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Developmental Cell Jul 2021In mammals, hematopoietic stem cells (HSCs) engage in hematopoiesis throughout adult life within the bone marrow, where they produce the mature cells necessary to... (Review)
Review
In mammals, hematopoietic stem cells (HSCs) engage in hematopoiesis throughout adult life within the bone marrow, where they produce the mature cells necessary to maintain blood cell counts and immune function. In the bone marrow and spleen, HSCs are sustained in perivascular niches (microenvironments) associated with sinusoidal blood vessels-specialized veins found only in hematopoietic tissues. Endothelial cells and perivascular leptin receptor stromal cells produce the known factors required to maintain HSCs and many restricted progenitors in the bone marrow. Various other cells synthesize factors that maintain other restricted progenitors or modulate HSC or niche function. Recent studies identified new markers that resolve some of the heterogeneity among stromal cells and refine the localization of restricted progenitor niches. Other recent studies identified ways in which niches regulate HSC function and hematopoiesis beyond growth factors. We summarize the current understanding of hematopoietic niches, review recent progress, and identify important unresolved questions.
Topics: Blood Vessels; Bone Marrow; Endothelial Cells; Hematopoiesis; Humans; Intercellular Signaling Peptides and Proteins; Receptors, Leptin; Spleen; Stem Cell Niche; Stem Cells
PubMed: 34146467
DOI: 10.1016/j.devcel.2021.05.018 -
Hepatology Communications May 2022Patients with compensated advanced chronic liver disease who develop clinically significant portal hypertension (CSPH) are at high risk for hepatic decompensation and... (Review)
Review
Patients with compensated advanced chronic liver disease who develop clinically significant portal hypertension (CSPH) are at high risk for hepatic decompensation and mortality if left untreated. Liver biopsy and hepatic venous pressure gradient (HVPG) measurements are the current gold standard procedures for determining fibrosis severity and diagnosing CSPH, respectively; however, both are invasive, limiting their use in clinical practice and larger trials of novel agents. As such, there is an unmet clinical need for reliable, validated, noninvasive measures to detect CSPH and to further assess portal hypertension (PH) severity. Alterations in the biomechanical properties of the liver or spleen in patients with cirrhosis can be quantified by tissue elastography, which examines the elastic behavior of tissue after a force has been applied. A variety of methods are available, including magnetic resonance elastography, shear-wave elastography, and the most thoroughly investigated measure, vibration-controlled transient elastography. Liver stiffness (LS) and spleen stiffness (SS) measurements offer valuable alternatives to detect and monitor CSPH. Both LS and SS correlate well with HVPG, with thresholds of LS >20-25 kPa and SS >40-45 kPa indicating a high likelihood of CSPH. Because SS is a direct and dynamic surrogate of portal pressure, it has the potential to monitor PH severity and assess PH improvement as a surrogate marker for clinical outcomes. Importantly, SS seems to be superior to LS for monitoring treatment response in clinical trials focusing on reducing PH.
Topics: Elasticity Imaging Techniques; Humans; Hypertension, Portal; Liver Cirrhosis; Spleen
PubMed: 34904404
DOI: 10.1002/hep4.1855 -
Hepatology (Baltimore, Md.) May 2023Monocyte-derived macrophages (MoMFs), a dominant population of hepatic macrophages under inflammation, play a crucial role in liver fibrosis progression. The spleen...
BACKGROUND AND AIMS
Monocyte-derived macrophages (MoMFs), a dominant population of hepatic macrophages under inflammation, play a crucial role in liver fibrosis progression. The spleen serves as an extra monocyte reservoir in inflammatory conditions; however, the precise mechanisms of involvement of the spleen in the pathogenesis of liver fibrosis remain unclear.
APPROACH AND RESULTS
By splenectomy and splenocyte transfusion, it was observed that splenic CD11b + cells accumulated intrahepatically as Ly6C lo MoMFs to exacerbate CCl 4 -induced liver fibrosis. The splenocyte migration into the fibrotic liver was further directly visualized by spleen-specific photoconversion with KikGR mice and confirmed by CD45.1 + /CD45.2 + spleen transplantation. Spleen-derived CD11b + cells purified from fibrotic livers were then annotated by single-cell RNA sequencing, and a subtype of CD11b + CD43 hi Ly6C lo splenic monocytes (sM-1s) was identified, which was markedly expanded in both spleens and livers of mice with liver fibrosis. sM-1s exhibited mature feature with high expressions of F4/80, produced much ROS, and manifested preferential migration into livers. Once recruited, sM-1s underwent sequential transformation to sM-2s (highly expressed Mif , Msr1 , Clec4d , and Cstb ) and then to spleen-derived macrophages (sMφs) with macrophage features of higher expressions of CX 3 CR1, F4/80, MHC class II, and CD64 in the fibrotic hepatic milieu. Furthermore, sM-2s and sMφs were demonstrated capable of activating hepatic stellate cells and thus exacerbating liver fibrosis.
CONCLUSIONS
CD11b + CD43 hi Ly6C lo splenic monocytes migrate into the liver and shift to macrophages, which account for the exacerbation of liver fibrosis. These findings reveal precise mechanisms of spleen-liver axis in hepatic pathogenesis and shed light on the potential of sM-1 as candidate target for controlling liver diseases.
Topics: Mice; Animals; Spleen; Macrophages; Liver; Liver Cirrhosis; Monocytes; Mice, Inbred C57BL
PubMed: 36098707
DOI: 10.1002/hep.32782 -
Science (New York, N.Y.) Feb 2022Dendritic cells (DCs) are crucial for initiating adaptive immune responses. However, the factors that control DC positioning and homeostasis are incompletely understood....
Dendritic cells (DCs) are crucial for initiating adaptive immune responses. However, the factors that control DC positioning and homeostasis are incompletely understood. We found that type-2 conventional DCs (cDC2s) in the spleen depend on Gα and adhesion G protein-coupled receptor family member-E5 (Adgre5, or CD97) for positioning in blood-exposed locations. CD97 function required its autoproteolytic cleavage. CD55 is a CD97 ligand, and cDC2 interaction with CD55-expressing red blood cells (RBCs) under shear stress conditions caused extraction of the regulatory CD97 N-terminal fragment. Deficiency in CD55-CD97 signaling led to loss of splenic cDC2s into the circulation and defective lymphocyte responses to blood-borne antigens. Thus, CD97 mechanosensing of RBCs establishes a migration and gene expression program that optimizes the antigen capture and presentation functions of splenic cDC2s.
Topics: Actins; Animals; Antigen Presentation; Antigens; Blood Circulation; CD55 Antigens; Cell Movement; Dendritic Cells; Erythrocytes; GTP-Binding Protein alpha Subunits, G12-G13; Homeostasis; Interferon Regulatory Factors; Ligands; Mice; Receptors, G-Protein-Coupled; Signal Transduction; Spleen; Transcription, Genetic; Transcriptome
PubMed: 35143305
DOI: 10.1126/science.abi5965 -
Genome Biology Dec 2019The Human Cell Atlas is a large international collaborative effort to map all cell types of the human body. Single-cell RNA sequencing can generate high-quality data for...
BACKGROUND
The Human Cell Atlas is a large international collaborative effort to map all cell types of the human body. Single-cell RNA sequencing can generate high-quality data for the delivery of such an atlas. However, delays between fresh sample collection and processing may lead to poor data and difficulties in experimental design.
RESULTS
This study assesses the effect of cold storage on fresh healthy spleen, esophagus, and lung from ≥ 5 donors over 72 h. We collect 240,000 high-quality single-cell transcriptomes with detailed cell type annotations and whole genome sequences of donors, enabling future eQTL studies. Our data provide a valuable resource for the study of these 3 organs and will allow cross-organ comparison of cell types. We see little effect of cold ischemic time on cell yield, total number of reads per cell, and other quality control metrics in any of the tissues within the first 24 h. However, we observe a decrease in the proportions of lung T cells at 72 h, higher percentage of mitochondrial reads, and increased contamination by background ambient RNA reads in the 72-h samples in the spleen, which is cell type specific.
CONCLUSIONS
In conclusion, we present robust protocols for tissue preservation for up to 24 h prior to scRNA-seq analysis. This greatly facilitates the logistics of sample collection for Human Cell Atlas or clinical studies since it increases the time frames for sample processing.
Topics: Cold Temperature; Esophagus; Humans; Lung; Refrigeration; Sequence Analysis, RNA; Single-Cell Analysis; Spleen; Tissue Preservation
PubMed: 31892341
DOI: 10.1186/s13059-019-1906-x -
STAR Protocols Mar 2021Direct killing of diseased cells is a hallmark function of NK cells. This protocol describes a flow-based assay to measure activated murine NK cells' ability to kill...
Direct killing of diseased cells is a hallmark function of NK cells. This protocol describes a flow-based assay to measure activated murine NK cells' ability to kill target cells . Existing published protocols for assaying NK cell killing utilized the radioactive chromium release assay or were designed for human NK cells. This protocol details specifically an cytotoxicity assay using primary murine NK cells enriched from splenocytes that were activated with poly(I:C). For complete details on the use and execution of this protocol, please refer to Wagner et al. (2020).
Topics: Animals; Cytotoxicity Tests, Immunologic; Cytotoxicity, Immunologic; Flow Cytometry; Humans; Killer Cells, Natural; Mice; Spleen
PubMed: 33490978
DOI: 10.1016/j.xpro.2020.100262 -
Journal of Experimental & Clinical... May 2023Emerging studies have identified chronic psychological stress as an independent risk factor influencing breast cancer growth and metastasis. However, the effects of...
BACKGROUND
Emerging studies have identified chronic psychological stress as an independent risk factor influencing breast cancer growth and metastasis. However, the effects of chronic psychological stress on pre-metastatic niche (PMN) formation and the underlying immunological mechanisms remain largely unknown.
METHODS
The effects and molecular mechanisms of chronic unpredictable mild stress (CUMS) on modulating tumor-associated macrophages (TAMs) and PMN formation were clarified by multiplex immunofluorescence technique, cytokine array, chromatin immunoprecipitation, the dual-luciferase reporter assay, and breast cancer xenografts. Transwell and CD8 T cytotoxicity detection were used to analyze the mobilization and function of myeloid-derived suppressor cells (MDSCs). mCherry-labeled tracing strategy and bone marrow transplantation were applied to explore the crucial role of splenic CXCR2 MDSCs facilitating PMN formation under CUMS.
RESULTS
CUMS significantly promoted breast cancer growth and metastasis, accompanied by TAMs accumulation in the microenvironment. CXCL1 was identified as a crucial chemokine in TAMs facilitating PMN formation in a glucocorticoid receptor (GR)-dependent manner. Interestingly, the spleen index was significantly reduced under CUMS, and splenic MDSCs were validated as a key factor mediating CXCL1-induced PMN formation. The molecular mechanism study revealed that TAM-derived CXCL1 enhanced the proliferation, migration, and anti-CD8 T cell functions of MDSCs via CXCR2. Moreover, CXCR2 knockout and CXCR2MDSCs transplantation significantly impaired CUMS-mediated MDSC elevation, PMN formation, and breast cancer metastasis.
CONCLUSION
Our findings shed new light on the association between chronic psychological stress and splenic MDSC mobilization, and suggest that stress-related glucocorticoid elevation can enhance TAM/CXCL1 signaling and subsequently recruit splenic MDSCs to promote PMN formation via CXCR2.
Topics: Female; Humans; Breast Neoplasms; Chemokine CXCL1; Melanoma; Myeloid-Derived Suppressor Cells; Spleen; Tumor Microenvironment; Stress, Psychological; Melanoma, Cutaneous Malignant
PubMed: 37210553
DOI: 10.1186/s13046-023-02696-z -
Current Oncology (Toronto, Ont.) Nov 2021Primary splenic lymphoma (PSL) is a rare malignancy representing about 1% of all lymphoproliferative disorders, when using a strict definition that allows only... (Review)
Review
Primary splenic lymphoma (PSL) is a rare malignancy representing about 1% of all lymphoproliferative disorders, when using a strict definition that allows only involvement of spleen and hilar lymph nodes. In contrast, secondary low-grade B-cell lymphomas in the spleen, such as follicular lymphomas (FL), lymphoplasmacytic lymphoma and chronic lymphocytic leukemia/ small lymphocytic lymphoma, particularly as part of advanced stage disease, are more common. Indolent B cell lymphomas expressing CD10 almost always represent FL, which in its primary splenic form is the focus of this review. Primary splenic follicular lymphoma (PSFL) is exceedingly infrequent. This type of lymphoproliferative disorder is understudied and, in most cases, clinically characterized by splenomegaly or cytopenias related to hypersplenism. The diagnosis requires correlation of histopathology of spleen, blood and/or bone marrow with the correct immunophenotype (determined by flow cytometry and/or immunohistochemistry) and if necessary, additional molecular profiling. Management of this incurable disease is evolving, and splenectomy remains the mainstream treatment for stage I PSFL.
Topics: Humans; Immunohistochemistry; Immunophenotyping; Lymphoma, B-Cell; Lymphoma, Follicular; Spleen
PubMed: 34898578
DOI: 10.3390/curroncol28060407 -
Frontiers in Immunology 2022The liver is a site of complex immune activity. The hepatic immune system tolerates harmless immunogenic loads in homeostasis status, shelters liver function, while... (Review)
Review
The liver is a site of complex immune activity. The hepatic immune system tolerates harmless immunogenic loads in homeostasis status, shelters liver function, while maintaining vigilance against possible infectious agents or tissue damage and providing immune surveillance at the same time. Activation of the hepatic immunity is initiated by a diverse repertoire of hepatic resident immune cells as well as non-hematopoietic cells, which can sense "danger signals" and trigger robust immune response. Factors that mediate the regulation of hepatic immunity are elicited not only in liver, but also in other organs, given the dual blood supply of the liver both portal vein blood and arterial blood. Emerging evidence indicates that inter-organ crosstalk between the liver and other organs such as spleen, gut, lung, adipose tissue, and brain is involved in the pathogenesis of liver diseases. In this review, we present the features of hepatic immune regulation, with particular attention to the correlation with factors from extrahepatic organ. We describe the mechanisms by which other organs establish an immune association with the liver and then modulate the hepatic immune response. We discuss their roles and distinct mechanisms in liver homeostasis and pathological conditions from the cellular and molecular perspective, highlighting their potential for liver disease intervention. Moreover, we review the available animal models and methods for revealing the regulatory mechanisms of these extrahepatic factors. With the increasing understanding of the mechanisms by which extrahepatic factors regulate liver immunity, we believe that this will provide promising targets for liver disease therapy.
Topics: Adipose Tissue; Animals; Homeostasis; Liver Diseases; Spleen
PubMed: 36052075
DOI: 10.3389/fimmu.2022.941721 -
Digestive Diseases (Basel, Switzerland) 2022Myeloid-derived suppressor cells (MDSCs) are immunosuppressive in nature, originate in the bone marrow, and are mainly found in the blood, spleen, and liver. In fact,... (Review)
Review
BACKGROUND
Myeloid-derived suppressor cells (MDSCs) are immunosuppressive in nature, originate in the bone marrow, and are mainly found in the blood, spleen, and liver. In fact, liver acts as an important organ for induction and accumulation of MDSCs, especially during infection, inflammation, and cancer. In humans and rodents, models of liver diseases revealed that MDSCs promote regeneration and drive the inflammatory processes, leading to hepatitis, fibrogenesis, and cirrhosis, ultimately resulting in hepatocellular carcinoma.
SUMMARY
This brief review is focused on the in-depth understanding of the key molecules involved in the expansion and regulation of MDSCs and their underlying immunosuppressive mechanisms in liver diseases.
KEY MESSAGE
Modulated MDSCs can be used for therapeutic purposes in inflammation, cancer, and sepsis.
Topics: Humans; Inflammation; Liver Diseases; Myeloid-Derived Suppressor Cells; Neoplasms; Spleen
PubMed: 34157708
DOI: 10.1159/000517459