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Background <p>The Lung is the major focus of therapeutic approaches for the inherited disorder cystic fibrosis (CF) as without treatment lung disease is life-limiting. However, the initiating events that predispose the CF lung to cycles of infection, inflammation and resultant tissue damage are still unclear. Inflammation may occur in the CF lung prior to birth in human and several large animal models suggesting an in utero origin for the disease and encouraging further studies prior to birth.</p> Methods <p>Here we used the sheep model of CF (<i>CFTR</i><sup><i>−/−</i></sup>) and age-matched wild-type (WT) sheep of the same breed to investigate the single cell transcriptomes of proximal and distal lung tissue at 80&#xa0;days and 120&#xa0;days of gestation and at term (147&#xa0;days). Single cell RNA-seq was performed on tissues from 4 to 7 animals of each genotype (WT and <i>CFTR</i><sup><i>−/−</i></sup>) at each time point.</p> Results <p>At term, FOXJ1-expressing ciliated cells are overrepresented in both lung regions from <i>CFTR</i><sup><i>−/−</i></sup> lambs, while secretory epithelial and basal cells are underrepresented in proximal lung, as are T cells and monocytes in distal lung. The imbalance in ciliated and basal cells was confirmed by immunohistochemistry. At 120&#xa0;days of gestation, lymphoid cells are slightly more abundant in proximal and distal lung from <i>CFTR</i><sup><i>−/−</i></sup> animals compared to WT, consistent with the transient CF-associated inflammatory response in utero. At 80&#xa0;days of gestation, T and B cells are underrepresented in both lung regions.</p> Conclusions <p>The differences in epithelial cell abundance observed in the <i>CFTR</i><sup><i>−/−</i></sup> lambs at term may reflect sequelae from the loss of CFTR on lung development and differentiation in utero. These findings provide novel insights into the cellular mechanisms of pathology and may be relevant to the design of new therapeutic approaches for CF lung disease.</p>

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Cellular imbalance in proximal and distal lung of CFTR−/− sheep in utero and at birth

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月11日

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  • Shih-Hsing Leir,
  • Svyatoslav Tkachenko,
  • Alekh Paranjapye,
  • Arnaud J. Van Wettere,
  • Jenny L. Kerschner,
  • Iuri Viotti Perisse,
  • Cheyenne M. Marriott,
  • Tayler Patrick,
  • Ying Liu,
  • Kenneth L. White,
  • Irina A. Polejaeva,
  • Ann Harris

摘要

Background

The Lung is the major focus of therapeutic approaches for the inherited disorder cystic fibrosis (CF) as without treatment lung disease is life-limiting. However, the initiating events that predispose the CF lung to cycles of infection, inflammation and resultant tissue damage are still unclear. Inflammation may occur in the CF lung prior to birth in human and several large animal models suggesting an in utero origin for the disease and encouraging further studies prior to birth.

Methods

Here we used the sheep model of CF (CFTR−/−) and age-matched wild-type (WT) sheep of the same breed to investigate the single cell transcriptomes of proximal and distal lung tissue at 80 days and 120 days of gestation and at term (147 days). Single cell RNA-seq was performed on tissues from 4 to 7 animals of each genotype (WT and CFTR−/−) at each time point.

Results

At term, FOXJ1-expressing ciliated cells are overrepresented in both lung regions from CFTR−/− lambs, while secretory epithelial and basal cells are underrepresented in proximal lung, as are T cells and monocytes in distal lung. The imbalance in ciliated and basal cells was confirmed by immunohistochemistry. At 120 days of gestation, lymphoid cells are slightly more abundant in proximal and distal lung from CFTR−/− animals compared to WT, consistent with the transient CF-associated inflammatory response in utero. At 80 days of gestation, T and B cells are underrepresented in both lung regions.

Conclusions

The differences in epithelial cell abundance observed in the CFTR−/− lambs at term may reflect sequelae from the loss of CFTR on lung development and differentiation in utero. These findings provide novel insights into the cellular mechanisms of pathology and may be relevant to the design of new therapeutic approaches for CF lung disease.