Biology subjects

Shen, W.-B.

Publications and source records attributed to Shen, W.-B..

5 recordsLinked to original sources

bioRxiv2026

Ferroptosis of selective progenitor cell types during embryogenesis ensures proper organ morphogenesis

Ferroptosis, a form of non-apoptotic cell death, is induced by lipid peroxidation resulting from an intracellular accumulation of labile iron (1). While apoptosis is involved in embryonic development (2), the role of ferroptosis in embryogenesis is unknown. Here, we report that the ferroptosis process occurs in the embryonic lung and kidney at mid- and late-gestation. In these tissues, pro-ferroptotic cells include subpopulations of the Sox9+ distal lung epithelial cells and the Flk1+ vascular progenitors in the kidney glomeruli. Lipidomic analysis reveals mixed lipid peroxidation as the driver for ferroptosis. The role of ferroptosis in the morphogenesis of these organs was confirmed by triple positivity of TfR1, 4-HNE and TUNEL, mitochondrial defects, cell membrane breakage, dead cell remnants, single-cell RNA-sequencing of a ferroptosis gene signature. Genetic manipulation of Gpx4, an endogenous inhibitor of ferroptosis. Further, genetic knockout or transgenic overexpression of Gpx4 affects lung and kidney development and results in cystic lungs and kidneys. Notably, conditional deletion Gpx4 results in hypoplasia of the lung epithelia and of the renal glomeruli, while transgenic overexpression of Gpx4 resulted in atelectasis with collapsed lung alveoli and hypertrophic glomeruli. Together, these findings show that ferroptosis regulates lung and kidney morphogenesis by acting in key progenitor cell populations during gestation. Supplementation of iron or polyunsaturated fatty acid during pregnancy has implications for organogenesis.

developmental biology↗

bioRxiv2026

Early Insulin Signaling Defects and Oxidative Stress Kinase Activation Precede Tau Pathology in PS19 Tau Transgenic Mice

Pathological tau accumulation is a hallmark of Alzheimers disease (AD), yet its relationship with impaired insulin signaling remains unclear. Previously, we reported altered IRS1 phosphorylation reduced p IR beta, and GLUT3 expression in young AD transgenic mice prior to overt pathology. Here, we investigated insulin signaling and oxidative stress pathways in the Tau P301S (PS19) mouse model. We found that alterations in phospho IRS1, phospho IR beta, and the glucose transporters GLUT3 and GLUT4 occur before pathogenic tau deposition. In stable tau expressing human neuronal cell lines, tau expression was similarly associated with impaired insulin signaling. Concurrent dysregulation of insulin signaling and activation of oxidative stress responsive kinases, accompanied by increased microglial abundance, were evident in 2 month old PS19 mice and persisted into adulthood. Together, these findings demonstrate that insulin signaling abnormalities and oxidative stress kinase activation are early and sustained features of PS19 tauopathy, preceding the onset of overt neuropathology.

neuroscience↗

bioRxiv2025

Isoflurane and Surgical Stress Disrupt Fatty Acid and Carbon Metabolism Leading to Cardiomyopathy

Aging alters cardiac resilience to anesthetic and surgical stress, yet the molecular basis of these effects remains poorly understood. To define age-dependent cardiac transcriptional responses to isoflurane exposure and operative (ISO/OP) stress, we analyzed gene expression profiles across young adult (3m), late middle-aged (17m), and geriatric mice (27m) following short-term 2 h ISO/OP exposure. At 24 h after cessation, all age groups exhibited distinct cardiac transcriptional signatures separating ISO/OP from sham controls. In young adult hearts, transcriptional alterations 24 hours after cessation of ISO/OP were characterized by dysregulation of small molecule catabolic processes, fatty acid metabolism, disruptions to protein processing in endoplasmic reticulum and cytoskeletal organization. Late middle-aged mice displayed amplified perturbations in lipid metabolism alongside suppression of muscle system and calcium signaling pathways, while old mice showed robust activation of PPAR and AMPK signaling and downregulation of genes governing contractility and morphogenesis. In contrast, geriatric mice showed upregulation of fatty acid metabolic pathways, robust activation of PPAR and AMPK signaling, coupled with suppression of muscle differentiation and actin organization following ISO exposure, indicating a maladaptive metabolic reprogramming. Overlapping DEGs across all age groups converged on pathways regulating oxidative stress, Ca2+ handling, hypertrophy, and energy metabolism, suggesting a conserved but age-intensified cardiac stress response. Longitudinal profiling in aged mice revealed persistent transcriptomic remodeling five weeks after stress. Crucially, this remodeling was observed even after ISO exposure alone, indicating that general anesthesia is a primary driver of this long-term effect. This persistent signature was marked by mitochondrial dysfunction and dysregulation of genes associated with diabetic cardiomyopathy, extracellular matrix integrity, and neurodegenerative signaling. Together, these findings identify isoflurane exposure as a potent inducer of persistent, age-dependent metabolic and structural reprogramming in the heart, implicating impaired lipid utilization and mitochondrial homeostasis as central mechanisms linking the perioperative period, and specifically anesthetic exposure, to long-term cardiovascular vulnerability.

pharmacology and toxicology↗

bioRxiv2022

SARS-CoV-2 invades cognitive centers of the brain and induces Alzheimer's-like neuropathology

Major cell entry factors of SARS-CoV-2 are present in neurons; however, the neurotropism of SARS-CoV-2 and the phenotypes of infected neurons are still unclear. Acute neurological disorders occur in many patients, and one-third of COVID-19 survivors suffer from "brain diseases". Here, we show that SARS-CoV-2 invades the brains of five patients with COVID-19 and Alzheimers, autism, frontotemporal dementia or no underlying condition by infecting neurons and other cells in the cortex. SARS-CoV-2 induces or enhances Alzheimers-like neuropathology with manifestations of {beta}-amyloid aggregation and plaque formation, tauopathy, neuroinflammation and cell death. SARS-CoV-2 infects mature but not immature neurons derived from inducible pluripotent stem cells from healthy and Alzheimers individuals through its receptor ACE2 and facilitator neuropilin-1. SARS-CoV-2 triggers Alzheimers-like gene programs in healthy neurons and exacerbates Alzheimers neuropathology. A gene signature defined as an Alzheimers infectious etiology is identified through SARS-CoV-2 infection, and silencing the top three downregulated genes in human primary neurons recapitulates the neurodegenerative phenotypes of SARS-CoV-2. Thus, SARS-CoV-2 invades the brain and activates an Alzheimers-like program.

neuroscience↗

bioRxiv2020

Maternal diabetes induces senescence and neural tube defects sensitive to the senomorphic Rapamycin

Neural tube defects (NTDs) are the second most common structural birth defects. Senescence, a state of permanent cell cyle arrest, only occurs after neural tube closure. Maternal diabetes-induced NTDs, severe diabetic complications leading to infant mortality or lifelong morbidity, may be linked to premature senescence. Here we report that premature senescence occurs in the mouse neuroepithelium and disrupts neurulation, leading to NTDs in diabetic pregnancy. Premature senescence and NTDs were abolished by deleting the transcription factor Foxo3a, the miR-200c gene, the cell cycle inhibitors p21 or p27, or by transgenic expression of the dominant-negative FoxO3a mutant or by the senomorphic rapamycin. Double transgenic expression of p21 and p27 mimicked maternal diabetes in inducing premature neuroepithelium senescence and NTDs. These findings integrate transcription- and epigenome-regulated miRNAs and cell cycle regulators in premature neruoepithelium senescence, and provide a mechanistic basis for targeting premature senescence and NTDs using senomorphs.

developmental biology↗