Biology subjects

Yang, M. M.

Publications and source records attributed to Yang, M. M..

3 recordsLinked to original sources

bioRxiv2026

Comparative molecular analysis of histopathologic subtypes reveals shared epithelial remodeling yet distinct fibroblast programs in scleroderma lung disease

Rationale: Interstitial lung disease (ILD) drives mortality in systemic sclerosis (SSc), with a subset developing progressive pulmonary fibrosis (PPF) resembling idiopathic pulmonary fibrosis (IPF). Despite recognition of two distinct histopathologic patterns, the cellular basis of nonspecific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP) remains poorly understood. Objectives: To define shared and distinct cellular and molecular features of SSc-NSIP and SSc-UIP compared to IPF. Methods: Single-nucleus RNA sequencing and spatial transcriptomics were performed on explanted lungs from patients with SSc-NSIP (n=6), SSc-UIP (n=6), or IPF (n=6), and control donors (n=12) with immunohistochemistry and western blot validation. Main Results: Across 120,254 nuclei from 35 cell types, there was striking similarity across fibrotic subgroups in epithelial, endothelial, and immune compartments, including alveolar type 1 cell loss, pathologic alveolar type 2 (AT2) gene expression, and expansion of COL15A1 endothelial cells and profibrotic macrophages. Diseased AT2s showed activation of the p53/DNA damage pathway. Aberrant basaloid (AB) cells were present in both SSc-ILD subtypes and transcriptionally similar to IPF ABs. They consistently neighbored profibrotic CTHRC1 fibroblasts, even in SSc-NSIP, despite lacking fibroblast foci. Fibroblast heterogeneity differentiated the histopathologic subtypes. Inflammatory fibroblasts were enriched in SSc-NSIP and CTHRC1 fibroblasts in UIP. AB-to-pathologic fibroblast crosstalk was defined by profibrotic signaling, with amplified TGF-{beta} signaling in UIP. Conclusions: Convergent epithelial remodeling is a hallmark of PPF in SSc-ILD and IPF. Fibroblast heterogeneity characterized by altered TGF-beta signaling distinguishes SSc-NSIP from SSc-UIP and IPF. Accelerated aging, DNA damage, and p53-dependent senescence pathways may represent shared drivers of PPF.

genomics↗

bioRxiv2023

Gene Expression Meta-Analysis Reveals Aging and Cellular Senescence Signatures in Scleroderma-associated Interstitial Lung Disease

Aging and cellular senescence are increasingly recognized as key contributors to pulmonary fibrosis. However, our understanding in the context of scleroderma associated interstitial lung disease (SSc-ILD) is limited. To investigate, we leveraged previously established lung aging and cell-specific senescence signatures to determine their presence and potential relevance to SSc-ILD. We performed a gene expression meta-analysis of lung tissue from 38 SSc-ILD and 18 healthy controls and found markers (GDF15, COMP, CDKN2A) and pathways (p53) of senescence were significantly increased in SSc-ILD. When probing the established aging and cellular senescence signatures, we found epithelial and fibroblast senescence signatures had a 3.6-fold and 3.7-fold enrichment respectively in the lung tissue of SSc-ILD and that lung aging genes (CDKN2A, FRZB, PDE1A, NAPI12) were increased in SSc-ILD. These signatures were also enriched in SSc skin and associated with degree of skin involvement (limited vs. diffuse cutaneous). To further support these findings, we examined telomere length (TL), a surrogate for aging, in lung tissue and found independent of age, SSc-ILD had significantly shorter telomeres than controls in type II alveolar cells in the lung. TL in SSc-ILD was comparable to idiopathic pulmonary fibrosis, a disease of known aberrant aging. Taken together, this study provides novel insight into the possible mechanistic effects of accelerated aging and aberrant cellular senescence in SSc-ILD pathogenesis.

bioinformatics↗

bioRxiv2023

PhIP-Seq uncovers novel autoantibodies and unique endotypes in interstitial lung disease

Interstitial lung diseases (ILDs) are a heterogeneous group of disorders that can develop in patients with connective tissue diseases (CTD). Establishing autoimmunity in ILD impacts prognosis and treatment. ILD patients are screened for autoimmunity by assaying for anti-nuclear autoantibodies, rheumatoid factors and other non-specific tests. However, this approach has not been rigorously validated and may miss autoimmunity that manifests as autoantibodies to tissue antigens not previously defined in ILD. Here, we use Phage Immunoprecipitation-Sequencing (PhIP-Seq) to conduct a large, multi-center unbiased autoantibody discovery screen of ILD patients and controls. PhIP-Seq identified 17 novel autoreactive targets, and machine learning classifiers derived from these targets discriminated ILD serum from controls. Among these 17 candidates, we validated Cadherin Related Family Member 5 (CDHR5) as an autoantigen and found CDHR5 autoantibodies in patients with rheumatologic disorders and importantly, subjects not previously diagnosed with autoimmunity. Lung tissue of CDHR5 autoreactive patients showed transcriptional profiles consistent with activation of NF{kappa}B signaling and upregulation of chitotriosidase (CHIT1), a molecular pathway linked to fibrosis. Our study shows PhIP-Seq uncovers novel autoantibodies in ILD patients not revealed by standard clinical tests. Furthermore, CDHR5 autoantibodies may define a novel molecular endotype of ILD characterized by inflammation and fibrosis.

molecular biology↗