Modeling Obliterative Bronchiolitis
Obliterative bronchiolitis (OB) following lung transplantation is an irreversible lethal complication. Using a tracheal transplant mouse model of OB, Krebs et al (Am J Pathol, 254–269) studied the effect of vascular endothelial growth factor receptors (VEGFRs) 1 and 2 in the development of obliterative airway disease (OAD). OAD was induced by heterotopically transplanting fully major histocompatibility complex–mismatched mouse tracheal allografts. Blocking VEGFR significantly decreased the innate and adaptive immune responses and the development of OAD, likely by inhibiting these receptors on epithelial and endothelial cells of the airways wall. Targeting VEGFR signaling may help manage OB following lung transplantation.
Managing Graft Survival Post Corneal Transplantation
The rate of corneal endothelial cell (CEnC) loss increases post corneal transplantation, which can threaten sight. Using human and mouse CEnC lines and a mouse model, Lužnik Marzidovšek et al (Am J Pathol, 270–280) studied the role of the cytoprotective neuropeptide alpha-melanocyte-stimulating hormone (α-MSH) on corneal transplantation. The α-MSH receptor melanocortin 1 receptor (MC1R) is highly expressed on CEnCs. In vitro and in MC1R signaling-deficient mice, α-MSH had cytoprotective effects on CEnCs post corneal transplantation. In vivo, the loss of MC1R signaling significantly reduced long-term graft survival. Targeting α-MSH/MC1R signaling may enhance graft survival post corneal transplantation.
Understanding Podocyte Injury
Podocyte injury can aggravate chronic kidney diseases (CKDs). Using single-cell RNA sequencing of glomerular-enriched kidney tissue from an inducible mouse model of a progressing glomerular disease, Clark et al (Am J Pathol, 281–294) studied the effects of podocyte injury at a single-cell resolution after a week of disease induction. Data reveal the initial changes within the kidney filter and point to novel actionable markers that may be therapeutically targeted to manage CKDs.
Linking Gut Inflammation to Brain Immune Repopulation
Peripheral monocyte-derived CX3CR1+ cells promote immune repopulation of the brain parenchyma and gut after systemic inflammation. Using adoptive bone marrow transfer from fluorescently labelled CX3CR1 reporter mice, Batra et al (Am J Pathol, 295–307) studied the underlying mechanisms. Colon inflammation and injury increased tissue colonization by labelled CX3CR1 cells, promoted brain colonization by peripheral labelled CX3CR1 cells, and increased recruitment and association of labelled CX3CR1 cells with the vessel wall, macrophage colonization of the colon and the brain, and macrophage chemotactic ligands in the brain. Gut inflammation affects the repopulation of the brain and intestines and may have dramatic clinical implications on neurologic outcomes in health and disease.
Classifying Cancer
miRNAs are excellent classification markers. Using miRNA expression profiles from over 1000 human breast and skin tissue samples, Kaczmarek et al (Am J Pathol, 344–352) adapted an existing deep learning–based deep cancer classifier (DCC) to discriminate neoplastic and non-neoplastic samples. This adapted DCC outperforms traditional machine learning and feature selection approaches, and may be useful in identifying miRNA biomarkers using a custom feature selection algorithm.
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Published online: December 14, 2021
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© 2022 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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- The Neuropeptide Alpha-Melanocyte–Stimulating Hormone Is Critical for Corneal Endothelial Cell Protection and Graft Survival after TransplantationThe American Journal of PathologyVol. 192Issue 2
- PreviewCorneal transplantation is the most common form of tissue transplantation. The success of corneal transplantation mainly relies on the integrity of corneal endothelial cells (CEnCs), which maintain tissue transparency by pumping out excess water from the cornea. After transplantation, the rate of CEnC loss far exceeds that seen with normal aging, which can threaten sight. The underlying mechanisms are poorly understood. Alpha-melanocyte–stimulating hormone (α-MSH) is a neuropeptide that is constitutively found in the aqueous humor with both cytoprotective and immunomodulatory effects.
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- Single-Cell Transcriptomics Reveal Disrupted Kidney Filter Cell-Cell Interactions after Early and Selective Podocyte InjuryThe American Journal of PathologyVol. 192Issue 2
- PreviewThe health of the kidney filtration barrier requires communication among podocytes, endothelial cells, and mesangial cells. Disruption of these cell-cell interactions is thought to contribute to disease progression in chronic kidney diseases (CKDs). Podocyte ablation via doxycycline-inducible deletion of an essential endogenous molecule, CTCF [inducible podocyte-specific CTCF deletion (iCTCFpod−/−)], is sufficient to drive progressive CKD. However, the earliest events connecting podocyte injury to disrupted intercellular communication within the kidney filter remain unclear.
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- Inhibition of Vascular Endothelial Growth Factor Receptors 1 and 2 Attenuates Natural Killer Cell and Innate Immune Responses in an Experimental Model for Obliterative BronchiolitisThe American Journal of PathologyVol. 192Issue 2
- PreviewObliterative bronchiolitis (OB) after lung transplantation is a nonreversible, life-threatening complication. Herein, the role of vascular endothelial growth factor receptor (Vegfr)-1 and -2 was investigated in the development of obliterative airway disease (OAD), an experimental model for OB. The nonimmunosuppressed recipients underwent transplantation with fully major histocompatibility complex mismatched heterotopic tracheal allografts and received Vegfr1 and -2–specific monoclonal antibodies either alone or in combination, or rat IgG as a control.
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- Discriminating Neoplastic from Nonneoplastic Tissues Using an miRNA-Based Deep Cancer ClassifierThe American Journal of PathologyVol. 192Issue 2
- PreviewNext-generation sequencing has enabled the collection of large biological data sets, allowing novel molecular-based classification methods to be developed for increased understanding of disease. miRNAs are small regulatory RNA molecules that can be quantified using next-generation sequencing and are excellent classificatory markers. Herein, a deep cancer classifier (DCC) was adapted to differentiate neoplastic from nonneoplastic samples using comprehensive miRNA expression profiles from 1031 human breast and skin tissue samples.
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- Experimental Colitis Enhances Temporal Variations in CX3CR1 Cell Colonization of the Gut and Brain Following IrradiationThe American Journal of PathologyVol. 192Issue 2
- PreviewPeripheral monocyte-derived CX3C chemokine receptor 1 positive (CX3CR1+) cells play important roles in tissue homeostasis and gut repopulation. Increasing evidence also supports their role in immune repopulation of the brain parenchyma in response to systemic inflammation. Adoptive bone marrow transfer from CX3CR1 fluorescence reporter mice and high-resolution confocal microscopy was used to assess the time course of CX3CR1+ cell repopulation of steady-state and dextran sodium sulfate (DSS)-inflamed small intestine/colon and the brain over 4 weeks after irradiation.
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