Biology subjects

Lee-Ferris, R.

Publications and source records attributed to Lee-Ferris, R..

3 recordsLinked to original sources

bioRxiv2026

Versatile and Cross-Species Alveolar Type II Cell Isolation Using Humanized Monoclonal Antibody Upifitamab

Alveolar type 2 (AT2) cells are primary adult alveolar stem cells that maintain healthy alveoli. AT2 cell dysfunction is broadly linked to many lung pathologies from emphysema to fibrosis. Isolation of AT2 cells with high purity is therefore central to diagnostic studies, proteomics, transcriptomics and ex vivo experiments that can lead to future AT2 cellular therapies. Current markers for AT2 isolation exhibit various limitations from species-restrictions (e.g., mouse vs human) to limited AT2 specificity, which creates challenges for flow cytometric gating/sorting and application to magnetic-activated cell isolation. While underrepresented in the literature, these bottlenecks have made AT2 cell isolation inherently difficult and slowed AT2 cell research. Here we leverage surface protein-restricted transcriptomics to identify the sodium phosphate transporter NaPi2b (SLC34A2) as a highly specific AT2 cell marker optimally detected with the humanized monoclonal antibody upifitamab. Upifitamab-based labeling of AT2 cells is compatible with flow cytometric or magnetic-activated AT2 isolation and applies to both mouse and human AT2 cells, thus streamlining protocols and circumventing species-specific nuances. AT2 cells obtained with upifitamab can be cultured as organoids, in monolayers or differentiated to AT1 cells. This simplified AT2 isolation approach should overcome several current barriers while facilitating ex vivo studies on alveolar biology and related therapeutic developments.

molecular biology↗

bioRxiv2026

Alveolar Cytochrome P450 Mediates Butylated Hydroxytoluene-Induced Electrophilic Injury and Apoptosis

Butylated hydroxytoluene (BHT) is a synthetic phenolic antioxidant utilized as a preservative in many products from foods to cosmetics. Population-based studies have detected BHT in the vast majority (>90%) of human specimens (serum, urine, fingernails) as well as home dust samples. Thus, BHT constitutes a ubiquitous environmental contaminant without obvious adverse health effects to humans. In contrast, exposure of mice to a single intraperitoneal dose of BHT triggers distal epithelial damage including loss of gas-exchanging alveolar type 1 epithelial cells, thus providing an invaluable tool to study alveolar repair and transient fibrosis. Presently, the molecular basis of BHT lung toxicity remains unknown. To address this, mouse lung single cell transcriptomic data were used to identify cytochrome P450 2B10 (CYP2B10) in AT1 cells as a BHT-activating enzyme. In cell culture systems, expression of CYP2B10 leads to marked BHT sensitization consistent with bioactivation of BHT into a toxic quinone methide. Targeted and proteome-wide experiments identify BHT-induced protein alkylation, DNA damage response, stress kinase activation and intrinsic apoptosis in a CYP2B10-dependent manner. Structure-activity relationship studies reveal the necessity of para-methyl and ortho-t-butyl groups necessary for BHT bioactivation. Our findings elucidate the molecular basis by which BHT is converted from an innocuous antioxidant into a highly toxic quinone methide and identify the first mammalian enzyme known to catalyze BHT bioactivation. Further, CYP2B10-catalyzed BHT bioactivation may provide a strategy for future targeted cell ablation technologies or environmental remediation of BHT.

molecular biology↗

bioRxiv2026

Region-specific molecular regulatory programs define epithelial identity, progenitor states, and mucus homeostasis in human distal airways

Small distal airways differ from proximal large airways in structure, airflow dynamics, and epithelial composition, and represent a central site of muco-obstructive lung disease pathogenesis. However, due in part to their inaccessibility, the molecular mechanisms that establish regional epithelial identity and govern mucociliary defense in distal airway epithelia remain poorly defined. Here, we integrate transcriptomic, secretomic, and chromatin accessibility analyses of matched primary human large and small airway epithelial cultures to define region-specific regulatory networks. We identify distal airway-specific transcriptional and chromatin programs required for maintaining epithelial identity and mucus homeostasis. Loss of NKX2-1 impairs distal airway secretory cell (DASC) differentiation and shifts mucus properties toward a disease-associated state. Lineage-resolved organoid assays identify an NKX2-1-high distal airway basal cell population with hybrid basal-secretory features as a selective progenitor for DASCs. Collectively, these findings establish a molecular framework for distal airway epithelial biology and define mechanisms regulating region-specific mucociliary host defense.

Cell Biology↗