- Molecular and Cell Biophysics Laboratory, University of Pennsylvania, Philadelphia, PA 19104, USA
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Jenne CN, Kubes P. Immune surveillance by the liver. Nat Immunol 2013; 14:996-1006. [PMID: 24048121 DOI: 10.1038/ni.2691] [Citation(s) in RCA: 766] [Impact Index Per Article: 63.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2013] [Accepted: 07/22/2013] [Indexed: 12/11/2022]
Abstract
Receiving both portal vein blood and arterial blood, the liver is an important and critical component in the defense against blood-borne infection. To accomplish this role, the liver contains numerous innate and adaptive immune cells that specialize in detection and capture of pathogens from the blood. Further, these immune cells participate in coordinated immune responses leading to pathogen clearance, leukocyte recruitment and antigen presentation to lymphocytes within the vasculature. Finally, this role in host defense must be tightly regulated to ensure that inappropriate immune responses are not raised against nonpathogenic exogenous blood-borne molecules, such as those derived from food. It is this balance between activation and tolerance that characterizes the liver as a frontline immunological organ.
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Affiliation(s)
- Craig N Jenne
- 1] Calvin, Phoebe & Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada. [2] Department of Critical Care Medicine, University of Calgary, Calgary, Alberta, Canada
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Ikarashi M, Nakashima H, Kinoshita M, Sato A, Nakashima M, Miyazaki H, Nishiyama K, Yamamoto J, Seki S. Distinct development and functions of resident and recruited liver Kupffer cells/macrophages. J Leukoc Biol 2013; 94:1325-36. [PMID: 23964119 DOI: 10.1189/jlb.0313144] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Although mouse liver F4/80(+) Kupffer cells consist of cytokine-producing CD11b(+) cells and phagocytic CD68(+) cells, an undefined CD11b(-) CD68(-) subset (30%) also exists. We herein demonstrate a more fundamental classification by adding CD32 (FcγRII), which covers most liver F4/80(+) cells and the distinct functions of them. Among the F4/80(+) cells, 50%, 40%, and 30% of cells were CD32(+), CD68(+), and CD11b(+), respectively, and one-half of the CD68(+) cells coexpressed CD32. CD68(+) and CD32(+) cells, but not CD11b(+) cells, expressed a phagocytosis-related CRIg. Gy (6) irradiation depleted liver CD11b(+) cells and those in the spleen, bone marrow, and peripheral blood but not liver CD32/CD68(+) cells. Transfer of bone marrow cells into the irradiated mice reconstituted liver CD11b(+) cells. Conversely, clodronate pretreatment depleted only liver CD32/CD68(+) cells but not liver CD11b(+) cells and peripheral blood or spleen CD11b(+) monocytes/macrophages. Moreover, the CD32(+) cells might be precursors of CD68(+) cells, as a large proportion of CD32(+) cells expressed the c-kit (CD117), and CD34 and CD32(+) cells acquired CD68 immediately after bacteria administration. CD32/CD68(+) cells, but not CD11b(+) cells, expressed resident macrophage-specific MerTK and CD64 (FcγRI). Challenge with Staphylococcus aureus or liver metastatic EL-4 tumor cells indicated that the CD68(+) subset is engaged in systemic bactericidal activity, whereas the CD11b(+) subset is pivotal for liver antitumor immunity. Human liver CD14(+) Kupffer cells could also be classified into three similar subsets. These results suggest that liver CD68(+) Kupffer cells and CD11b(+) Kupffer cells/macrophages are developmentally and functionally distinct subsets.
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Affiliation(s)
- Masami Ikarashi
- 1.National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513 Japan.
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Srivastava B, Gimson A. Hepatic changes in systemic infection. Best Pract Res Clin Gastroenterol 2013; 27:485-95. [PMID: 24090937 DOI: 10.1016/j.bpg.2013.06.011] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Accepted: 06/23/2013] [Indexed: 01/31/2023]
Abstract
Liver is an integral part of the host-defense mechanism and facilitates clearance of pathogenic organisms in systemic infection by modulating the immunological response. It undergoes several cellular and molecular changes resulting in the release of pro-inflammatory cytokines, which regulate various metabolic and immunological signalling pathways. Some of these changes are pathogen-specific and essential in determining the host response to systemic infection. However, alterations in the immunological homeostasis can adversely affect the liver and lead to hepatic dysfunction. This article focuses on these molecular and immunological changes that occur within the liver in response to extra-hepatic systemic infection and its consequences.
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Jiang X, Chen Y, Peng H, Tian Z. Memory NK cells: why do they reside in the liver? Cell Mol Immunol 2013; 10:196-201. [PMID: 23563088 DOI: 10.1038/cmi.2013.8] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Immune memory is the hallmark of adaptive immunity. However, recent studies have shown that natural killer (NK) cells, key components of the innate immune system, also mediate memory responses in mice and humans. Strikingly, memory NK cells were liver-resident in some models, raising the question as to whether the liver is a special organ for the acquisition of NK cell memory. Here, we review the characteristics of NK cell memory by summarizing recent progress and discuss how the liver may generate both the initiation and the recall phase of memory. We propose that the liver may have unique precursors for memory NK cells, which are developmentally distinct from NK cells derived from bone marrow.
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Affiliation(s)
- Xiaojun Jiang
- Hefei National Laboratory for Physical Sciences at Microscale, Hefei, China
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Wang XQ, Lo CM, Chen L, Cheung CKY, Yang ZF, Chen YX, Ng MN, Yu WC, Ming X, Zhang W, Ho DWY, Chan SC, Fan ST. Hematopoietic chimerism in liver transplantation patients and hematopoietic stem/progenitor cells in adult human liver. Hepatology 2012; 56:1557-66. [PMID: 22544823 DOI: 10.1002/hep.25820] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Abstract
UNLABELLED Liver transplantation (LT) is a cure for many liver diseases. Blood chimerism of donor origin can develop after LT, which raises the possibility of the existence of hematopoietic stem/progenitor cells (HSPCs) in the liver. We characterized the blood chimerism in a large cohort of 249 LT patients and analyzed putative HSPCs in adult human livers. The overall incidence of chimerism was 6.43%, of which 11.11% was among short-term (1 day to 6 months) and 3.77% was among long-term (6 months to 8 years) LT patients. Hematopoietic Lin(-) CD34(+) CD38(-) CD90(+) populations have been demonstrated to generate long-term lymphomyeloid grafts in transplantations. In human adult livers, we detected Lin(-) CD34(+) CD38(-) CD90(+) populations accounting for 0.03% ± 0.017% of the total single liver cells and for 0.05% ± 0.012% of CD45(+) liver cells. Both Lin(-) CD34(+) and Lin(-) CD45(+) liver cells, from extensively perfused human liver grafts, were capable of forming hematopoietic myeloid-lineage and erythroid-lineage methylcellulose colonies. More importantly, Lin(-) CD45(+) or CD45(+) liver cells could be engrafted into hematopoietic cells in an immunodeficient mouse model. These results are the first evidence of the presence of putative HSPC populations in the adult human liver, where the liver is a good ectopic niche. The discovery of the existence of HSPCs in the adult liver have implications for the understanding of extramarrow hematopoiesis, liver regeneration, mechanisms of tolerance in organ transplantation, and de novo cancer recurrence in LT patients. CONCLUSION The human adult liver contains a small population of HSPCs. In LT patients, there are two types of chimerisms: transient chimerism, resulting from mature leucocytes, and long-term chimerism, derived from putative HSPCs in the liver graft.
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Affiliation(s)
- Xiao Qi Wang
- Department of Surgery, The University of Hong Kong, Pok Fu Lam, Hong Kong, China
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Abo T, Tomiyama C, Watanabe H. Biology of autoreactive extrathymic T cells and B-1 cells of the innate immune system. Immunol Res 2012; 52:224-30. [PMID: 22477526 DOI: 10.1007/s12026-012-8324-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Cumulative evidence has shown that extrathymic T cells can be autoreactive and that B-1 cells may produce autoantibodies. These T and B-1 cells, which form part of the innate immune system, tend to be activated simultaneously when conventional T and B cells are in a suppressive state, for example, when thymic atrophy occurs by stress or involution with aging. In other words, autoreactive T cells and autoantibody-producing B cells are different from thymus-derived T cells and bone marrow-derived B cells. Activated extrathymic T cells and B-1 cells are often observed in numerous autoimmune diseases, aging, malarial infection and chronic graft-versus-host disease. It is thought that the autoreactivity of extrathymic T cells and B-1 cells may be important for the elimination of "abnormal self" tissues or cells. However, over-activation of innate lymphocytes may be related to the onset of disease or self-tissue destruction. However, it must be emphasized that the autoreactivity of innate lymphocytes is not generated by failure of the thymic pathway of T-cell differentiation or the conventional pathway of B-2 cells.
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Affiliation(s)
- Toru Abo
- Department of Immunology, Niigata University School of Medicine, Niigata, 951-8510, Japan.
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