Research Areas

The Yao Lab studies lung epithelial progenitor cells in both healthy and diseased lungs, focusing on mechanisms that regulate their fate. We explore epigenetic and metabolic regulation, epithelial-fibroblast and -immune cross talk, and other key factors that influence lung epithelial homeostasis and regeneration.

Epithelial progenitor cell fate decisions during lung development, particularly in branching morphogenesis, are tightly regulated by various epigenetic factors. Using single-cell RNA sequencing, lineage tracing and CRISPR screening, we aim to uncover the mechanisms that govern epithelial progenitor cell fate decisions, differentiation and lung branching morphogenesis.

Basal cell (BC) hyperplasia is a hallmark of both chronic lung disease and acute respiratory viral infections, including H1N1 flu and SARS-CoV-2. However, the specific cell types contributing to BC expansion and the microenvironmental cues influencing their behavior needs further understanding.

To address this knowledge gap, we employed single-cell transcriptomics to investigate the dynamic molecular landscape and fate of lung epithelial cells in human lungs post-SARS-CoV-2 infection and in murine models following flu infection. Through this approach and advanced dural lineage tracing technology, we have identified key epigenetic regulators, transcription factors and innate immune signaling pathways that govern the origin, differentiation, migration and proliferation of BCs in the context of post-acute respiratory viral infection. These findings provide critical insights into the mechanisms driving BC plasticity and their potential role in lung repair and disease progression.

Our research aims to define the cellular and molecular defects within epithelial cells that contribute to impaired tissue repair and fibrosis. We model these pathological events using 3D culture systems, human patient samples and genetic manipulation in mice.

Furthermore, accelerated aging, loss of epithelial progenitor cell function and/or numbers, and cellular senescence have been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). We investigate the role of alveolar type 2 (AT2) cell senescence in the initiation and progression of pulmonary fibrosis, with a focus on the therapeutic potential of targeting senescence-related pathways and senescent cells.

Endothelial cells play a critical role in lung regeneration by regulating vascular integrity, immune responses and epithelial repair in both acute and chronic lung injuries. During acute lung injury, such as flu infection, endothelial cells control vascular permeability and immune cell recruitment while secreting angiocrine factors that support epithelial regeneration. However, excessive endothelial damage can lead to vascular leakage, exacerbating inflammation and impairing lung repair. In chronic lung diseases like fibrosis, persistent endothelial dysfunction disrupts angiogenesis and endothelial-epithelial cross talk, promoting fibrotic remodeling rather than regeneration. Given that vascular dysfunction is a key determinant of repair outcomes, understanding the dynamic role of endothelial cells in modulating inflammatory and regenerative processes is essential for developing targeted therapies that enhance lung repair and prevent fibrosis.

Lung cancer is the leading cause of cancer-related deaths in the United States, of which 80-90% are non-small cell lung carcinomas (NSCLC) linked to smoking and about 20% are lung squamous cell carcinomas (LUSC). Unlike lung adenocarcinoma (LUAD), which is often driven by oncogene activation, LUSC is usually driven by loss of tumor suppressor genes such as PTEN, CDKN2A and STK11 (LKB1), making it less targetable by small molecule drugs. Key biomarkers of LUSC, including SOX2, p63 and KRT5, overlap with those found in basal cells of healthy airways, suggesting LUSC as a malignant counterpart of basal cell dysplastic hyperplasia. EZH2 is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) and has been recognized for its ability to repress gene expression via the trimethylation of lysine 27 on histone 3 (H3K27me3). However, LUSC tumor cells showed lower H3K27me3 levels compared to nearby cell types, aligning with low expression of other PRC2 components like EED. This implies a novel PRC2-independent function for EZH2 in controlling LUSC cell dysplastic hyperplasticity. We are aiming to identify novel EZH2 targets in LUSC tumor cells and identify the factors that initiate these interactions and changes.