Disrupting pathogenic cell states to combat pulmonary fibrosis

Image Credit: Scientific Frontline

Scientific Frontline: "At a Glance" Summary

• Main Discovery: Inhibition of the epigenetic co-activators p300/CBP prevents alveolar type 2 (AT2) cells from becoming trapped in a pathogenic "alveolar transitional cell state" (ATCS), thereby blocking the progression of idiopathic pulmonary fibrosis (IPF).
• Methodology: Researchers utilized a phenotypic drug screen of 264 compounds on human iPS cell-derived models and validated efficacy using a bleomycin-induced mouse lung injury model and a telomere-driven senescence model.
• Key Data: The p300/CBP inhibitor CBP30 significantly decreased fibrotic gene expression and myofibroblast activation, while single-cell profiling identified CD54 (ICAM1) as a distinct surface marker for isolating pathogenic ATCS cells.
• Significance: This study demonstrates that the accumulation of ATCS is a reversible, epigenetically driven process central to fibrosis, identifying a novel therapeutic target for a disease characterized by irreversible tissue scarring.
• Future Application: Development of targeted p300/CBP inhibitors as a new class of antifibrotic drugs for treating idiopathic pulmonary fibrosis and potentially other interstitial lung diseases.
• Branch of Science: Regenerative Medicine / Epigenetics.
• Additional Detail: Transcriptomic analysis confirmed that the iPS cell-derived ATCS (iATCs) generated in the study closely match the pathological cell states found in the lungs of human IPF patients.

A research team led by Professor Shimpei Gotoh (Department of Clinical Application) has uncovered a key regulatory mechanism driving idiopathic pulmonary fibrosis (IPF) and identified a promising therapeutic strategy. 

IPF is a severe and progressive lung disease marked by irreversible tissue scarring, but the cellular events that drive its progression have remained unclear. Under normal conditions, alveolar type 2 (AT2) cells differentiate into alveolar type 1 (AT1) cells to maintain normal alveolar structure and gas exchange. In disease, however, this differentiation process breaks down, leading to the accumulation of cells trapped in an abnormal differentiation state within fibrotic regions, referred to here as the alveolar transitional cell state (ATCS). Yet, whether ATCS actively contributes to fibrosis has not been definitively established. To address this, the researchers developed iPS cell-derived lung organoid models that accurately mimic the epithelial injury, fibroblast activation, and extracellular matrix contraction seen in fibrotic lungs. 

Using these models, the team performed a phenotypic drug screen, evaluating 264 biologically annotated compounds. Among the hits, p300/CBP inhibitors emerged as the most promising class, consistently reducing fibrosis-like gel contraction. This observation was later explained by a central mechanistic discovery: inhibiting the epigenetic co-activators p300/CBP blocks the emergence of ATCS, a pathogenic epithelial state strongly linked to fibrotic remodeling. By suppressing this maladaptive cell transition, p300/CBP inhibitors also reduced fibroblast activation, thus revealing a coordinated epithelial-mesenchymal interplay driven by ATCS. 

Gene expression analyses further revealed that p300/CBP inhibition downregulated profibrotic markers in fibroblasts while strongly suppressing ATCS-associated genes in epithelial cells. The active form of p300 was concentrated within ATCS-like cells, and both p300 activation and ATCS accumulation were diminished when organoids were treated with the p300/CBP inhibitors. 

To further establish the causal role of epithelial dysfunction, the researchers engineered an iPS cell-based model in which a telomere-related dominant negative TRF2 variant induced senescence specifically in AT2 cells. These senescent AT2 cells triggered fibroblast activation and matrix contraction—effects that were also reversed by p300/CBP inhibition, thus demonstrating that epithelial injury, through ATCS formation, can initiate fibrosis and that p300/CBP is a critical molecular driver of this process. 

The team extended their findings to an in vivo mouse model of bleomycin-induced lung injury. Treatment with the p300/CBP inhibitor CBP30 reduced fibrotic gene expression, decreased ATCS abundance, and lowered myofibroblast activation, confirming the antifibrotic potential of targeting p300/CBP across both human and animal models. 

To better understand ATCS itself, the researchers established a micropatterned culture system, allowing precise differentiation of iPS cell-derived AT2 cells into either AT1 cells or ATCS (iATCs). Single-cell transcriptomic and epigenomic profiling revealed that the iATCs closely matched those found in the lungs of IPF patients. The team also identified CD54 (ICAM1) as a reliable surface marker for isolating iATCs, enabling deeper functional investigation. When isolated CD54⁺ iATCs were co-cultured with adult lung fibroblasts, the fibroblasts markedly activated the profibrotic gene program, thus demonstrating that ATCS actively drive fibroblast pathogenicity. 

To determine whether the ATCS represents a fixed or reversible cell state, the researchers examined the plasticity of iATCs. They found that these cells retain cellular plasticity and can revert to functional alveolar epithelial lineages, including both AT2 and AT1 cells, under appropriate conditions. 

Further epigenomic analysis revealed that p300/CBP inhibitors selectively reduced H3K27ac in enhancer regions enriched for AP-1 and HNF1B transcription factor motifs. Silencing ATF3, a component of the AP-1 transcription factor complex, or HNF1B diminished ATCS markers, establishing these factors as essential partners of p300/CBP in maintaining the pathogenic transitional state. 

Together, these findings reveal that the alveolar transitional cell state is a reversible, epigenetically regulated condition that plays a central role in pulmonary fibrosis—and that disrupting its formation through p300/CBP inhibition offers a promising new therapeutic strategy. 

Published in journal: Nature Communications

Title: Human iPSC-based Modeling of Pulmonary Fibrosis Reveals p300/CBP Inhibition Suppresses Alveolar Transitional Cell State

Authors: Yusuke Tsutsui, Atsushi Masui, Satoshi Konishi, Taro Tsujimura, Mio Iwasaki, Takuya Yamamoto, and Shimpei Gotoh

Source/Credit: Center for iPS Cell Research and Application

Reference Number: gen021426_01

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