Biology subjects

Steffes, L. C.

Publications and source records attributed to Steffes, L. C..

3 recordsLinked to original sources

bioRxiv2026

Imatinib Reduces Right Ventricular Systolic Pressure Independent of Arterial or Venous Remodeling in an Inflammatory Murine Model of Pulmonary Hypertension

Pulmonary arterial hypertension is a progressive, fatal disease driven by pathologic vascular remodeling including arterial medial hypertrophy, occlusive neointimal lesion formation, and venous muscularization. Current vasodilatory therapies improve hemodynamics but do not reverse established remodeling. Imatinib mesylate, a tyrosine kinase inhibitor targeting the PDGF-PDGFR signaling axis, has been proposed as an anti-remodeling therapy for pulmonary arterial hypertension and has demonstrated hemodynamic benefit in both preclinical models and clinical trials. However, prior preclinical models lack the neointimal lesions characteristic of human disease, effects on venous remodeling have not been examined, and direct histologic assessment in human trials is precluded by the invasiveness of serial lung biopsy. Here, leveraging the house dust mite mouse model of pulmonary hypertension, which recapitulates medial thickening, neointimal lesion formation, and venous muscularization, we rigorously evaluate the anti-remodeling and hemodynamic effects of imatinib during two defined remodeling stages: neointimal lesion growth and neointimal lesion maintenance. Imatinib treatment significantly reduced right ventricular systolic pressure at both stages. Despite this hemodynamic improvement, quantitative vessel-level analysis of over 1,700 arteries and 1,200 veins revealed no significant effect of imatinib on arterial medial thickness, neointimal lesion growth, neointimal lesion maintenance, or venous muscularization across any vessel size class. These findings dissociate imatinibs hemodynamic benefit from structural vascular remodeling and suggest that imatinib functions primarily as a pulmonary vasodilator rather than an anti-remodeling agent.

physiology↗

bioRxiv2025

Chromatin and gene-regulatory dynamics of human pulmogenesis by single cell multiomic sequencing

Human lung development is governed by complex gene regulatory networks that orchestrate cellular differentiation and organogenesis. We present a single cell multiomic atlas of human pulmogenesis, simultaneously capturing both the chromatin accessibility profile and the transcriptome from each cell across fetal lungs spanning from post-conception weeks (PCW) 12 to 23. We identified 44 distinct developing cell clusters and mapped 581,745 candidate cis-regulatory elements and nominated 121,486 non-redundant peak-to-gene linkages. We identify highly regulated genes (HRGs) and the cognate highly regulating peaks (HRPs) that describe the most salient regulatory gene programs and developmental enhancer sites for each cell type. Trajectory analysis along with interpretable cell type specific convolutional neural network models were developed to delineate dynamic regulatory programs driving key developmental transitions, including aerocyte and arterial differentiation and alveolar formation. Furthermore, we identified distinct vascular smooth muscle subpopulations with unique spatial associations to either arterial or venous structures with reciprocal signaling within each niche. We also uncovered the regulatory modules of surfactant production in alveolar progenitors, implicating a direct role for the glucocorticoid receptor alongside novel transcription factors. Finally, using cell type specific models linking DNA sequence to chromatin accessibility we prioritize variants associated with impaired pulmonary function or disease and nominate mechanisms of motif disruption. Overall, our multiomic atlas deepens our understanding of the gene-regulatory architecture underlying human lung development and provides a valuable resource for the community to dissect the cellular and molecular programs of pulmonary physiology and disease at the cellular and nucleotide precision.

genomics↗

bioRxiv2025

Excessive Postnatal Smooth Muscle Differentiation in a Lung Specific Model of TBX4-related Pulmonary Hypertension

Heterozygous TBX4 variants are the second most common genetic cause of pediatric pulmonary hypertension (PH), yet the mechanisms underlying the pathophysiology of TBX4-related lung disease remain poorly understood. We developed a lung mesenchyme-specific Tbx4 loss of function (Tbx4cKO) mouse model that bypasses embryonic lethality to investigate TBX4-related lung disease. Echocardiography of adult Tbx4cKO mice demonstrated significant hemodynamic changes consistent with PH. Three-dimensional whole-mount analysis of embryonic day 18.5 lungs revealed reduced lobe volumes and decreased distance between pleural edges and muscularized vessels. In adult Tbx4cKO lungs, high-resolution spatial quantitation identified extensive vascular remodeling characterized by significant medial thickening, distal muscularization of small diameter arteries, and extension of muscularized vessels into normally non-muscularized subpleural zones. Contrary to previous reports suggesting vascular simplification with Tbx4 loss, our comprehensive three-dimensional approach demonstrated an elaborated arterial tree with pathologic muscularization. Additional heterozygous loss of Tbx5 (Tbx4cKO;Tbx5het) exacerbated vascular phenotypes without worsening hemodynamic parameters. We also documented dysregulated airway smooth muscle patterning and prominent subpleural smooth muscle bands that share molecular features with myofibroblasts and airway smooth muscle cells, echoing pathologic findings in human TBX4 syndrome lung tissue. Collectively, our findings identify TBX4 as a critical suppressor of smooth muscle differentiation across multiple pulmonary compartments. This model recapitulates key features of human TBX4 syndrome and reveals mild developmental underpinnings with subsequent progressive postnatal smooth muscle dysregulation, highlighting a postnatal window during which therapeutic regulation of mesenchymal differentiation may be beneficial.

genetics↗