Biology subjects

Snyder, E. Y.

Publications and source records attributed to Snyder, E. Y..

4 recordsLinked to original sources

bioRxiv2025

The cryo-EM-delineated mechanism underlying mimicry of CXCR4 agonism enables widespread stem cell neuroprotection in a mouse model of ALS

G-protein coupled receptors (GPCRs) are transmembrane proteins that mediate a range of signaling functions and, therefore, offer targets for a number of therapeutic interventions. Chemokine receptor CXCR4, a GPCR, plays versatile roles in normal and abnormal physiological processes. Synthetic CXCR4 antagonists have been extensively studied and approved for the clinical treatment of cancer and other diseases. We recently elucidated the structural mechanisms underlying CXCR4 antagonism using cryogenic electron microscopy (cryo-EM). CXCR4 agonism by synthetic molecules is an unanticipated therapeutic intervention we recently unveiled. The structural mechanisms underlying those actions remain poorly understood yet could help elucidate a new class of drugs. Here we demonstrate a synthetic dual-moiety strategy that combines simplified agonistic and antagonistic moieties taken from natural agonistic and antagonistic chemokines, respectively, to design de novo peptide mimics of biological function of natural CXCR4 agonist SDF-1. Two peptides so generated, SDV1a and SDVX1 were shown to mimic the action of SDF-1 in activating CXCR4 signaling pathways and cell migration. The structural mechanism of these peptides in the mimicry of CXCR4 agonism was illustrated by cryo-EM structures of CXCR4 bound and activated by the peptides in the presence of G protein, revealing common interactions with the receptor by these peptides in comparison with SDF-1 that explain their close mimicry and conformational changes leading to CXCR4 signal activation. The therapeutic benefit of one of these peptides, SDV1a, was demonstrated in the SOD1G93A mouse model of the spinal motor neuron degenerative disease, amyotrophic lateral sclerosis (ALS) wherein the success of neuroprotective actions of transplanted human neural stem cells (hNSCs) is directly correlated with the expanse of diseased neuroaxis traversed by the donor cells; SDV1a enabled broader neuroprotective coverage while also permitting a much less invasive route of cell administration for extending life. Taken together, these results provide insights into the structural determinants of therapeutic CXCR4 agonism which may allow the design of adjunctive drugs that improve cell-based treatments of central nervous system (CNS) diseases.

neuroscience↗

bioRxiv2025

Modeling the Aging Human Lung: Generation of a Senescent Human Lung Organoid Culture System

IntroductionThe aging lung enters into a state of irreversible cellular growth arrest characterized by senescence. While senescence is beneficial in preventing oncogenic cell proliferation, it becomes detrimental when persistent, promoting chronic inflammation and fibrosis through the senescence-associated secretory phenotype (SASP). Such senescence-related pathophysiological processes play key roles in lung diseases like chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). However, few models accurately represent senescence in the human lung. MethodsTo generate a human lung senescence in vitro model, we first generated a human induced pluripotent stem cell (hiPSC)-derived lung organoid (LO) system which was dissociated into monolayers and air-liquid interface (ALI) cultures to enhance visualization and allow uniform exposure to agents. Cellular senescence was induced using doxorubicin, a DNA-damaging agent. Senescence markers, such as {beta}-galactosidase ({beta}-gal) activity, SASP cytokine production and secretion, cell morphology, proliferative capacity, and barrier integrity were evaluated to validate the senescent phenotype. ResultsThe doxorubicin-induced senescent hiPSC-derived lung cells demonstrated the hallmark characteristics of cellular senescence, including increased {beta}-gal activity and increased production of the pro-inflammatory SASP cytokine IL-6 and increased secretion of TNF-. Senescent cells displayed enlarged morphology, decreased proliferation, and reduced wound repair capacity. Barrier integrity was impaired with decreased electrical resistance, and increased permeability, as well as expression of abnormal tight junction proteins and increased fibrosis, all consistent with the senescent lung. ConclusionOur hiPSC-derived lung cell senescent model reproduces key aspects of human lung senescence and offer an in vitro tool for studying age-related lung disease mechanisms and therapeutic interventions. This model has potential applications in exploring the impact of environmental factors (e.g., toxins, infectious pathogens, etc.) on the senescent lung and assessing treatments that could mitigate pathologies associated with pulmonary aging including barrier impairment, inflammation and fibrosis.

cell biology↗

bioRxiv2023

The effects of cell-cell orientation in modeling the hallmarks of lung cancer in vitro

To better understand and develop treatments for lung cancer, it is important to have reliable and physiologically relevant culture models. Traditional methods of growing lung cancer cells in two- dimensional (2D) monolayers have limitations in mimicking the complex architecture and microenvironment of lung tumors in vivo, limiting their value as reliably informative disease models. In this study, we introduce a new cell culture platform called "tumoroids," which involves growing HCC827 lung cancer cells in three-dimensional (3D) configurations. By comparing transcriptional profiles of HCC827 cells grown as tumoroids versus the same cells grown in 2D monolayers, we investigate how cell-cell orientation and signaling impact the cancer-driving properties of lung cancer. We examine key features associated with cancer progression, such as epithelial mesenchymal transition, replicative ability, and induction of angiogenesis. Additionally, we assess the functional characteristics of the 3D tumoroid culture system by subjecting the cells to irradiation. Through comparing the gene expression profiles of the 3D tumoroid and 2D cultures with those of primary human lung adenocarcinoma, we find that the 3D tumoroid cultures more closely resemble the characteristics of primary human lung cancer. This suggests that the 3D tumoroid culture platform can serve as a valuable in vitro model for studying lung cancer, offering greater clinical relevance compared to traditional 2D cultures. Overall, this study highlights the importance of using advanced culture models like 3D tumoroids to improve our understanding of lung cancer and facilitate the development of effective treatments.

cancer biology↗

bioRxiv2023

The lung employs an intrinsic surfactant-mediated inflammatory response for viral defense

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) causes an acute respiratory distress syndrome (ARDS) that resembles surfactant deficient RDS. Using a novel multi-cell type, human induced pluripotent stem cell (hiPSC)-derived lung organoid (LO) system, validated against primary lung cells, we found that inflammatory cytokine/chemokine production and interferon (IFN) responses are dynamically regulated autonomously within the lung following SARS-CoV-2 infection, an intrinsic defense mechanism mediated by surfactant proteins (SP). Single cell RNA sequencing revealed broad infectability of most lung cell types through canonical (ACE2) and non-canonical (endocytotic) viral entry routes. SARS-CoV-2 triggers rapid apoptosis, impairing viral dissemination. In the absence of surfactant protein B (SP-B), resistance to infection was impaired and cytokine/chemokine production and IFN responses were modulated. Exogenous surfactant, recombinant SP-B, or genomic correction of the SP-B deletion restored resistance to SARS-CoV-2 and improved viability.

immunology↗