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Nature Reviews. Molecular Cell Biology Jul 2020Multiple modes of cell death have been identified, each with a unique function and each induced in a setting-dependent manner. As billions of cells die during mammalian... (Review)
Review
Multiple modes of cell death have been identified, each with a unique function and each induced in a setting-dependent manner. As billions of cells die during mammalian embryogenesis and daily in adult organisms, clearing dead cells and associated cellular debris is important in physiology. In this Review, we present an overview of the phagocytosis of dead and dying cells, a process known as efferocytosis. Efferocytosis is performed by macrophages and to a lesser extent by other 'professional' phagocytes (such as monocytes and dendritic cells) and 'non-professional' phagocytes, such as epithelial cells. Recent discoveries have shed light on this process and how it functions to maintain tissue homeostasis, tissue repair and organismal health. Here, we outline the mechanisms of efferocytosis, from the recognition of dying cells through to phagocytic engulfment and homeostatic resolution, and highlight the pathophysiological consequences that can arise when this process is abrogated.
Topics: Animals; Apoptosis; Homeostasis; Host-Pathogen Interactions; Humans; Inflammation; Macrophages; Phagocytes; Phagocytosis; Signal Transduction
PubMed: 32251387
DOI: 10.1038/s41580-020-0232-1 -
Cell May 2021Damaged mitochondria need to be cleared to maintain the quality of the mitochondrial pool. Here, we report mitocytosis, a migrasome-mediated mitochondrial...
Damaged mitochondria need to be cleared to maintain the quality of the mitochondrial pool. Here, we report mitocytosis, a migrasome-mediated mitochondrial quality-control process. We found that, upon exposure to mild mitochondrial stresses, damaged mitochondria are transported into migrasomes and subsequently disposed of from migrating cells. Mechanistically, mitocytosis requires positioning of damaged mitochondria at the cell periphery, which occurs because damaged mitochondria avoid binding to inward motor proteins. Functionally, mitocytosis plays an important role in maintaining mitochondrial quality. Enhanced mitocytosis protects cells from mitochondrial stressor-induced loss of mitochondrial membrane potential (MMP) and mitochondrial respiration; conversely, blocking mitocytosis causes loss of MMP and mitochondrial respiration under normal conditions. Physiologically, we demonstrate that mitocytosis is required for maintaining MMP and viability in neutrophils in vivo. We propose that mitocytosis is an important mitochondrial quality-control process in migrating cells, which couples mitochondrial homeostasis with cell migration.
Topics: Animals; Biological Transport; Cell Line; Cell Movement; Cytoplasm; Exocytosis; Female; Homeostasis; Male; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; Microscopy, Electron, Transmission; Mitochondria; Mitochondrial Membranes; Organelles
PubMed: 34048705
DOI: 10.1016/j.cell.2021.04.027 -
Science (New York, N.Y.) Mar 2018In the adult brain, the neural stem cell (NSC) pool comprises quiescent and activated populations with distinct roles. Transcriptomic analysis revealed that quiescent...
In the adult brain, the neural stem cell (NSC) pool comprises quiescent and activated populations with distinct roles. Transcriptomic analysis revealed that quiescent and activated NSCs exhibited differences in their protein homeostasis network. Whereas activated NSCs had active proteasomes, quiescent NSCs contained large lysosomes. Quiescent NSCs from young mice accumulated protein aggregates, and many of these aggregates were stored in large lysosomes. Perturbation of lysosomal activity in quiescent NSCs affected protein-aggregate accumulation and the ability of quiescent NSCs to activate. During aging, quiescent NSCs displayed defects in their lysosomes, increased accumulation of protein aggregates, and reduced ability to activate. Enhancement of the lysosome pathway in old quiescent NSCs cleared protein aggregates and ameliorated the ability of quiescent NSCs to activate, allowing them to regain a more youthful state.
Topics: Aging; Animals; Cell Division; Cellular Senescence; Lysosomes; Mice; Mice, Inbred C57BL; Neural Stem Cells
PubMed: 29590078
DOI: 10.1126/science.aag3048 -
Nature Mar 2017With age, haematopoietic stem cells lose their ability to regenerate the blood system, and promote disease development. Autophagy is associated with health and...
With age, haematopoietic stem cells lose their ability to regenerate the blood system, and promote disease development. Autophagy is associated with health and longevity, and is critical for protecting haematopoietic stem cells from metabolic stress. Here we show that loss of autophagy in haematopoietic stem cells causes accumulation of mitochondria and an activated metabolic state, which drives accelerated myeloid differentiation mainly through epigenetic deregulations, and impairs haematopoietic stem-cell self-renewal activity and regenerative potential. Strikingly, most haematopoietic stem cells in aged mice share these altered metabolic and functional features. However, approximately one-third of aged haematopoietic stem cells exhibit high autophagy levels and maintain a low metabolic state with robust long-term regeneration potential similar to healthy young haematopoietic stem cells. Our results demonstrate that autophagy actively suppresses haematopoietic stem-cell metabolism by clearing active, healthy mitochondria to maintain quiescence and stemness, and becomes increasingly necessary with age to preserve the regenerative capacity of old haematopoietic stem cells.
Topics: Animals; Autophagy; Cell Self Renewal; Cellular Senescence; Epigenesis, Genetic; Female; Hematopoiesis; Hematopoietic Stem Cells; Male; Mice; Mitochondria; Myeloid Cells
PubMed: 28241143
DOI: 10.1038/nature21388 -
Journal of Neuroinflammation Jun 2021Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by brain accumulation of aggregated amyloid-beta (Aβ) and alpha-synuclein (αSYN), respectively....
BACKGROUND
Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by brain accumulation of aggregated amyloid-beta (Aβ) and alpha-synuclein (αSYN), respectively. In order to develop effective therapies, it is crucial to understand how the Aβ/αSYN aggregates can be cleared. Compelling data indicate that neuroinflammatory cells, including astrocytes and microglia, play a central role in the pathogenesis of AD and PD. However, how the interplay between the two cell types affects their clearing capacity and consequently the disease progression remains unclear.
METHODS
The aim of the present study was to investigate in which way glial crosstalk influences αSYN and Aβ pathology, focusing on accumulation and degradation. For this purpose, human-induced pluripotent cell (hiPSC)-derived astrocytes and microglia were exposed to sonicated fibrils of αSYN or Aβ and analyzed over time. The capacity of the two cell types to clear extracellular and intracellular protein aggregates when either cultured separately or in co-culture was studied using immunocytochemistry and ELISA. Moreover, the capacity of cells to interact with and process protein aggregates was tracked using time-lapse microscopy and a customized "close-culture" chamber, in which the apical surfaces of astrocyte and microglia monocultures were separated by a <1 mm space.
RESULTS
Our data show that intracellular deposits of αSYN and Aβ are significantly reduced in co-cultures of astrocytes and microglia, compared to monocultures of either cell type. Analysis of conditioned medium and imaging data from the "close-culture" chamber experiments indicate that astrocytes secrete a high proportion of their internalized protein aggregates, while microglia do not. Moreover, co-cultured astrocytes and microglia are in constant contact with each other via tunneling nanotubes and other membrane structures. Notably, our live cell imaging data demonstrate that microglia, when attached to the cell membrane of an astrocyte, can attract and clear intracellular protein deposits from the astrocyte.
CONCLUSIONS
Taken together, our data demonstrate the importance of astrocyte and microglia interactions in Aβ/αSYN clearance, highlighting the relevance of glial cellular crosstalk in the progression of AD- and PD-related brain pathology.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Astrocytes; Brain; Cell Membrane Structures; Cells, Cultured; Coculture Techniques; Humans; Induced Pluripotent Stem Cells; Microglia; Microscopy, Confocal; Nanotubes; Parkinson Disease; Protein Aggregates; Protein Aggregation, Pathological; Proteolysis; alpha-Synuclein
PubMed: 34082772
DOI: 10.1186/s12974-021-02158-3 -
Cell Research Aug 2018Tissue clearing technique enables visualization of opaque organs and tissues in 3-dimensions (3-D) by turning tissue transparent. Current tissue clearing methods are...
Tissue clearing technique enables visualization of opaque organs and tissues in 3-dimensions (3-D) by turning tissue transparent. Current tissue clearing methods are restricted by limited types of tissues that can be cleared with each individual protocol, which inevitably led to the presence of blind-spots within whole body or body parts imaging. Hard tissues including bones and teeth are still the most difficult organs to be cleared. In addition, loss of endogenous fluorescence remains a major concern for solvent-based clearing methods. Here, we developed a polyethylene glycol (PEG)-associated solvent system (PEGASOS), which rendered nearly all types of tissues transparent and preserved endogenous fluorescence. Bones and teeth could be turned nearly invisible after clearing. The PEGASOS method turned the whole adult mouse body transparent and we were able to image an adult mouse head composed of bones, teeth, brain, muscles, and other tissues with no blind areas. Hard tissue transparency enabled us to reconstruct intact mandible, teeth, femur, or knee joint in 3-D. In addition, we managed to image intact mouse brain at sub-cellular resolution and to trace individual neurons and axons over a long distance. We also visualized dorsal root ganglions directly through vertebrae. Finally, we revealed the distribution pattern of neural network in 3-D within the marrow space of long bone. These results suggest that the PEGASOS method is a useful tool for general biomedical research.
Topics: Animals; Bone and Bones; Brain; Dogs; Female; Histological Techniques; Humans; Imaging, Three-Dimensional; Male; Mice; Mice, Inbred C57BL; Muscles; Nerve Net; Neurons; Polyethylene Glycols; Rats; Rats, Sprague-Dawley; Solvents; Whole Body Imaging
PubMed: 29844583
DOI: 10.1038/s41422-018-0049-z -
Seminars in Immunology May 2023When we can understand what natural killer (NK) cells recognize during an encounter with an infectious pathogen or a tumor cell, and when we can understand how the NK... (Review)
Review
When we can understand what natural killer (NK) cells recognize during an encounter with an infectious pathogen or a tumor cell, and when we can understand how the NK cell responds to that encounter, we can then begin to understand the role of NK cells in human health and how to improve upon their role for the prevention and treatment of human disease. In the quest to understand how these cells function in antiviral and antitumoral immunity, there have been previously described mechanisms established for NK cells to participate in clearing viral infections and tumors, including classical NK cell antibody dependent cellular cytotoxicity (ADCC) as well as recognition and elimination of transformed malignant cells through direct ligand interactions. However, it is now clear that there are additional mechanisms by which NK cells can participate in these critical immune tasks. Here we review two recently described types of NK cell recognition and response: the first is to primary infection with herpes virus, recognized and responded to by non-specific Fc bridged cellular cytotoxicity (FcBCC), and the second describes a novel phenotypic and functional response when a subset of NK cells recognize myeloid leukemia.
Topics: Humans; Killer Cells, Natural; Antibody-Dependent Cell Cytotoxicity; Neoplasms; Antiviral Agents
PubMed: 36965383
DOI: 10.1016/j.smim.2023.101749 -
The Plant Journal : For Cell and... Jan 2018Higher plant function is contingent upon the complex three-dimensional (3D) architecture of plant tissues, yet severe light scattering renders deep, 3D tissue imaging...
Higher plant function is contingent upon the complex three-dimensional (3D) architecture of plant tissues, yet severe light scattering renders deep, 3D tissue imaging very problematic. Although efforts to 'clear' tissues have been ongoing for over a century, many innovations have been made in recent years. Among them, a protocol called ClearSee efficiently clears tissues and diminishes chlorophyll autofluorescence while maintaining fluorescent proteins - thereby allowing analysis of gene expression and protein localisation in cleared samples. To further increase the usefulness of this protocol, we have developed a ClearSee-based toolbox in which a number of classical histological stains for lignin, suberin and other cell wall components can be used in conjunction with fluorescent reporter lines. We found that a number of classical dyes are highly soluble in ClearSee solution, allowing the old staining protocols to be enormously simplified; these additionally have been unsuitable for co-visualisation with fluorescent markers due to harsh fixation and clearing. Consecutive staining with several dyes allows 3D co-visualisation of distinct cell wall modifications with fluorescent proteins - used as transcriptional reporters or protein localisation tools - deep within tissues. Moreover, the protocol is easily applied on hand sections of different organs. In combination with confocal microscopy, this improves image quality while decreasing the time and cost of embedding/sectioning. It thus provides a low-cost, efficient method for studying thick plant tissues which are usually cumbersome to visualise. Our ClearSee-adapted protocols significantly improve and speed up anatomical and developmental investigations in numerous plant species, and we hope they will contribute to new discoveries in many areas of plant research.
Topics: Arabidopsis; Cell Wall; Cellulose; Chlorophyll; Fluorescent Antibody Technique; Fluorescent Dyes; Indicators and Reagents; Lignin; Membrane Lipids; Microscopy, Confocal; Plant Roots; Staining and Labeling; Urea; Xylitol
PubMed: 29171896
DOI: 10.1111/tpj.13784 -
Head and Neck Pathology Mar 2023Optically clear cytoplasm may occur in neoplastic and non-neoplastic conditions, either as a characteristic feature of a disease entity or as a morphologic rarity,... (Review)
Review
BACKGROUND
Optically clear cytoplasm may occur in neoplastic and non-neoplastic conditions, either as a characteristic feature of a disease entity or as a morphologic rarity, potentially creating diagnostic dilemmas in various organ systems. In the head and neck, clear cell change can occur in lesions of salivary, odontogenic, thyroid, parathyroid, or sinonasal/skull base origin, as well as in metastases to these regions.
METHODS
This review elaborates the top ten clear cell lesions in the head and neck, emphasizing their distinguishing histologic, immunohistochemical, and molecular attributes, and presents a rational approach to arriving at an accurate classification.
RESULTS
Cytoplasmic pallor or clearing may be caused by accumulations of glycogen, lipid, mucin, mucopolysaccharides, water, foreign material, hydropic organelles, or immature zymogen granules. Overlapping morphologic features may present a diagnostic challenge to the surgical pathologist. Similarity in immunohistochemical profiles, often due to common cell type, as well as rare non-neoplastic mimics, furthers the diagnostic conundrum.
CONCLUSIONS
The top ten lesions reviewed in this article are as follows: (1) clear cell carcinoma (salivary and odontogenic), (2) mucoepidermoid carcinoma, (3) myoepithelial and epithelial-myoepithelial carcinoma, (4) oncocytic salivary gland lesions, (5) squamous cell carcinoma, (6) parathyroid water clear cell adenoma, (7) metastatic renal cell carcinoma (especially in comparison to clear cell thyroid neoplasms), (8) sinonasal renal cell-like adenocarcinoma, (9) chordoma, and (10) rhinoscleroma.
Topics: Humans; Carcinoma, Renal Cell; Kidney Neoplasms; Epithelial Cells; Carcinoma, Squamous Cell; Adenocarcinoma, Clear Cell; Salivary Gland Neoplasms
PubMed: 36928734
DOI: 10.1007/s12105-022-01518-6 -
Neuron Nov 2022CNS-resident macrophages-including parenchymal microglia and border-associated macrophages (BAMs)-contribute to neuronal development and health, vascularization, and... (Review)
Review
CNS-resident macrophages-including parenchymal microglia and border-associated macrophages (BAMs)-contribute to neuronal development and health, vascularization, and tissue integrity at steady state. Border-patrolling mononuclear phagocytes such as dendritic cells and monocytes confer important immune functions to the CNS, protecting it from pathogenic threats including aberrant cell growth and brain malignancies. Even though we have learned much about the contribution of lymphocytes to CNS pathologies, a better understanding of differential roles of tissue-resident and -invading phagocytes is slowly emerging. In this perspective, we propose that in CNS neuroinflammatory diseases, tissue-resident macrophages (TRMs) contribute to the clearing of debris and resolution of inflammation, whereas blood-borne phagocytes are drivers of immunopathology. We discuss the remaining challenges to resolve which specialized mononuclear phagocyte populations are driving or suppressing immune effector function, thereby potentially dictating the outcome of autoimmunity or brain cancer.
Topics: Humans; Mononuclear Phagocyte System; Microglia; Phagocytes; Macrophages; Monocytes; Brain Neoplasms
PubMed: 36327896
DOI: 10.1016/j.neuron.2022.10.005