Biology subjects

Lin, S. M.

Publications and source records attributed to Lin, S. M..

4 recordsLinked to original sources

bioRxiv2026

A Single-Cell Atlas of PVOD Across the Lifespan Reveals Cellular and Molecular Therapeutic Targets

Rationale Pulmonary veno-occlusive disease (PVOD) is a progressive and lethal disease cured only lung transplant. While genetic mutations in EIF2AK4 have been identified in some cases, 70% of PVOD patients have no known etiology. Objectives To construct a single-cell atlas to define the cellular and molecular constituents driving pathophysiology in PVOD. Methods Lung samples were collected from four idiopathic non-EIF2AK4 mutation pediatric and adult PVOD patients and age-matched controls. Analyses of single-cell RNA sequencing, Xenium spatial transcriptomics, and immunohistochemistry were performed to identify cell state changes and differential gene expression between controls and PVOD and subsequent transcriptome comparison between our PVOD and published pulmonary arterial hypertension (PAH) datasets. Measurement and Main Results The single-cell atlas reveals marked changes in the PVOD endothelium compared to controls. EndMT and ectopic COL15A1+ systemic venous shunts and pulmonary vein endothelium are hallmarks of PVOD. Molecular analyses reveal activation of the integrated stress response (ISR)/ATF4, TGF{beta} signaling, MAPK signaling, and BRD4 are potential key players in the pathophysiology of PVOD. While PVOD and PAH share both pathological and some molecular mechanisms, ISR and TGF{beta} signaling are more prominent in PVOD than PAH. Conclusions These data indicate that endothelial dysfunction is a primary etiology in the development of PVOD with activation of multiple pathways with druggable targets.

molecular biology↗

bioRxiv2026

A postnatal human lung developmental atlas reveals windows of genetic vulnerability to chronic lung disease

At birth, the lungs undergo an abrupt physiologic change, as the function of gas exchange transitions from the placenta to the lung. Subsequent postnatal development of the lungs is marked by a rapid and profound increase in the growth of the distal airways and alveolar gas exchange compartment. Insults during this period increase the risk of developing lung disease later in life, though how early-life events affect adult disease onset remains unclear. We generated a single-cell atlas of postnatal human lung development from birth through adulthood and mapped temporally regulated gene expression changes in each cell lineage. Using this atlas, we identified disease risk-associated genes with developmentally regulated expression. These analyses reveal cell type-specific and temporally restricted expression of genes associated with adult lung disease risk, including COPD. Heritability enrichment analysis demonstrated that COPD genetic risk is enriched in genes active during early postnatal endothelial development, linking early-life vascular maturation to adult disease susceptibility. These findings characterize the early window of susceptibility for adult chronic lung diseases and establish a framework to guide mechanistic studies of disease-associated genes.

developmental biology↗

bioRxiv2022

Hyperactive mTOR in Lung Mesenchyme Induces Endothelial Dysfunction and Pulmonary Vascular Remodeling

Pulmonary vascular remodeling is the key structural abnormality in pulmonary hypertension (PH). Mechanistic target of rapamycin (mTOR) has long been suspected to play a role in the development of pulmonary vascular remodeling. However, underlying cellular and molecular mechanisms leading to this pathophysiological condition remain incompletely understood. To elucidate the crosstalk between lung mesenchyme with activated mTOR and endothelial cells (ECs), we focused on a monogenic lung disease, pulmonary lymphangioleiomyomatosis (LAM). LAM is a progressive cystic lung disease caused by a mutational inactivation of tuberous sclerosis complex (TSC1/TSC2), which results in constitutive mTOR activation in mesenchymal LAM cells. ECs derived from LAM lung explants showed increased proliferation, migration, and defective angiogenesis compared to age- and sex-matched ECs from control human lung. In LAM cells, we found increased WNT2 ligand expression. We also identified corresponding Frizzled 4 (FZD) receptors on ECs isolated from distal LAM lung, suggesting cellular crosstalk between LAM cells and ECs. In endothelial-fibroblast cocultures, treatment of normal ECs with WNT2 ligands recapitulated LAM EC phenotype and morphology. We observed transcriptomic upregulation in metabolic, angiogenic and growth pathways in ECs of young mice, while 1-year-old Tsc2KO mice spontaneously developed pulmonary vascular remodeling with concurrent elevation in right ventricular systolic pressure. Our study demonstrates that LAM cells are not just a pathological mesenchymal cell state but a signaling hub that contributes to dysregulated cellular response in the surrounding vasculature, eventual pulmonary vascular remodeling and PH.

molecular biology↗

bioRxiv2022

Guided construction of single cell reference for human and mouse lung

Accurate cell type identification is a key and rate-limiting step in single cell data analysis. Single cell references with comprehensive cell types, reproducible and functional validated cell identities, and common nomenclatures are much needed by the research community to optimize automated cell type annotation and facilitate data integration, sharing, and collaboration. In the present study, we developed a novel computational pipeline to utilize the LungMAP CellCards as a dictionary to consolidate single-cell transcriptomic datasets of 104 human lungs and 17 mouse lung samples and constructed "LungMAP CellRef" and "LungMAP CellRef Seed" for both normal human and mouse lungs. "CellRef Seed" has an equivalent prediction power and produces consistent cell annotation as does "CellRef" but improves computational efficiency and simplifies its utilization for fast automated cell type annotation and online visualization. This atlas set incorporates 48 human and 40 mouse well-defined lung cell types catalogued from diverse anatomic locations and developmental time points. Using independent datasets, we demonstrated the utility of our CellRefs for automated cell type annotation analysis of both normal and disease lungs. User-friendly web interfaces were developed to support easy access and maximal utilization of the LungMAP CellRefs. LungMAP CellRefs are freely available to the pulmonary research community through fast interactive web interfaces to facilitate hypothesis generation, research discovery, and identification of cell type alterations in disease conditions.

bioinformatics↗