Biology subjects

Dobrinskikh, E.

Publications and source records attributed to Dobrinskikh, E..

5 recordsLinked to original sources

bioRxiv2026

IPF AT2 cells are stuck in transition and biophysically dysfunctional

Idiopathic Pulmonary Fibrosis (IPF) is an incurable disease with extensive molecular, cellular, and organ level dysfunction. A major gap in IPF research is the lack of understanding of how short-term cellular behavior causes long-term tissue remodeling. By optimizing lung slices from explanted human lungs, we discovered foci of migratory non-canonical alveolar type 2 (AT2) cells in regions of established lung fibrosis and found that these cells are trapped in states of cellular transition that are driven by persistent developmental repair programs. Consistent with these biophysical behaviors, pharmacological activation of {beta}-catenin reproduced persistent migration, whereas YAP activation restrained it. We conclude that imbalanced developmental programs drive AT2 cell motility and lesion heterogeneity, providing a mechanistic link between short-term cellular dynamics and slowly progressive fibrosis of IPF.

cell biology↗

bioRxiv2026

Maternal Western-style Diet Promotes Immune Tolerance and Liver Sinusoidal Endothelial Cell Dysfunction in Nonhuman Primate Juvenile Offspring Liver

Maternal Western-style diet (mWSD) consumption during pregnancy and lactation is associated with developmental programming of metabolic dysfunction-associated steatotic liver disease (MASLD) in offspring. To understand the roles of immune and endothelial cells, we used single-cell RNA-sequencing of liver non-parenchymal cells from 3-year-old juvenile nonhuman primates exposed to mWSD during their gestation through weaning, followed by control diet consumption after weaning. We identified unique clusters of macrophages in mWSD-exposed juvenile livers with non-reparative, pro-fibrotic phenotypes characterized by predicted inactivation of NF-{kappa}B, decreased oxidative phosphorylation, and gene expression facilitating hepatic stellate cell-macrophage interactions. Kupffer cell and dendritic cell (DC) numbers were decreased by mWSD exposure, with inactivation of inflammatory and antigen presentation pathways in DCs, supporting DC immaturity. B cells increased in mWSD-exposed offspring, with RNA showing reduced inflammation and impaired differentiation, while T cells had RNA profiles consistent with apoptosis and reduced inflammatory function. mWSD exposure increased clusters of liver sinusoidal endothelial cells (LSECs), with activation of inflammation and proliferation pathways but decreased immune cell communication. Immunocytochemistry and RNAscope identified increased association of LSECs and immune cells in periportal regions. In summary, mWSD exposure during gestation and lactation selectively modulated LSEC-immune cell interactions consistent with immune tolerant B and T cells and fibrogenic pathways together with decreased pro-resolving macrophages in juvenile offspring. We conclude that mWSD exposure establishes an immune-tolerant environment in offspring liver, marked by a durable, pro-fibrotic microenvironment that resists postnatal dietary correction.

immunology↗

bioRxiv2023

Altered Metabolism and DAM-signatures in Female Brains and Microglia with Aging

Despite Alzheimers disease (AD) disproportionately affecting women, the mechanisms remain elusive. In AD, microglia undergo metabolic reprogramming, which contributes to microglial dysfunction and AD pathology. However, how sex and age contribute to metabolic reprogramming in microglia is understudied. Here, we use metabolic imaging, transcriptomics, and metabolic assays to probe age-and sex-associated changes in brain and microglial metabolism. Glycolytic and oxidative metabolism in the whole brain was determined using Fluorescence Lifetime Imaging Microscopy (FLIM). Young female brains appeared less glycolytic than male brains, but with aging, the female brain became male-like. Transcriptomic analysis revealed increased expression of disease-associated microglia (DAM) genes (e.g., ApoE, Trem2, LPL), and genes involved in glycolysis and oxidative metabolism in microglia from aged females compared to males. To determine whether estrogen can alter the expression of these genes, BV-2 microglia-like cell lines, which abundantly express DAM genes, were supplemented with 17{beta}-estradiol (E2). E2 supplementation resulted in reduced expression of DAM genes, reduced lipid and cholesterol transport, and substrate-dependent changes in glycolysis and oxidative metabolism. Consistent with the notion that E2 may suppress DAM-associated factors, LPL activity was elevated in the brains of aged female mice. Similarly, DAM gene and protein expression was higher in monocyte-derived microglia-like (MDMi) cells derived from middle-aged females compared to age-matched males and was responsive to E2 supplementation. FLIM analysis of MDMi from young and middle-aged females revealed reduced oxidative metabolism and FAD+ with age. Overall, our findings show that altered metabolism defines age-associated changes in female microglia and suggest that estrogen may inhibit the expression and activity of DAM-associated factors, which may contribute to increased AD risk, especially in post-menopausal women.

neuroscience↗

bioRxiv2021

Single cell RNA Sequencing Identifies G-protein Coupled Receptor 87 as a Novel Basal Cell Marker of Distal Honeycomb Cysts in Idiopathic Pulmonary Fibrosis

Idiopathic Pulmonary Fibrosis (IPF) is a progressive and fatal lung disease with limited therapeutic options. Epithelial reprogramming and honeycomb cysts are key pathological features of IPF, however, the IPF distal bronchiole cell subtypes and their potential contribution to IPF development and progression still remain poorly characterized. Here, we utilized single-cell RNA sequencing on enriched EpCAM+ cells of the distal IPF and Donor lung. Using the 10x Genomics platform, we generated a dataset of 47,881 cells and found distinct cell clusters, including rare cell types, such as suprabasal cells recently reported in the healthy lung. We identified G-protein coupled receptor (GPR) 87 as a novel surface marker of distal Keratin (KRT)5+ basal cells. GPR87 expression was localized to distal bronchioles and honeycomb cysts in IPF in situ by RNA Scope and immunolabeling. Modulation of GPR87 in primary human bronchial epithelial cells cultures resulted in impaired airway differentiation and ciliogenesis. Thus, GPR87 is a novel marker and potentially druggable target of KRT5+ basal progenitor cells likely contributing to bronchiole remodeling and honeycomb cyst development in IPF.

cell biology↗

bioRxiv2018

Differential trafficking of albumin and IgG facilitated by the neonatal Fc receptor in podocytes in vitro and in vivo.

Proteinuria is strongly associated with kidney disease progression but the mechanisms underlying podocyte handling of serum proteins such as albumin and IgG remain to be elucidated. We have previously shown that albumin and IgG are transcytosed by podocytes in vitro. In other epithelial cells, the neonatal Fc receptor (FcRn) is required to salvage albumin and IgG from the degradative pathway thereby allowing these proteins to be transcytosed or recycled. Here we directly examine the role of FcRn in albumin and IgG trafficking in podocytes by studying handling of these proteins in FcRn knockout (KO) podocytes in vitro and in a podocyte-specific FcRn knockout mice in vivo. In vitro, we find that knockout of FcRn leads to IgG accumulation in podocytes but does not alter albumin trafficking. Similarly, in vivo, podocyte-specific knockout of FcRn does not result in albumin accumulation in podocytes in vivo as measured by mean albumin fluorescence intensity whereas these mice demonstrate significant intraglomerular accumulation of IgG over time. In addition we find that podocyte-specific FcRn KO mice demonstrate mesangial expansion as they age and activation of mesangial cells as demonstrated by increased expression of -smooth muscle actin. Taken together, these results suggest that trafficking pathways for albumin and IgG differ in podocytes and that sustained disruption of trafficking of plasma proteins alters glomerular structure.

cell biology↗