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Kidney International Jun 2016Podocytes maintain the glomerular filtration barrier, and the stability of this barrier depends on their highly differentiated postmitotic phenotype, which also defines... (Review)
Review
Podocytes maintain the glomerular filtration barrier, and the stability of this barrier depends on their highly differentiated postmitotic phenotype, which also defines the particular vulnerability of the glomerulus. Recent podocyte biology and gene disruption studies in vivo indicate a causal relationship between abnormalities of single podocyte molecules and proteinuria and glomerulosclerosis. Podocytes live under various stresses and pathological stimuli. They adapt to maintain homeostasis, but excessive stress leads to maladaptation with complex biological changes including loss of integrity and dysregulation of cellular metabolism. Podocyte injury causes proteinuria and detachment from the glomerular basement membrane. In addition to "sick" podocytes and their detachment, our understanding of glomerular responses following podocyte loss needs to address the pathways from podocyte injury to sclerosis. Studies have found a variety of glomerular responses to podocyte dysfunction in vivo, such as disruption of podocyte-endothelial cross talk and activation of podocyte-parietal cell interactions, all of which help us to understand the complex scenario of podocyte injury and its consequences. This review focuses on the cellular aspects of podocyte dysfunction and the adaptive or maladaptive glomerular responses to podocyte injury that lead to its major consequence, glomerulosclerosis.
Topics: Apoptosis; Bowman Capsule; Cell Communication; Cell Differentiation; Endothelial Cells; Glomerular Basement Membrane; Glomerulosclerosis, Focal Segmental; Humans; Oxidative Stress; Podocytes; Proteinuria; Sclerosis; Stress, Mechanical
PubMed: 27165817
DOI: 10.1016/j.kint.2016.01.012 -
Med (New York, N.Y.) Jul 2022Pro-inflammatory fibroblasts are critical for pathogenesis in rheumatoid arthritis, inflammatory bowel disease, interstitial lung disease, and Sjögren's syndrome and...
BACKGROUND
Pro-inflammatory fibroblasts are critical for pathogenesis in rheumatoid arthritis, inflammatory bowel disease, interstitial lung disease, and Sjögren's syndrome and represent a novel therapeutic target for chronic inflammatory disease. However, the heterogeneity of fibroblast phenotypes, exacerbated by the lack of a common cross-tissue taxonomy, has limited our understanding of which pathways are shared by multiple diseases.
METHODS
We profiled fibroblasts derived from inflamed and non-inflamed synovium, intestine, lungs, and salivary glands from affected individuals with single-cell RNA sequencing. We integrated all fibroblasts into a multi-tissue atlas to characterize shared and tissue-specific phenotypes.
FINDINGS
Two shared clusters, CXCL10CCL19 immune-interacting and SPARCCOL3A1 vascular-interacting fibroblasts, were expanded in all inflamed tissues and mapped to dermal analogs in a public atopic dermatitis atlas. We confirmed these human pro-inflammatory fibroblasts in animal models of lung, joint, and intestinal inflammation.
CONCLUSIONS
This work represents a thorough investigation into fibroblasts across organ systems, individual donors, and disease states that reveals shared pathogenic activation states across four chronic inflammatory diseases.
FUNDING
Grant from F. Hoffmann-La Roche (Roche) AG.
Topics: Animals; Arthritis, Rheumatoid; Fibroblasts; Phenotype; Stromal Cells; Synovial Membrane
PubMed: 35649411
DOI: 10.1016/j.medj.2022.05.002 -
Nature Reviews. Microbiology Jun 2018Autophagy is a powerful tool that host cells use to defend against viral infection. Double-membrane vesicles, termed autophagosomes, deliver trapped viral cargo to the... (Review)
Review
Autophagy is a powerful tool that host cells use to defend against viral infection. Double-membrane vesicles, termed autophagosomes, deliver trapped viral cargo to the lysosome for degradation. Specifically, autophagy initiates an innate immune response by cooperating with pattern recognition receptor signalling to induce interferon production. It also selectively degrades immune components associated with viral particles. Following degradation, autophagy coordinates adaptive immunity by delivering virus-derived antigens for presentation to T lymphocytes. However, in an ongoing evolutionary arms race, viruses have acquired the potent ability to hijack and subvert autophagy for their benefit. In this Review, we focus on the key regulatory steps during viral infection in which autophagy is involved and discuss the specific molecular mechanisms that diverse viruses use to repurpose autophagy for their life cycle and pathogenesis.
Topics: Animals; Autophagy; Humans; Immunity, Innate; Virus Diseases; Viruses
PubMed: 29556036
DOI: 10.1038/s41579-018-0003-6 -
Nature Nov 2019Mitochondrial homeostasis depends on mitophagy, the programmed degradation of mitochondria. Only a few proteins are known to participate in mitophagy. Here we develop a...
Mitochondrial homeostasis depends on mitophagy, the programmed degradation of mitochondria. Only a few proteins are known to participate in mitophagy. Here we develop a multidimensional CRISPR-Cas9 genetic screen, using multiple mitophagy reporter systems and pro-mitophagy triggers, and identify numerous components of parkin-dependent mitophagy. Unexpectedly, we find that the adenine nucleotide translocator (ANT) complex is required for mitophagy in several cell types. Whereas pharmacological inhibition of ANT-mediated ADP/ATP exchange promotes mitophagy, genetic ablation of ANT paradoxically suppresses mitophagy. Notably, ANT promotes mitophagy independently of its nucleotide translocase catalytic activity. Instead, the ANT complex is required for inhibition of the presequence translocase TIM23, which leads to stabilization of PINK1, in response to bioenergetic collapse. ANT modulates TIM23 indirectly via interaction with TIM44, which regulates peptide import through TIM23. Mice that lack ANT1 show blunted mitophagy and consequent profound accumulation of aberrant mitochondria. Disease-causing human mutations in ANT1 abrogate binding to TIM44 and TIM23 and inhibit mitophagy. Together, our findings show that ANT is an essential and fundamental mediator of mitophagy in health and disease.
Topics: Animals; Cell Line; Mice; Mitochondrial Membrane Transport Proteins; Mitochondrial Precursor Protein Import Complex Proteins; Mitophagy; Nucleotides; Protein Binding; Protein Kinases
PubMed: 31618756
DOI: 10.1038/s41586-019-1667-4 -
Indian Journal of Ophthalmology Sep 2018Lamellar keratoplasty (LK) has revolutionized corneal graft surgery in several ways. Deep anterior LK (DALK) has eliminated risk of failure due to endothelial rejection.... (Review)
Review
Lamellar keratoplasty (LK) has revolutionized corneal graft surgery in several ways. Deep anterior LK (DALK) has eliminated risk of failure due to endothelial rejection. Endothelial keratoplasty (EK) has almost eliminated induced astigmatism and the "weak" graft-host junction as seen with penetrating keratoplasty (PK) and also reduced the risk of endothelial rejection. LK provided new insights into posterior corneal anatomy that led to better understanding and performance of DALK and to the development of another EK procedure, namely pre-Descemet's EK (PDEK). Surgical procedures for LK were further refined based on the improved understanding and are able to deliver better surgical outcomes in terms of structural integrity and long-term patient satisfaction, reducing the need of further surgeries and minimizing patient discomfort. In most specialist centers, anterior lamellar techniques like DALK and EK techniques like Descemet's stripping EK (DSEK) and Descemet's membrane EK (DMEK) have replaced the full-thickness PK where possible. The introduction of microkeratome, femtosecond laser, and PDEK clamp have made LK techniques easier and more predictable and have led to the innovation of another LK procedure, namely Bowman membrane transplant (BMT). In this article, we discuss the evolution of different surgical techniques, their principles, main outcomes, and limitations. To date, experience with BMT is limited, but DALK has become the gold standard for anterior LK. The EK procedures too have undergone a rapid transition from DSEK to DMEK and PDEK emerging as a viable option. Ultrathin-DSEK may still have a role in modern EK.
Topics: Cornea; Corneal Diseases; Humans; Keratoplasty, Penetrating; Visual Acuity
PubMed: 30127133
DOI: 10.4103/ijo.IJO_95_18 -
F1000Research 2016Podocytes are highly specialized cells of the kidney glomerulus that wrap around capillaries and that neighbor cells of the Bowman's capsule. When it comes to glomerular... (Review)
Review
Podocytes are highly specialized cells of the kidney glomerulus that wrap around capillaries and that neighbor cells of the Bowman's capsule. When it comes to glomerular filtration, podocytes play an active role in preventing plasma proteins from entering the urinary ultrafiltrate by providing a barrier comprising filtration slits between foot processes, which in aggregate represent a dynamic network of cellular extensions. Foot processes interdigitate with foot processes from adjacent podocytes and form a network of narrow and rather uniform gaps. The fenestrated endothelial cells retain blood cells but permit passage of small solutes and an overlying basement membrane less permeable to macromolecules, in particular to albumin. The cytoskeletal dynamics and structural plasticity of podocytes as well as the signaling between each of these distinct layers are essential for an efficient glomerular filtration and thus for proper renal function. The genetic or acquired impairment of podocytes may lead to foot process effacement (podocyte fusion or retraction), a morphological hallmark of proteinuric renal diseases. Here, we briefly discuss aspects of a contemporary view of podocytes in glomerular filtration, the patterns of structural changes in podocytes associated with common glomerular diseases, and the current state of basic and clinical research.
PubMed: 26918173
DOI: 10.12688/f1000research.7255.1 -
Cell Stem Cell Nov 2019Transcriptional regulators, including the cohesin complex member STAG2, are recurrently mutated in cancer. The role of STAG2 in gene regulation, hematopoiesis, and tumor...
Transcriptional regulators, including the cohesin complex member STAG2, are recurrently mutated in cancer. The role of STAG2 in gene regulation, hematopoiesis, and tumor suppression remains unresolved. We show that Stag2 deletion in hematopoietic stem and progenitor cells (HSPCs) results in altered hematopoietic function, increased self-renewal, and impaired differentiation. Chromatin immunoprecipitation (ChIP) sequencing revealed that, although Stag2 and Stag1 bind a shared set of genomic loci, a component of Stag2 binding sites is unoccupied by Stag1, even in Stag2-deficient HSPCs. Although concurrent loss of Stag2 and Stag1 abrogated hematopoiesis, Stag2 loss alone decreased chromatin accessibility and transcription of lineage-specification genes, including Ebf1 and Pax5, leading to increased self-renewal and reduced HSPC commitment to the B cell lineage. Our data illustrate a role for Stag2 in transformation and transcriptional dysregulation distinct from its shared role with Stag1 in chromosomal segregation.
Topics: Animals; B-Lymphocytes; Cell Cycle Proteins; Cell Lineage; Cell Self Renewal; Chromatin; Chromatin Immunoprecipitation; Gene Expression Regulation; Gene Knockout Techniques; Hematopoiesis; Hematopoietic Stem Cells; Humans; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myelodysplastic Syndromes; Nuclear Proteins; PAX5 Transcription Factor; RNA-Seq; Synthetic Lethal Mutations; Trans-Activators
PubMed: 31495782
DOI: 10.1016/j.stem.2019.08.003