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Nature Oct 2019Definitive haematopoiesis in the fetal liver supports self-renewal and differentiation of haematopoietic stem cells and multipotent progenitors (HSC/MPPs) but remains...
Definitive haematopoiesis in the fetal liver supports self-renewal and differentiation of haematopoietic stem cells and multipotent progenitors (HSC/MPPs) but remains poorly defined in humans. Here, using single-cell transcriptome profiling of approximately 140,000 liver and 74,000 skin, kidney and yolk sac cells, we identify the repertoire of human blood and immune cells during development. We infer differentiation trajectories from HSC/MPPs and evaluate the influence of the tissue microenvironment on blood and immune cell development. We reveal physiological erythropoiesis in fetal skin and the presence of mast cells, natural killer and innate lymphoid cell precursors in the yolk sac. We demonstrate a shift in the haemopoietic composition of fetal liver during gestation away from being predominantly erythroid, accompanied by a parallel change in differentiation potential of HSC/MPPs, which we functionally validate. Our integrated map of fetal liver haematopoiesis provides a blueprint for the study of paediatric blood and immune disorders, and a reference for harnessing the therapeutic potential of HSC/MPPs.
Topics: Blood Cells; Cellular Microenvironment; Female; Fetus; Flow Cytometry; Gene Expression Profiling; Hematopoiesis; Humans; Liver; Lymphoid Tissue; Single-Cell Analysis; Stem Cells
PubMed: 31597962
DOI: 10.1038/s41586-019-1652-y -
Cancer Immunology Research Apr 2023Pancreatic ductal adenocarcinoma (PDAC) has a poor clinical outlook. Responses to immune checkpoint blockade are suboptimal and a much more detailed understanding of the...
Pancreatic ductal adenocarcinoma (PDAC) has a poor clinical outlook. Responses to immune checkpoint blockade are suboptimal and a much more detailed understanding of the tumor immune microenvironment is needed if this situation is to be improved. Here, we characterized tumor-infiltrating T-cell populations in patients with PDAC using cytometry by time of flight (CyTOF) and single-cell RNA sequencing. T cells were the predominant immune cell subset observed within tumors. Over 30% of CD4+ T cells expressed a CCR6+CD161+ Th17 phenotype and 17% displayed an activated regulatory T-cell profile. Large populations of CD8+ tissue-resident memory (TRM) T cells were also present and expressed high levels of programmed cell death protein 1 (PD-1) and TIGIT. A population of putative tumor-reactive CD103+CD39+ T cells was also observed within the CD8+ tumor-infiltrating lymphocytes population. The expression of PD-1 ligands was limited largely to hemopoietic cells whilst TIGIT ligands were expressed widely within the tumor microenvironment. Programmed death-ligand 1 and CD155 were expressed within the T-cell area of ectopic lymphoid structures and colocalized with PD-1+TIGIT+ CD8+ T cells. Combinatorial anti-PD-1 and TIGIT blockade enhanced IFNγ secretion and proliferation of T cells in the presence of PD-1 and TIGIT ligands. As such, we showed that the PDAC microenvironment is characterized by the presence of substantial populations of TRM cells with an exhausted PD-1+TIGIT+ phenotype where dual checkpoint receptor blockade represents a promising avenue for future immunotherapy.
Topics: Humans; Memory T Cells; CD8-Positive T-Lymphocytes; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Tumor Microenvironment; Receptors, Immunologic
PubMed: 36689623
DOI: 10.1158/2326-6066.CIR-22-0121 -
The Journal of Pathology Jul 2022The dynamical process of cell division that underpins homeostasis in the human body cannot be directly observed in vivo, but instead is measurable from the pattern of... (Review)
Review
The dynamical process of cell division that underpins homeostasis in the human body cannot be directly observed in vivo, but instead is measurable from the pattern of somatic genetic or epigenetic mutations that accrue in tissues over an individual's lifetime. Because somatic mutations are heritable, they serve as natural lineage tracing markers that delineate clonal expansions. Mathematical analysis of the distribution of somatic clone sizes gives a quantitative readout of the rates of cell birth, death, and replacement. In this review we explore the broad range of somatic mutation types that have been used for lineage tracing in human tissues, introduce the mathematical concepts used to infer dynamical information from these clone size data, and discuss the insights of this lineage tracing approach for our understanding of homeostasis and cancer development. We use the human colon as a particularly instructive exemplar tissue. There is a rich history of human somatic cell dynamics surreptitiously written into the cell genomes that is being uncovered by advances in sequencing and careful mathematical analysis lineage of tracing data. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Topics: Cell Lineage; Colon; Humans; Mutation; Neoplasms; United Kingdom
PubMed: 35415852
DOI: 10.1002/path.5911 -
Biomedicine & Pharmacotherapy =... Feb 2022Human exposure to radiation has expanded considerably in recent years, due to a wide range of medical, agricultural, and industrial applications. Despite its beneficial... (Review)
Review
Human exposure to radiation has expanded considerably in recent years, due to a wide range of medical, agricultural, and industrial applications. Despite its beneficial utilities, radiation is also known to have a deleterious effect on cells and tissues, largely through the creation of free radicals, which cause severe damage to biological systems through processes such as DNA double/single-strand fragmentation, protein modification, and upregulation of lipid peroxidation pathways. In addition, radiation damages genetic material while inducing hereditary genotoxicity. Developing measures to counter radiation-induced damage is thus considered to be of significant importance. Considering the inherent capability of plants to survive radiative conditions, certain plants and natural compounds have been the subject of investigations to explore and harness their natural radioprotective abilities. Podophyllum hexandrum, an Indian medicinal plant with several known traditional phytotherapeutic uses, is considered in particular to be of immense therapeutic importance. Recent studies have been conducted to validate its radioprotective potential alongside discovering its protective mechanisms following γ-radiation-induced mortality and disorder in both mice and human cells. These findings show that Podophyllum and its constituents/natural compounds protect the lungs, gastrointestinal tissues, hemopoietic system, and testis by inducing DNA repair pathways, apoptosis inhibition, free radical scavenging, metal chelation, anti-oxidation and anti-inflammatory mechanisms. In this review, we have provided an updated, comprehensive summary of ionizing radiations and their impacts on biological systems, highlighting the mechanistic and radioprotective role of natural compounds from Podophyllum hexandrum.
Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Berberidaceae; Cell Survival; Chelating Agents; DNA Repair; Free Radical Scavengers; Maximum Tolerated Dose; Medicine, Traditional; Mitochondria; Plant Extracts; Radiation-Protective Agents
PubMed: 34954639
DOI: 10.1016/j.biopha.2021.112555 -
Journal of Translational Medicine Oct 2023Bone marrow fibrosis represents an important structural change in the marrow that interferes with some of its normal functions. The aetiopathogenesis of fibrosis is not... (Review)
Review
Bone marrow fibrosis represents an important structural change in the marrow that interferes with some of its normal functions. The aetiopathogenesis of fibrosis is not well established except in its primary form. The present review consolidates current understanding of marrow fibrosis. We searched PubMed without time restriction using key words: bone marrow and fibrosis as the main stem against the terms: growth factors, cytokines and chemokines, morphology, megakaryocytes and platelets, myeloproliferative disorders, myelodysplastic syndrome, collagen biosynthesis, mesenchymal stem cells, vitamins and minerals and hormones, and mechanism of tissue fibrosis. Tissue marrow fibrosis-related papers were short listed and analysed for the review. It emerged that bone marrow fibrosis is the outcome of complex interactions between growth factors, cytokines, chemokines and hormones together with their facilitators and inhibitors. Fibrogenesis is initiated by mobilisation of special immunophenotypic subsets of mesenchymal stem cells in the marrow that transform into fibroblasts. Fibrogenic stimuli may arise from neoplastic haemopoietic or non-hematopoietic cells, as well as immune cells involved in infections and inflammatory conditions. Autoimmunity is involved in a small subset of patients with marrow fibrosis. Megakaryocytes and platelets are either directly involved or are important intermediaries in stimulating mesenchymal stem cells. MMPs, TIMPs, TGF-β, PDGRF, and basic FGF and CRCXL4 chemokines are involved in these processes. Genetic and epigenetic changes underlie many of these conditions.
Topics: Humans; Bone Marrow; Primary Myelofibrosis; Cytokines; Fibrosis; Chemokines; Hormones
PubMed: 37814319
DOI: 10.1186/s12967-023-04393-z -
Nature Nov 2023Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I...
Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs), conferring a predisposition to life-threatening COVID-19 pneumonia. Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52/IκBδ). By contrast, neutralizing autoantibodies against type I IFNs are not found in individuals who are heterozygous for NFKB2 variants causing haploinsufficiency of p100 and p52 (hereafter, p52/IκBδ) or gain-of-function of p52 (hereafter, p52/IκBδ). In contrast to patients with APS-1, patients with disorders of NIK, RELB or NF-κB2 have very few tissue-specific autoantibodies. However, their thymuses have an abnormal structure, with few AIRE-expressing medullary thymic epithelial cells. Human inborn errors of the alternative NF-κB pathway impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases.
Topics: Humans; Autoantibodies; COVID-19; Gain of Function Mutation; Genetic Predisposition to Disease; Heterozygote; I-kappa B Proteins; Interferon Type I; Loss of Function Mutation; NF-kappa B; NF-kappa B p52 Subunit; Pneumonia, Viral; Thymus Gland; Thyroid Epithelial Cells; AIRE Protein; NF-kappaB-Inducing Kinase
PubMed: 37938781
DOI: 10.1038/s41586-023-06717-x -
Cells Feb 2021Eosinophilic asthma is the most prevalent phenotype of asthma. Although most asthmatics are adequately controlled by corticosteroid therapy, a subset (5-10%) remain... (Review)
Review
Eosinophilic asthma is the most prevalent phenotype of asthma. Although most asthmatics are adequately controlled by corticosteroid therapy, a subset (5-10%) remain uncontrolled with significant therapy-related side effects. This indicates the need for a consideration of alternative treatment strategies that target airway eosinophilia with corticosteroid-sparing benefits. A growing body of evidence shows that a balance between systemic differentiation and local tissue eosinophilopoietic processes driven by traffic and lung homing of bone marrow-derived hemopoietic progenitor cells (HPCs) are important components for the development of airway eosinophilia in asthma. Interleukin (IL)-5 is considered a critical and selective driver of terminal differentiation of eosinophils. Studies targeting IL-5 or IL-5R show that although mature and immature eosinophils are decreased within the airways, there is incomplete ablation, particularly within the bronchial tissue. Eotaxin is a chemoattractant for mature eosinophils and eosinophil-lineage committed progenitor cells (EoP), yet anti-CCR3 studies did not yield meaningful clinical outcomes. Recent studies highlight the role of epithelial cell-derived alarmin cytokines, IL-33 and TSLP, (Thymic stromal lymphopoietin) in progenitor cell traffic and local differentiative processes. This review provides an overview of the role of EoP in asthma and discusses findings from clinical trials with various therapeutic targets. We will show that targeting single mediators downstream of the inflammatory cascade may not fully attenuate tissue eosinophilia due to the multiplicity of factors that can promote tissue eosinophilia. Blocking lung homing and local eosinophilopoiesis through mediators upstream of this cascade may yield greater improvement in clinical outcomes.
Topics: Animals; Asthma; Cell Lineage; Eosinophils; Hematopoiesis; Humans; Molecular Targeted Therapy; Stem Cells
PubMed: 33669458
DOI: 10.3390/cells10020412 -
Cancer Drug Resistance (Alhambra,... 2020Cell free nucleic acids (CFNAs) are nucleic acids released from cells that circulate within bodily fluids. Recent advances in molecular techniques have led the ability... (Review)
Review
Cell free nucleic acids (CFNAs) are nucleic acids released from cells that circulate within bodily fluids. Recent advances in molecular techniques have led the ability to interrogate CFNAs in a clinically meaningful way, for example the identification and assessment of foetal CFNAs in maternal blood, allowing minimally invasive testing for foetal genetic abnormalities. The majority of CFNAs arise from haemopoietic cells, making it a particularly rich source of genetic information in haematological conditions. Furthermore, the innate genetic heterogeneity of haematological malignancies, as epitomised by multiple myeloma, lend itself well to "liquid biopsies". This approach promises to provide a more wholistic assessment of whole disease genetics, especially when contrasted against the current gold-standard of single site tissue biopsies. This review briefly summarises the definitions and physiology of CFNAs, both cell free DNA (cfDNA) and extracellular RNA (exRNA), before exploring the literature surrounding the current and future roles of cfDNA in the haematological malignancies and patient care.
PubMed: 35582436
DOI: 10.20517/cdr.2019.93 -
Mediterranean Journal of Hematology and... 2019Inherited hemoglobin disorders, including beta-thalassemia (BT) and sickle-cell disease (SCD), are the most common monogenic diseases worldwide, with a global carrier... (Review)
Review
Inherited hemoglobin disorders, including beta-thalassemia (BT) and sickle-cell disease (SCD), are the most common monogenic diseases worldwide, with a global carrier frequency of over 5%.1 With migration, they are becoming more common worldwide, making their management and care an increasing concern for health care systems. BT is characterized by an imbalance in the α/β-globin chain ratio, ineffective erythropoiesis, chronic hemolytic anemia, and compensatory hemopoietic expansion.1 Globally, there are over 25,000 births each year with transfusion-dependent thalassemia (TDT). The currently available treatment for TDT is lifelong transfusions and iron chelation therapy or allogenic bone marrow transplantation as a curative option. SCD affects 300 million people worldwide2 and severely impacts the quality of life of patients who experience unpredictable, recurrent acute and chronic severe pain, stroke, infections, pulmonary disease, kidney disease, retinopathy, and other complications. While survival has been dramatically extended, quality of life is markedly reduced by disease- and treatment-associated morbidity. The development of safe, tissue-specific and efficient vectors, and efficient gene-editing technologies have led to the development of several gene therapy trials for BT and SCD. However, the complexity of the approach presents its hurdles. Fundamental factors at play include the requirement for myeloablation on a patient with benign disease, the age of the patient, and the consequent bone marrow microenvironment. A successful path from proof-ofconcept studies to commercialization must render gene therapy a sustainable and accessible approach for a large number of patients. Furthermore, the cost of these therapies is a considerable challenge for the health care system. While new promising therapeutic options are emerging,3,4 and many others are on the pipeline,5 gene therapy can potentially cure patients. We herein provide an overview of the most recent, likely potentially curative therapies for hemoglobinopathies and a summary of the challenges that these approaches entail.
PubMed: 31700592
DOI: 10.4084/MJHID.2019.067 -
International Journal of Environmental... Jul 2022Carp kidney is comprised of nephrons, hemopoietic tissue, and also hormonally-active thyroid follicles. Given this anatomical trait, it has been used to assess the...
Carp kidney is comprised of nephrons, hemopoietic tissue, and also hormonally-active thyroid follicles. Given this anatomical trait, it has been used to assess the thyroid disrupting potential of perfluorooctanoic acid (PFOA), a widespread and feared per- poly-fluoroalkyl substance and a persistent organic pollutant capable of interfering with the endocrine system in animals and humans. The occurrence and morphology of thyroid follicles in kidneys of carp experimentally exposed to 200 ng L or 2 mg L waterborne PFOA for 56 days were studied. The abundance of thyroid follicles was significantly higher and vesiculation increased in exposed fish as compared to controls. The number of vesiculated follicles/total number of follicles was positively correlated with PFOA blood concentration in fish exposed to the highest dose (2 mg L). The structure and ultrastructure of thyroid follicles were affected by PFOA also at the lower, environmentally relevant, concentration (200 ng L). Increased cellular projections, enhanced colloid endocytosis, rough endoplasmic reticulum enlargement and fragmentation and cytoplasm vacuolation were the main features displayed by PFOA-exposed carp. These results show that PFOA affects the occurrence and status of follicles and suggest the utility of fish kidney as a multipurpose biomarker organ in environmental pathology research, according to the One Health approach.
Topics: Animals; Caprylates; Carps; Fluorocarbons; Humans; Thyroid Gland
PubMed: 35897426
DOI: 10.3390/ijerph19159049