Biology subjects

Ghelfi, E.

Publications and source records attributed to Ghelfi, E..

3 recordsLinked to original sources

bioRxiv2026

Membrane Tension Integrates Physical and Signaling Cues to Gate Cell Fate Transitions

Physical forces shape cell behavior, yet how they integrate with signaling to control fate and disease remains unclear. The alveolar epithelium is patterned by FGF signaling and mechanical stretch, but how these cues specify AT1 and AT2 cells is poorly understood. Here we show that cell membrane tension (CMT) is a conserved regulator of epithelial fate in mouse and human lungs. CMT drops before differentiation and is spatially patterned, defining where bipotent progenitors acquire AT1 or AT2 identity. Lower CMT enhances FGFR2 endocytosis and ERK signaling to drive AT2 differentiation and permits architectural remodeling that enables stretch-mediated YAP/TAZ nuclear entry for AT1 maturation. {beta}-catenin elevates CMT cell-intrinsically independent of its role in canonical WNT transcription, while embedding, osmotic compression, or fibroblast wrapping elevate CMT extrinsically. Combined intrinsic and extrinsic tension traps alveolar epithelial cells in a KRT8 transitional state seen in fibrotic lungs. Membrane tension thus integrates physical and molecular cues linking morphogenesis to fibrosis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=160 HEIGHT=200 SRC="FIGDIR/small/708749v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@1a9c04forg.highwire.dtl.DTLVardef@190bee2org.highwire.dtl.DTLVardef@1e41664org.highwire.dtl.DTLVardef@17a3ec7_HPS_FORMAT_FIGEXP M_FIG C_FIG In BriefWe identify a conserved drop in cell membrane tension (CMT) that gates epithelial fate transitions across mouse and human lungs. In bipotent progenitors, reduced CMT promotes Alveolar Type 2 (AT2) fate via FGFR2 endocytosis and ERK signaling, as well as Alveolar Type 1 (AT1) fate by enabling architectural remodeling required for YAP/TAZ nuclear entry. We further show that intrinsic {beta}-catenin and extrinsic confinement cues, including mesenchymal contact, converge to elevate CMT, restricting differentiation and--in adult AT2s--inducing a KRT8 transitional state associated with fibrosis. HighlightsO_LICell membrane tension drops before differentiation and is required for AT1 and AT2 fate acquisition. C_LIO_LIReduced tension enhances FGFR2 endocytosis and ERK signaling to drive AT2 specification. C_LIO_LIReduced tension permits architectural remodeling and YAP/TAZ nuclear entry required for AT1 maturation. C_LIO_LIIntrinsic {beta}-catenin and extrinsic confinement elevate CMT to restrict differentiation and together strongly induce a KRT8 transitional state associated with fibrosis. C_LI

cell biology↗

bioRxiv2022

Alveolar cell fate selection and lifelong maintenance of AT2 cells by FGF signaling

The lungs gas exchange surface comprises thin alveolar type 1 (AT1) cells and cuboidal surfactant-secreting AT2 cells that are corrupted in some of the most common and deadly diseases including adenocarcinoma, emphysema, and SARS/Covid-19. These cells arise from an embryonic progenitor whose development into an AT1 or AT2 cell is thought to be dictated by differential mechanical forces. Here we show the critical determinant is FGF signaling. FGF Receptor 2 (Fgfr2) is expressed in mouse progenitors then restricts to nascent AT2 cells and remains on throughout life. Its ligands are expressed in surrounding mesenchyme and can, in the absence of differential mechanical cues, induce purified, uncommitted E16.5 progenitors to form alveolus-like structures with intermingled AT2 and AT1 cells. FGF signaling directly and cell autonomously specifies AT2 fate; progenitors lacking Fgfr2 in vitro and in vivo exclusively acquire AT1 fate. Fgfr2 loss in AT2 cells perinatally results in reprogramming to AT1 fate, whereas loss or inhibition later in life immediately triggers AT2 apoptosis followed by a compensatory regenerative response. We propose Fgfr2 signaling directly selects AT2 fate during development, induces a cell non-autonomous secondary signal for AT1 fate, and stays on throughout life to continuously maintain healthy AT2 cells. One Sentence SummaryFGF signaling induces and distinguishes the two cell types of the lungs gas exchange surface, and the pathway remains on throughout life to maintain one that can be transformed into lung cancer or targeted in the deadly form of SARS/Covid-19.

developmental biology↗

bioRxiv2020

Age-dependent regulation of SARS-CoV-2 cell entry genes and cell death programs correlates with COVID-19 disease severity

Angiotensin-converting enzyme 2 (ACE2) maintains cardiovascular and renal homeostasis but also serves as the entry receptor for the novel severe acute respiratory syndrome coronavirus (SARS-CoV-2), the causal agent of novel coronavirus disease 2019 (COVID-19)1. COVID-19 disease severity, while highly variable, is typically lower in pediatric patients than adults (particularly the elderly), but increased rates of hospitalizations requiring intensive care are observed in infants than in older children. The reasons for these differences are unknown. To detect potential age-based correlates of disease severity, we measured ACE2 protein expression at the single cell level in human lung tissue specimens from over 100 donors from [~]4 months to 75 years of age. We found that expression of ACE2 in distal lung epithelial cells generally increases with advancing age but exhibits extreme intra- and inter-individual heterogeneity. Notably, we also detected ACE2 expression on neonatal airway epithelial cells and within the lung parenchyma. Similar patterns were found at the transcript level: ACE2 mRNA is expressed in the lung and trachea shortly after birth, downregulated during childhood, and again expressed at high levels in late adulthood in alveolar epithelial cells. Furthermore, we find that apoptosis, which is a natural host defense system against viral infection, is also dynamically regulated during lung maturation, resulting in periods of heightened apoptotic priming and dependence on pro-survival BCL-2 family proteins including MCL-1. Infection of human lung cells with SARS-CoV-2 triggers an unfolded protein stress response and upregulation of the endogenous MCL-1 inhibitor Noxa; in juveniles, MCL-1 inhibition is sufficient to trigger apoptosis in lung epithelial cells - this may limit virion production and inflammatory signaling. Overall, we identify strong and distinct correlates of COVID-19 disease severity across lifespan and advance our understanding of the regulation of ACE2 and cell death programs in the mammalian lung. Furthermore, our work provides the framework for potential translation of apoptosis modulating drugs as novel treatments for COVID-19.

cell biology↗