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Updated: Apr 5, 2026

Isolating Bronchial Epithelial Cells from Resected Lung Tissue for Biobanking and Establishing Well-Differentiated Air-Liquid Interface Cultures
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Syndecan 4 Mediates Nrf2-dependent Expansion of Bronchiolar Progenitors That Protect Against Lung Inflammation

Arif Santoso1, Toshiaki Kikuchi1,2, Naoki Tode3

  • 1Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|August 27, 2015
PubMed

Insights

Secretory leukocyte protease inhibitor (SLPI) and syndecan 4 regulate lung progenitor cells. Targeting these molecules may offer new therapies for inflammatory lung diseases.

Area of Science:

  • Pulmonary Medicine
  • Regenerative Medicine
  • Cell Biology

Background:

  • Lung progenitor cells are crucial for regenerative medicine, but their biology remains incompletely understood.
  • Bronchiolar progenitors, a subset of mouse club cells, exhibit anti-inflammatory properties linked to secretory leukocyte protease inhibitor (SLPI).
  • Dysregulated SLPI expression impacts progenitor numbers and lung inflammation.

Purpose of the Study:

  • To investigate the role of SLPI and identify novel factors regulating bronchiolar progenitors.
  • To explore the therapeutic potential of identified factors in inflammatory lung conditions.

Main Methods:

  • Cell sorting and characterization of mouse bronchiolar progenitors.
  • Transcriptional profiling of Slpi-deficient bronchiolar progenitors.
  • Systemic administration of recombinant syndecan 4 protein in mice.
  • Analysis of the Keap1-Nrf2 antioxidant pathway.
  • 3D cell culture models to study cell differentiation.

Main Results:

  • Impaired SLPI expression in mice led to increased bronchiolar progenitors and reduced lung inflammation.
  • Syndecan 4 was identified as upregulated in Slpi-deficient progenitors.
  • Recombinant syndecan 4 administration increased progenitor numbers and attenuated airway and alveolar inflammation.
  • Syndecan 4 activated the Keap1-Nrf2 antioxidant pathway, crucial for therapeutic effects.
  • Syndecan 4 induced Nrf2-dependent club cell transition to bronchiolar progenitors in 3D culture.

Conclusions:

  • Differentiative switching between bronchiolar progenitors and club cells is controlled by the Nrf2 pathway, modulated by SLPI and syndecan 4.
  • These findings suggest novel therapeutic strategies for inflammatory lung diseases by targeting the SLPI-syndecan 4-Nrf2 axis.

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