JoVE - Journal of Visualized Experiments
JoVE Visualize
Contact Us

Single-cell multi-omic analysis of mesenchymal cells reveals molecular signatures and putative regulators of lung allograft fibrosis

Biorxiv : the Preprint Server for Biology +

|

July 15, 2025

|

July 15, 2025

View abstract on PubMed

Summary

This summary is machine-generated.

Chronic lung allograft dysfunction (CLAD) involves mesenchymal cells (MCs) with unknown drivers. This study identifies CEBPD as a key transcription factor in CLAD pathogenesis, offering potential therapeutic targets for lung transplant recipients.

Area Of Science

  • Immunology
  • Genomics
  • Cell Biology

Background

  • Lung transplant survival is limited by chronic lung allograft dysfunction (CLAD).
  • Mesenchymal cells (MCs) drive CLAD, but the underlying transcriptomic and epigenomic factors are unclear.
  • Understanding these drivers is crucial for developing targeted therapies.

Purpose Of The Study

  • To investigate the transcriptomic and epigenomic drivers of fibrogenic transformation in mesenchymal cells during CLAD.
  • To identify novel biomarkers and therapeutic targets for CLAD.

Main Methods

  • Single-cell multi-omic technologies (scRNA-seq, ATAC-seq) were used on MCs from lung transplant recipients.
  • Logistic regression models were employed for disease classification.
  • Chromatin accessibility, motif scan, and footprint analyses were performed.
  • CEBPD knockdown using siRNA and in situ validation in human lung tissue were conducted.

Main Results

  • CLAD-associated MCs (CLAD-MCs) exhibit a distinct transcriptomic signature, enabling accurate disease classification.
  • CEBPD was identified as a key transcription factor associated with CLAD-enriched MC subtypes.
  • CEBPD-driven regulatory changes emerge over time post-transplantation.
  • Knocking down CEBPD partially reversed the CLAD transcriptomic signature in CLAD-MCs.
  • In situ validation confirmed CEBPD expression changes in human CLAD tissue.

Conclusions

  • CEBPD plays a critical role in the dysregulated molecular state of CLAD-associated MCs.
  • The study identifies CEBPD as a potential therapeutic target for CLAD.
  • These findings offer insights into CLAD pathogenesis and nominate biomarkers for future interventions.