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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 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 -
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 -
Frontiers in Medicine 2021The glomerulus is the functional unit for filtration of blood and formation of primary urine. This intricate structure is composed of the endothelium with its glycocalyx... (Review)
Review
The glomerulus is the functional unit for filtration of blood and formation of primary urine. This intricate structure is composed of the endothelium with its glycocalyx facing the blood, the glomerular basement membrane and the podocytes facing the urinary space of Bowman's capsule. The mesangial cells are the central hub connecting and supporting all these structures. The components as a unit ensure a high permselectivity hindering large plasma proteins from passing into the urine while readily filtering water and small solutes. There has been a long-standing interest and discussion regarding the functional contribution of the different cellular components but the mesangial cells have been somewhat overlooked in this context. The mesangium is situated in close proximity to all other cellular components of the glomerulus and should be considered important in pathophysiological events leading to glomerular disease. This review will highlight the role of the mesangium in both glomerular function and intra-glomerular crosstalk. It also aims to explain the role of the mesangium as a central component involved in disease onset and progression as well as signaling to maintain the functions of other glomerular cells to uphold permselectivity and glomerular health.
PubMed: 35155460
DOI: 10.3389/fmed.2021.740527 -
Digital Journal of Ophthalmology : DJO Apr 2019Spheroidal degeneration, involving the cornea and/or the conjunctiva, is characterized by amber-colored homogeneous, translucent spherules in the corneal stroma,...
Spheroidal degeneration, involving the cornea and/or the conjunctiva, is characterized by amber-colored homogeneous, translucent spherules in the corneal stroma, Bowman's membrane, and subepithelium. The condition has a higher prevalence in areas with extreme temperatures, low humidity, high wind, and presence of sand. We report the case of a 46-year-old man with a 10-year history of gradual progressive diminution of vision, severe blepharospasm, and photophobia. Examination revealed bilateral plaques of amber-colored nodules covering about half of the cornea. Superficial keratectomy was performed for the lesions in both eyes, leaving an epithelial defect overlying a plane of opaque cornea. Histopathology showed amorphous protein in the anterior stroma, confirming the clinical diagnosis of advanced grade 4 spheroidal degeneration. Visual acuity and other symptoms dramatically improved, and the patient was scheduled for keratoplasty.
Topics: Cornea; Corneal Diseases; Disease Progression; Humans; Keratoplasty, Penetrating; Male; Middle Aged; Visual Acuity
PubMed: 32076391
DOI: 10.5693/djo.02.2019.11.001